INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83740, 2007, 'plos', 'A macaques-eye view of human insertions and deletions: differences in mechanisms', 'Kvikstad, Erika M|Tyekucheva, Svitlana|Chiaromonte, Francesca|Makova, Kateryna D', 'Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania, USA.|Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania, USA.|Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania, USA.|Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania, USA.', 'United States|United States|United States|United States', 42, 'Animals|Biological Evolution|Chromosome Mapping|Computer Simulation|DNA Mutational Analysis|DNA Transposable Elements|Evolution, Molecular|Gene Deletion|Genome, Human|Humans|Macaca|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.0030176', '17941704', 'Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.'),
(83741, 2007, 'plos', 'Characterization of protein hubs by inferring interacting motifs from protein interactions', 'Aragues, Ramon|Sali, Andrej|Bonet, Jaume|Marti-Renom, Marc A|Oliva, Baldo', 'Structural Bioinformatics Lab (GRIB), Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine (PRBB), Barcelona, Catalonia, Spain.|Structural Bioinformatics Lab (GRIB), Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine (PRBB), Barcelona, Catalonia, Spain.|Structural Bioinformatics Lab (GRIB), Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine (PRBB), Barcelona, Catalonia, Spain.|Structural Bioinformatics Lab (GRIB), Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine (PRBB), Barcelona, Catalonia, Spain.|Structural Bioinformatics Lab (GRIB), Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine (PRBB), Barcelona, Catalonia, Spain.', 'Spain|Spain|Spain|Spain|Spain', 0, 'Amino Acid Motifs|Amino Acid Sequence|Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Interaction Mapping|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030178', '17941705', 'The characterization of protein interactions is essential for understanding biological systems. While genome-scale methods are available for identifying interacting proteins, they do not pinpoint the interacting motifs (e.g., a domain, sequence segments, a binding site, or a set of residues). Here, we develop and apply a method for delineating the interacting motifs of hub proteins (i.e., highly connected proteins). The method relies on the observation that proteins with common interaction partners tend to interact with these partners through a common interacting motif. The sole input for the method are binary protein interactions, neither sequence nor structure information is needed. The approach is evaluated by comparing the inferred interacting motifs with domain families defined for 368 proteins in the Structural Classification of Proteins (SCOP). The positive predictive value of the method for detecting proteins with common SCOP families is 75% at sensitivity of 10%. Most of the inferred interacting motifs were significantly associated with sequence patterns, which could be responsible for the common interactions. We find that yeast hubs with multiple interacting motifs are more likely to be essential than hubs with one or two interacting motifs, thus rationalizing the previously observed correlation between essentiality and the number of interacting partners of a protein. We also find that yeast hubs with multiple interacting motifs evolve slower than the average protein, contrary to the hubs with one or two interacting motifs. The proposed method will help us discover unknown interacting motifs and provide biological insights about protein hubs and their roles in interaction networks.'),
(83742, 2007, 'plos', 'Differences in reactivation of tuberculosis induced from anti-TNF treatments are based on bioavailability in granulomatous tissue', 'Marino, Simeone|Sud, Dhruv|Plessner, Hillarie|Lin, Philana Ling|Chan, John|Flynn, JoAnne L|Kirschner, Denise E', 'Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.', 'United States|United States|United States|United States|United States|United States|United States', 67, 'Animals|Antitubercular Agents|Computational Biology|Granuloma|Humans|Models, Statistical|Models, Theoretical|Mycobacterium Infections|Mycobacterium tuberculosis|Sensitivity and Specificity|Signal Transduction|T-Lymphocytes|Tuberculosis|Tumor Necrosis Factor-alpha', 'Journal Article', '10.1371/journal.pcbi.0030194', '17953477', 'The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF--even at very low levels--is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNF-modulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely.'),
(83743, 2007, 'plos', 'Empirical multiscale networks of cellular regulation', 'de Bivort, Benjamin|Huang, Sui|Bar-Yam, Yaneer', 'Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA. bivort@fas.harvard.edu|Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA. bivort@fas.harvard.edu|Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA. bivort@fas.harvard.edu', 'United States|United States|United States', 0, 'Animals|B-Lymphocytes|Cell Cycle|Cell Growth Processes|Computational Biology|Gene Expression Regulation|Mice|Models, Biological|Models, Genetic|Models, Statistical|Models, Theoretical|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.0030207', '17953478', 'Grouping genes by similarity of expression across multiple cellular conditions enables the identification of cellular modules. The known functions of genes enable the characterization of the aggregate biological functions of these modules. In this paper, we use a high-throughput approach to identify the effective mutual regulatory interactions between modules composed of mouse genes from the Alliance for Cell Signaling (AfCS) murine B-lymphocyte database which tracks the response of approximately 15,000 genes following chemokine perturbation. This analysis reveals principles of cellular organization that we discuss along four conceptual axes. (1) Regulatory implications: the derived collection of influences between any two modules quantifies intuitive as well as unexpected regulatory interactions. (2) Behavior across scales: trends across global networks of varying resolution (composed of various numbers of modules) reveal principles of assembly of high-level behaviors from smaller components. (3) Temporal behavior: tracking the mutual module influences over different time intervals provides features of regulation dynamics such as duration, persistence, and periodicity. (4) Gene Ontology correspondence: the association of modules to known biological roles of individual genes describes the organization of functions within coexpressed modules of various sizes. We present key specific results in each of these four areas, as well as derive general principles of cellular organization. At the coarsest scale, the entire transcriptional network contains five divisions: two divisions devoted to ATP production/biosynthesis and DNA replication that activate all other divisions, an extracellular interaction division that represses all other divisions, and two divisions (proliferation/differentiation and membrane infrastructure) that activate and repress other divisions in specific ways consistent with cell cycle control.'),
(83744, 2007, 'plos', 'Getting started in tiling microarray analysis', 'Liu, X Shirley', 'Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts, USA. xsliu@jimmy.harvard.edu', 'United States', 40, 'Algorithms|Animals|Biotechnology|Computational Biology|Data Interpretation, Statistical|Deoxyribonucleases|Humans|Mice|Nucleosomes|Oligonucleotide Array Sequence Analysis|RNA, Messenger|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.0030183', '17967045', '-'),
(83745, 2007, 'plos', 'Computational biology in Brazil', 'Neshich, Goran', 'Embrapa Informática Agropecuária, Campinas, Brazil. neshich@cbi.cnptia.embrapa.br', 'Brazil', 0, 'Biotechnology|Brazil|Computational Biology|Entrepreneurship|Genomics|Government|Humans|Private Sector|Research Support as Topic|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030185', '17967046', '-'),
(83746, 2007, 'plos', 'Alternative splicing events identified in human embryonic stem cells and neural progenitors', 'Yeo, Gene W|Xu, Xiangdong|Liang, Tiffany Y|Muotri, Alysson R|Carson, Christian T|Coufal, Nicole G|Gage, Fred H', 'Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu|Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu|Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu|Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu|Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu|Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu|Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, La Jolla, California, USA. geneyeo@salk.edu', 'United States|United States|United States|United States|United States|United States|United States', 98, 'Algorithms|Alternative Splicing|Computational Biology|Embryonic Stem Cells|Exons|Expressed Sequence Tags|False Positive Reactions|Gene Expression Regulation|Humans|Models, Neurological|Nervous System|Nervous System Physiological Phenomena|Neurons|Reverse Transcriptase Polymerase Chain Reaction|Stem Cells', 'Journal Article', '10.1371/journal.pcbi.0030196', '17967047', 'Human embryonic stem cells (hESCs) and neural progenitor (NP) cells are excellent models for recapitulating early neuronal development in vitro, and are key to establishing strategies for the treatment of degenerative disorders. While much effort had been undertaken to analyze transcriptional and epigenetic differences during the transition of hESC to NP, very little work has been performed to understand post-transcriptional changes during neuronal differentiation. Alternative RNA splicing (AS), a major form of post-transcriptional gene regulation, is important in mammalian development and neuronal function. Human ESC, hESC-derived NP, and human central nervous system stem cells were compared using Affymetrix exon arrays. We introduced an outlier detection approach, REAP (Regression-based Exon Array Protocol), to identify 1,737 internal exons that are predicted to undergo AS in NP compared to hESC. Experimental validation of REAP-predicted AS events indicated a threshold-dependent sensitivity ranging from 56% to 69%, at a specificity of 77% to 96%. REAP predictions significantly overlapped sets of alternative events identified using expressed sequence tags and evolutionarily conserved AS events. Our results also reveal that focusing on differentially expressed genes between hESC and NP will overlook 14% of potential AS genes. In addition, we found that REAP predictions are enriched in genes encoding serine/threonine kinase and helicase activities. An example is a REAP-predicted alternative exon in the SLK (serine/threonine kinase 2) gene that is differentially included in hESC, but skipped in NP as well as in other differentiated tissues. Lastly, comparative sequence analysis revealed conserved intronic cis-regulatory elements such as the FOX1/2 binding site GCAUG as being proximal to candidate AS exons, suggesting that FOX1/2 may participate in the regulation of AS in NP and hESC. In summary, a new methodology for exon array analysis was introduced, leading to new insights into the complexity of AS in human embryonic stem cells and their transition to neural stem cells.'),
(83747, 2007, 'plos', 'Cerebellar motor learning: when is cortical plasticity not enough?', 'Porrill, John|Dean, Paul', 'Department of Psychology, Sheffield University, Sheffield, United Kingdom.|Department of Psychology, Sheffield University, Sheffield, United Kingdom.', 'United Kingdom|United Kingdom', 53, 'Action Potentials|Adaptation, Physiological|Algorithms|Animals|Brain Stem|Cerebellum|Computational Biology|Humans|Learning|Models, Neurological|Neuronal Plasticity|Neurons|Reflex, Vestibulo-Ocular|Synaptic Transmission|Task Performance and Analysis', 'Journal Article', '10.1371/journal.pcbi.0030197', '17967048', 'Classical Marr-Albus theories of cerebellar learning employ only cortical sites of plasticity. However, tests of these theories using adaptive calibration of the vestibulo-ocular reflex (VOR) have indicated plasticity in both cerebellar cortex and the brainstem. To resolve this long-standing conflict, we attempted to identify the computational role of the brainstem site, by using an adaptive filter version of the cerebellar microcircuit to model VOR calibration for changes in the oculomotor plant. With only cortical plasticity, introducing a realistic delay in the retinal-slip error signal of 100 ms prevented learning at frequencies higher than 2.5 Hz, although the VOR itself is accurate up to at least 25 Hz. However, the introduction of an additional brainstem site of plasticity, driven by the correlation between cerebellar and vestibular inputs, overcame the 2.5 Hz limitation and allowed learning of accurate high-frequency gains. This cortex-first learning mechanism is consistent with a wide variety of evidence concerning the role of the flocculus in VOR calibration, and complements rather than replaces the previously proposed brainstem-first mechanism that operates when ocular tracking mechanisms are effective. These results (i) describe a process whereby information originally learnt in one area of the brain (cerebellar cortex) can be transferred and expressed in another (brainstem), and (ii) indicate for the first time why a brainstem site of plasticity is actually required by Marr-Albus type models when high-frequency gains must be learned in the presence of error delay.'),
(83748, 2007, 'plos', 'Evolutionary models for formation of network motifs and modularity in the Saccharomyces transcription factor network', 'Ward, Jonathan J|Thornton, Janet M', 'European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. jward@embl.de|European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. jward@embl.de', 'United Kingdom|United Kingdom', 0, 'Amino Acid Motifs|Cell Physiological Phenomena|Computational Biology|Evolution, Molecular|Fungal Proteins|Gene Duplication|Gene Regulatory Networks|Genes, Regulator|Models, Genetic|Models, Statistical|Saccharomyces cerevisiae|Systems Biology|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0030198', '17967049', 'Many natural and artificial networks contain overrepresented subgraphs, which have been termed network motifs. In this article, we investigate the processes that led to the formation of the two most common network motifs in eukaryote transcription factor networks: the bi-fan motif and the feed-forward loop. Around 100 million y ago, the common ancestor of the Saccharomyces clade underwent a whole-genome duplication event. The simultaneous duplication of the genes created by this event enabled the origin of many network motifs to be established. The data suggest that there are two primary mechanisms that are involved in motif formation. The first mechanism, enabled by the substantial plasticity in promoter regions, is rewiring of connections as a result of positive environmental selection. The second is duplication of transcription factors, which is also shown to be involved in the formation of intermediate-scale network modularity. These two evolutionary processes are complementary, with the pre-existence of network motifs enabling duplicated transcription factors to bind different targets despite structural constraints on their DNA-binding specificities. This process may facilitate the creation of novel expression states and the increases in regulatory complexity associated with higher eukaryotes.'),
(83749, 2007, 'plos', 'Landscape as a model: the importance of geometry', 'Holland, E Penelope|Aegerter, James N|Dytham, Calvin|Smith, Graham C', 'Central Science Laboratory, Sand Hutton, York, United Kingdom.|Central Science Laboratory, Sand Hutton, York, United Kingdom.|Central Science Laboratory, Sand Hutton, York, United Kingdom.|Central Science Laboratory, Sand Hutton, York, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 35, 'Computational Biology|Computer Graphics|Computer Simulation|Environment|Geography|Models, Theoretical|Movement|Programming Languages|Software|Systems Theory|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.0030200', '17967050', 'In all models, but especially in those used to predict uncertain processes (e.g., climate change and nonnative species establishment), it is important to identify and remove any sources of bias that may confound results. This is critical in models designed to help support decisionmaking. The geometry used to represent virtual landscapes in spatially explicit models is a potential source of bias. The majority of spatial models use regular square geometry, although regular hexagonal landscapes have also been used. However, there are other ways in which space can be represented in spatially explicit models. For the first time, we explicitly compare the range of alternative geometries available to the modeller, and present a mechanism by which uncertainty in the representation of landscapes can be incorporated. We test how geometry can affect cell-to-cell movement across homogeneous virtual landscapes and compare regular geometries with a suite of irregular mosaics. We show that regular geometries have the potential to systematically bias the direction and distance of movement, whereas even individual instances of landscapes with irregular geometry do not. We also examine how geometry can affect the gross representation of real-world landscapes, and again show that individual instances of regular geometries will always create qualitative and quantitative errors. These can be reduced by the use of multiple randomized instances, though this still creates scale-dependent biases. In contrast, virtual landscapes formed using irregular geometries can represent complex real-world landscapes without error. We found that the potential for bias caused by regular geometries can be effectively eliminated by subdividing virtual landscapes using irregular geometry. The use of irregular geometry appears to offer spatial modellers other potential advantages, which are as yet underdeveloped. We recommend their use in all spatially explicit models, but especially for predictive models that are used in decisionmaking.'),
(83750, 2007, 'plos', 'A stochastic view of spliceosome assembly and recycling in the nucleus', 'Rino, José|Carvalho, Teresa|Braga, José|Desterro, Joana M P|Lührmann, Reinhard|Carmo-Fonseca, Maria', 'Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.|Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.|Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.|Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.|Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.|Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.', 'Portugal|Portugal|Portugal|Portugal|Portugal|Portugal', 0, 'Animals|Cell Nucleus|Computational Biology|Genes, Dominant|HeLa Cells|Humans|Kinetics|Models, Biological|Models, Theoretical|RNA, Messenger|Spliceosomes|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0030201', '17967051', 'How splicing factors are recruited to nascent transcripts in the nucleus in order to assemble spliceosomes on newly synthesised pre-mRNAs is unknown. To address this question, we compared the intranuclear trafficking kinetics of small nuclear ribonucleoprotein particles (snRNP) and non-snRNP proteins in the presence and absence of splicing activity. Photobleaching experiments clearly show that spliceosomal proteins move continuously throughout the entire nucleus independently of ongoing transcription or splicing. Using quantitative experimental data, a mathematical model was applied for spliceosome assembly and recycling in the nucleus. The model assumes that splicing proteins move by Brownian diffusion and interact stochastically with binding sites located at different subnuclear compartments. Inhibition of splicing, which reduces the number of pre-mRNA binding sites available for spliceosome assembly, was modeled as a decrease in the on-rate binding constant in the nucleoplasm. Simulation of microscopy experiments before and after splicing inhibition yielded results consistent with the experimental observations. Taken together, our data argue against the view that spliceosomal components are stored in nuclear speckles until a signal triggers their recruitment to nascent transcripts. Rather, the results suggest that splicing proteins are constantly diffusing throughout the entire nucleus and collide randomly and transiently with pre-mRNAs.'),
(83751, 2007, 'plos', 'Emergence of recombinant forms of HIV: dynamics and scaling', 'Suryavanshi, Gajendra W|Dixit, Narendra M', 'Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.|Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.', 'India|India', 19, 'Computational Biology|Disease Outbreaks|Drug Resistance, Viral|HIV|HIV Infections|Humans|Models, Biological|Models, Statistical|Models, Theoretical|Mutation|Probability|Software|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0030205', '17967052', 'The ability to accelerate the accumulation of favorable combinations of mutations renders recombination a potent force underlying the emergence of forms of HIV that escape multi-drug therapy and specific host immune responses. We present a mathematical model that describes the dynamics of the emergence of recombinant forms of HIV following infection with diverse viral genomes. Mimicking recent in vitro experiments, we consider target cells simultaneously exposed to two distinct, homozygous viral populations and construct dynamical equations that predict the time evolution of populations of uninfected, singly infected, and doubly infected cells, and homozygous, heterozygous, and recombinant viruses. Model predictions capture several recent experimental observations quantitatively and provide insights into the role of recombination in HIV dynamics. From analyses of data from single-round infection experiments with our description of the probability with which recombination accumulates distinct mutations present on the two genomic strands in a virion, we estimate that approximately 8 recombinational strand transfer events occur on average (95% confidence interval: 6-10) during reverse transcription of HIV in T cells. Model predictions of virus and cell dynamics describe the time evolution and the relative prevalence of various infected cell subpopulations following the onset of infection observed experimentally. Remarkably, model predictions are in quantitative agreement with the experimental scaling relationship that the percentage of cells infected with recombinant genomes is proportional to the percentage of cells coinfected with the two genomes employed at the onset of infection. Our model thus presents an accurate description of the influence of recombination on HIV dynamics in vitro. When distinctions between different viral genomes are ignored, our model reduces to the standard model of viral dynamics, which successfully predicts viral load changes in HIV patients undergoing therapy. Our model may thus serve as a useful framework to predict the emergence of multi-drug-resistant forms of HIV in infected individuals.'),
(83752, 2007, 'plos', 'Construction, visualisation, and clustering of transcription networks from microarray expression data', 'Freeman, Tom C|Goldovsky, Leon|Brosch, Markus|van Dongen, Stijn|Mazière, Pierre|Grocock, Russell J|Freilich, Shiri|Thornton, Janet|Enright, Anton J', 'Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Algorithms|Animals|Cluster Analysis|Computational Biology|Gene Expression|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Imaging, Three-Dimensional|Mice|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Software|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0030206', '17967053', 'Network analysis transcends conventional pairwise approaches to data analysis as the context of components in a network graph can be taken into account. Such approaches are increasingly being applied to genomics data, where functional linkages are used to connect genes or proteins. However, while microarray gene expression datasets are now abundant and of high quality, few approaches have been developed for analysis of such data in a network context. We present a novel approach for 3-D visualisation and analysis of transcriptional networks generated from microarray data. These networks consist of nodes representing transcripts connected by virtue of their expression profile similarity across multiple conditions. Analysing genome-wide gene transcription across 61 mouse tissues, we describe the unusual topography of the large and highly structured networks produced, and demonstrate how they can be used to visualise, cluster, and mine large datasets. This approach is fast, intuitive, and versatile, and allows the identification of biological relationships that may be missed by conventional analysis techniques. This work has been implemented in a freely available open-source application named BioLayout Express(3D).'),
(83753, 2007, 'plos', 'Ten simple rules for doing your best research, according to Hamming', 'Erren, Thomas C|Cullen, Paul|Erren, Michael|Bourne, Philip E', 'Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk|Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom. tfreeman@staffmail.ed.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 12, 'Biomedical Research|Computational Biology|Humans|Philosophy|Science', 'Editorial', '10.1371/journal.pcbi.0030213', '17967054', '-'),
(83754, 2007, 'plos', 'Getting started in: a series not to miss', 'Troyanskaya, Olga', 'Lewis-Sigler Institute for Integrative Genomics and the Department of Computer Science, Princeton University, Princeton, New Jersey, USA. ogt@cs.princeton.edu', 'Jersey', 0, 'Animals|Biomedical Research|Computational Biology|Humans|Oligonucleotide Array Sequence Analysis|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.0030224', '17967055', '-'),
(83755, 2007, 'plos', 'Meta-analysis of Drosophila circadian microarray studies identifies a novel set of rhythmically expressed genes', 'Keegan, Kevin P|Pradhan, Suraj|Wang, Ji-Ping|Allada, Ravi', 'Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America.|Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America.|Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America.|Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|Biological Clocks|Circadian Rhythm|Drosophila|Drosophila Proteins|Gene Expression Profiling|Nuclear Proteins|Oligonucleotide Array Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.0030208', '17983263', 'Five independent groups have reported microarray studies that identify dozens of rhythmically expressed genes in the fruit fly Drosophila melanogaster. Limited overlap among the lists of discovered genes makes it difficult to determine which, if any, exhibit truly rhythmic patterns of expression. We reanalyzed data from all five reports and found two sources for the observed discrepancies, the use of different expression pattern detection algorithms and underlying variation among the datasets. To improve upon the methods originally employed, we developed a new analysis that involves compilation of all existing data, application of identical transformation and standardization procedures followed by ANOVA-based statistical prescreening, and three separate classes of post hoc analysis: cross-correlation to various cycling waveforms, autocorrelation, and a previously described fast Fourier transform-based technique. Permutation-based statistical tests were used to derive significance measures for all post hoc tests. We find application of our method, most significantly the ANOVA prescreening procedure, significantly reduces the false discovery rate relative to that observed among the results of the original five reports while maintaining desirable statistical power. We identify a set of 81 cycling transcripts previously found in one or more of the original reports as well as a novel set of 133 transcripts not found in any of the original studies. We introduce a novel analysis method that compensates for variability observed among the original five Drosophila circadian array reports. Based on the statistical fidelity of our meta-analysis results, and the results of our initial validation experiments (quantitative RT-PCR), we predict many of our newly found genes to be bona fide cyclers, and suggest that they may lead to new insights into the pathways through which clock mechanisms regulate behavioral rhythms.'),
(83756, 2007, 'plos', 'Detecting coevolution in and among protein domains', 'Yeang, Chen-Hsiang|Haussler, David', 'Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, United States of America. chyeang@ias.edu|Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, United States of America. chyeang@ias.edu', 'Jersey|Jersey', 124, 'Amino Acid Sequence|Base Sequence|Computer Simulation|Evolution, Molecular|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Conformation|Protein Structure, Tertiary|Proteins|Sequence Alignment|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030211', '17983264', 'Correlated changes of nucleic or amino acids have provided strong information about the structures and interactions of molecules. Despite the rich literature in coevolutionary sequence analysis, previous methods often have to trade off between generality, simplicity, phylogenetic information, and specific knowledge about interactions. Furthermore, despite the evidence of coevolution in selected protein families, a comprehensive screening of coevolution among all protein domains is still lacking. We propose an augmented continuous-time Markov process model for sequence coevolution. The model can handle different types of interactions, incorporate phylogenetic information and sequence substitution, has only one extra free parameter, and requires no knowledge about interaction rules. We employ this model to large-scale screenings on the entire protein domain database (Pfam). Strikingly, with 0.1 trillion tests executed, the majority of the inferred coevolving protein domains are functionally related, and the coevolving amino acid residues are spatially coupled. Moreover, many of the coevolving positions are located at functionally important sites of proteins/protein complexes, such as the subunit linkers of superoxide dismutase, the tRNA binding sites of ribosomes, the DNA binding region of RNA polymerase, and the active and ligand binding sites of various enzymes. The results suggest sequence coevolution manifests structural and functional constraints of proteins. The intricate relations between sequence coevolution and various selective constraints are worth pursuing at a deeper level.'),
(83757, 2007, 'plos', 'From endosymbiont to host-controlled organelle: the hijacking of mitochondrial protein synthesis and metabolism', 'Gabaldón, Toni|Huynen, Martijn A', 'Nijmegen Center for Molecular Life Sciences, Center for Molecular and Biomolecular Informatics, University of Nijmegen, Nijmegen, The Netherlands. tgabaldon@cipf.es|Nijmegen Center for Molecular Life Sciences, Center for Molecular and Biomolecular Informatics, University of Nijmegen, Nijmegen, The Netherlands. tgabaldon@cipf.es', 'Netherlands|Netherlands', 0, 'Biological Evolution|Computer Simulation|DNA Mutational Analysis|Evolution, Molecular|Fungal Proteins|Genetic Variation|Humans|Mitochondria|Mitochondrial Proteins|Models, Genetic|Organelles|Protein Biosynthesis|Symbiosis', 'Journal Article', '10.1371/journal.pcbi.0030219', '17983265', 'Mitochondria are eukaryotic organelles that originated from the endosymbiosis of an alpha-proteobacterium. To gain insight into the evolution of the mitochondrial proteome as it proceeded through the transition from a free-living cell to a specialized organelle, we compared a reconstructed ancestral proteome of the mitochondrion with the proteomes of alpha-proteobacteria as well as with the mitochondrial proteomes in yeast and man. Overall, there has been a large turnover of the mitochondrial proteome during the evolution of mitochondria. Early in the evolution of the mitochondrion, proteins involved in cell envelope synthesis have virtually disappeared, whereas proteins involved in replication, transcription, cell division, transport, regulation, and signal transduction have been replaced by eukaryotic proteins. More than half of what remains from the mitochondrial ancestor in modern mitochondria corresponds to translation, including post-translational modifications, and to metabolic pathways that are directly, or indirectly, involved in energy conversion. Altogether, the results indicate that the eukaryotic host has hijacked the proto-mitochondrion, taking control of its protein synthesis and metabolism.'),
(83758, 2007, 'plos', 'From inverse problems in mathematical physiology to quantitative differential diagnoses', 'Zenker, Sven|Rubin, Jonathan|Clermont, Gilles', 'Center for Inflammation and Regenerative Modeling, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Center for Inflammation and Regenerative Modeling, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Center for Inflammation and Regenerative Modeling, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 46, 'Algorithms|Computer Simulation|Diagnosis, Computer-Assisted|Diagnosis, Differential|Humans|Hypotension|Mathematics|Models, Biological|Physiology', 'Journal Article', '10.1371/journal.pcbi.0030204', '17997590', 'The improved capacity to acquire quantitative data in a clinical setting has generally failed to improve outcomes in acutely ill patients, suggesting a need for advances in computer-supported data interpretation and decision making. In particular, the application of mathematical models of experimentally elucidated physiological mechanisms could augment the interpretation of quantitative, patient-specific information and help to better target therapy. Yet, such models are typically complex and nonlinear, a reality that often precludes the identification of unique parameters and states of the model that best represent available data. Hypothesizing that this non-uniqueness can convey useful information, we implemented a simplified simulation of a common differential diagnostic process (hypotension in an acute care setting), using a combination of a mathematical model of the cardiovascular system, a stochastic measurement model, and Bayesian inference techniques to quantify parameter and state uncertainty. The output of this procedure is a probability density function on the space of model parameters and initial conditions for a particular patient, based on prior population information together with patient-specific clinical observations. We show that multimodal posterior probability density functions arise naturally, even when unimodal and uninformative priors are used. The peaks of these densities correspond to clinically relevant differential diagnoses and can, in the simplified simulation setting, be constrained to a single diagnosis by assimilating additional observations from dynamical interventions (e.g., fluid challenge). We conclude that the ill-posedness of the inverse problem in quantitative physiology is not merely a technical obstacle, but rather reflects clinical reality and, when addressed adequately in the solution process, provides a novel link between mathematically described physiological knowledge and the clinical concept of differential diagnoses. We outline possible steps toward translating this computational approach to the bedside, to supplement todays evidence-based medicine with a quantitatively founded model-based medicine that integrates mechanistic knowledge with patient-specific information.'),
(83759, 2007, 'plos', 'Are there rearrangement hotspots in the human genome?', 'Alekseyev, Max A|Pevzner, Pavel A', 'Department of Computer Science and Engineering, University of California San Diego, San Diego, California, United States of America. maxal@cs.ucsd.edu|Department of Computer Science and Engineering, University of California San Diego, San Diego, California, United States of America. maxal@cs.ucsd.edu', 'United States|United States', 0, 'Base Sequence|Chromosome Mapping|Computer Simulation|Evolution, Molecular|Gene Rearrangement|Genetic Variation|Genome, Human|Humans|Models, Genetic|Molecular Sequence Data', 'Journal Article', '10.1371/journal.pcbi.0030209', '17997591', 'In a landmark paper, Nadeau and Taylor [18] formulated the random breakage model (RBM) of chromosome evolution that postulates that there are no rearrangement hotspots in the human genome. In the next two decades, numerous studies with progressively increasing levels of resolution made RBM the de facto theory of chromosome evolution. Despite the fact that RBM had prophetic prediction power, it was recently refuted by Pevzner and Tesler [4], who introduced the fragile breakage model (FBM), postulating that the human genome is a mosaic of solid regions (with low propensity for rearrangements) and fragile regions (rearrangement hotspots). However, the rebuttal of RBM caused a controversy and led to a split among researchers studying genome evolution. In particular, it remains unclear whether some complex rearrangements (e.g., transpositions) can create an appearance of rearrangement hotspots. We contribute to the ongoing debate by analyzing multi-break rearrangements that break a genome into multiple fragments and further glue them together in a new order. In particular, we demonstrate that (1) even if transpositions were a dominant force in mammalian evolution, the arguments in favor of FBM still stand, and (2) the gene deletion argument against FBM is flawed.'),
(83760, 2007, 'plos', 'Self-assembly and DNA binding of the blocking factor in x chromosome inactivation', 'Nicodemi, Mario|Prisco, Antonella', 'Complexity Science and Department of Physics, University of Warwick, Warwick, United Kingdom. Mario.Nicodemi@na.infn.it|Complexity Science and Department of Physics, University of Warwick, Warwick, United Kingdom. Mario.Nicodemi@na.infn.it', 'United Kingdom|United Kingdom', 0, 'Binding Sites|Chromosomes, Human, X|Computer Simulation|DNA|DNA-Binding Proteins|Female|Humans|Models, Genetic|Models, Statistical|Protein Binding|Sequence Analysis, DNA|X Chromosome Inactivation', 'Journal Article', '10.1371/journal.pcbi.0030210', '17997592', 'X chromosome inactivation (XCI) is the phenomenon occurring in female mammals whereby dosage compensation of X-linked genes is obtained by transcriptional silencing of one of their two X chromosomes, randomly chosen during early embryo development. The earliest steps of random X-inactivation, involving counting of the X chromosomes and choice of the active and inactive X, are still not understood. To explain counting and choice, the longstanding hypothesis is that a molecular complex, a blocking factor (BF), exists. The BF is present in a single copy and can randomly bind to just one X per cell which is protected from inactivation, as the second X is inactivated by default. In such a picture, the missing crucial step is to explain how the molecular complex is self-assembled, why only one is formed, and how it binds only one X. We answer these questions within the framework of a schematic Statistical Physics model, investigated by Monte Carlo computer simulations. We show that a single complex is assembled as a result of a thermodynamic process relying on a phase transition occurring in the system which spontaneously breaks the symmetry between the Xs. We discuss, then, the BF interaction with X chromosomes. The thermodynamics of the mechanism that directs the two chromosomes to opposite fates could be, thus, clarified. The insights on the self-assembling and X binding properties of the BF are used to derive a quantitative scenario of biological implications describing current experimental evidences on counting and choice.'),
(83761, 2007, 'plos', 'A nucleosome-guided map of transcription factor binding sites in yeast', 'Narlikar, Leelavati|Gordân, Raluca|Hartemink, Alexander J', 'Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.|Department of Computer Science, Duke University, Durham, North Carolina, United States of America.', 'United States|United States|United States', 78, 'Binding Sites|DNA, Fungal|Nucleosomes|Oligonucleotide Array Sequence Analysis|Protein Binding|Protein Interaction Mapping|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030215', '17997593', 'Finding functional DNA binding sites of transcription factors (TFs) throughout the genome is a crucial step in understanding transcriptional regulation. Unfortunately, these binding sites are typically short and degenerate, posing a significant statistical challenge: many more matches to known TF motifs occur in the genome than are actually functional. However, information about chromatin structure may help to identify the functional sites. In particular, it has been shown that active regulatory regions are usually depleted of nucleosomes, thereby enabling TFs to bind DNA in those regions. Here, we describe a novel motif discovery algorithm that employs an informative prior over DNA sequence positions based on a discriminative view of nucleosome occupancy. When a Gibbs sampling algorithm is applied to yeast sequence-sets identified by ChIP-chip, the correct motif is found in 52% more cases with our informative prior than with the commonly used uniform prior. This is the first demonstration that nucleosome occupancy information can be used to improve motif discovery. The improvement is dramatic, even though we are using only a statistical model to predict nucleosome occupancy, we expect our results to improve further as high-resolution genome-wide experimental nucleosome occupancy data becomes increasingly available.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83762, 2007, 'plos', 'MORPH: probabilistic alignment combined with hidden Markov models of cis-regulatory modules', 'Sinha, Saurabh|He, Xin', 'Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America. sinhas@cs.uiuc.edu|Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America. sinhas@cs.uiuc.edu', 'United States|United States', 0, 'Algorithms|Animals|Base Sequence|Chromosome Mapping|Computer Simulation|Data Interpretation, Statistical|Drosophila melanogaster|Markov Chains|Models, Genetic|Models, Statistical|Molecular Sequence Data|Pattern Recognition, Automated|Regulatory Sequences, Nucleic Acid|Sequence Alignment|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.0030216', '17997594', 'The discovery and analysis of cis-regulatory modules (CRMs) in metazoan genomes is crucial for understanding the transcriptional control of development and many other biological processes. Cross-species sequence comparison holds much promise for improving computational prediction of CRMs, for elucidating their binding site composition, and for understanding how they evolve. Current methods for analyzing orthologous CRMs from multiple species rely upon sequence alignments produced by off-the-shelf alignment algorithms, which do not exploit the presence of binding sites in the sequences. We present here a unified probabilistic framework, called MORPH, that integrates the alignment task with binding site predictions, allowing more robust CRM analysis in two species. The framework sums over all possible alignments of two sequences, thus accounting for alignment ambiguities in a natural way. We perform extensive tests on orthologous CRMs from two moderately diverged species Drosophila melanogaster and D. mojavensis, to demonstrate the advantages of the new approach. We show that it can overcome certain computational artifacts of traditional alignment tools and provide a different, likely more accurate, picture of cis-regulatory evolution than that obtained from existing methods. The burgeoning field of cis-regulatory evolution, which is amply supported by the availability of many related genomes, is currently thwarted by the lack of accurate alignments of regulatory regions. Our work will fill in this void and enable more reliable analysis of CRM evolution.'),
(83763, 2007, 'plos', 'Stochastic noise and synchronisation during dictyostelium aggregation make cAMP oscillations robust', 'Kim, Jongrae|Heslop-Harrison, Pat|Postlethwaite, Ian|Bates, Declan G', 'Control and Instrumentation Group, Department of Engineering, University of Leicester, Leicester, United Kingdom. jkim@aero.gla.ac.uk|Control and Instrumentation Group, Department of Engineering, University of Leicester, Leicester, United Kingdom. jkim@aero.gla.ac.uk|Control and Instrumentation Group, Department of Engineering, University of Leicester, Leicester, United Kingdom. jkim@aero.gla.ac.uk|Control and Instrumentation Group, Department of Engineering, University of Leicester, Leicester, United Kingdom. jkim@aero.gla.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Biological Clocks|Computer Simulation|Cyclic AMP|Dictyostelium|Food Deprivation|Models, Biological|Models, Statistical|Signal Transduction|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0030218', '17997595', 'Stable and robust oscillations in the concentration of adenosine 3, 5-cyclic monophosphate (cAMP) are observed during the aggregation phase of starvation-induced development in Dictyostelium discoideum. In this paper we use mathematical modelling together with ideas from robust control theory to identify two factors which appear to make crucial contributions to ensuring the robustness of these oscillations. Firstly, we show that stochastic fluctuations in the molecular interactions play an important role in preserving stable oscillations in the face of variations in the kinetics of the intracellular network. Secondly, we show that synchronisation of the aggregating cells through the diffusion of extracellular cAMP is a key factor in ensuring robustness of the oscillatory waves of cAMP observed in Dictyostelium cell cultures to cell-to-cell variations. A striking and quite general implication of the results is that the robustness analysis of models of oscillating biomolecular networks (circadian clocks, Ca(2+) oscillations, etc.) can only be done reliably by using stochastic simulations, even in the case where molecular concentrations are very high.'),
(83764, 2007, 'plos', 'Computational analysis of mouse piRNA sequence and biogenesis', 'Betel, Doron|Sheridan, Robert|Marks, Debora S|Sander, Chris', 'Computational and Systems Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. betel@cbio.mskcc.org|Computational and Systems Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. betel@cbio.mskcc.org|Computational and Systems Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. betel@cbio.mskcc.org|Computational and Systems Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. betel@cbio.mskcc.org', 'United States|United States|United States|United States', 0, 'Animals|Base Sequence|Conserved Sequence|Evolution, Molecular|Genetic Variation|Mice|Molecular Sequence Data|Origin of Life|RNA, Small Interfering|Sequence Alignment|Sequence Analysis, RNA|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0030222', '17997596', 'The recent discovery of a new class of 30-nucleotide long RNAs in mammalian testes, called PIWI-interacting RNA (piRNA), with similarities to microRNAs and repeat-associated small interfering RNAs (rasiRNAs), has raised puzzling questions regarding their biogenesis and function. We report a comparative analysis of currently available piRNA sequence data from the pachytene stage of mouse spermatogenesis that sheds light on their sequence diversity and mechanism of biogenesis. We conclude that (i) there are at least four times as many piRNAs in mouse testes than currently known, (ii) piRNAs, which originate from long precursor transcripts, are generated by quasi-random enzymatic processing that is guided by a weak sequence signature at the piRNA 5ends resulting in a large number of distinct sequences, and (iii) many of the piRNA clusters contain inverted repeats segments capable of forming double-strand RNA fold-back segments that may initiate piRNA processing analogous to transposon silencing.'),
(83765, 2007, 'plos', 'Genetic progression and the waiting time to cancer', 'Beerenwinkel, Niko|Antal, Tibor|Dingli, David|Traulsen, Arne|Kinzler, Kenneth W|Velculescu, Victor E|Vogelstein, Bert|Nowak, Martin A', 'Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. niko.beerenwinkel@bsse.ethz.ch', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Adenoma|Carcinoma|Cell Transformation, Neoplastic|Colonic Neoplasms|Computer Simulation|DNA, Neoplasm|Genetic Predisposition to Disease|Humans|Models, Genetic|Mutation|Neoplasm Proteins', 'Journal Article', '10.1371/journal.pcbi.0030225', '17997597', 'Cancer results from genetic alterations that disturb the normal cooperative behavior of cells. Recent high-throughput genomic studies of cancer cells have shown that the mutational landscape of cancer is complex and that individual cancers may evolve through mutations in as many as 20 different cancer-associated genes. We use data published by Sjöblom et al. (2006) to develop a new mathematical model for the somatic evolution of colorectal cancers. We employ the Wright-Fisher process for exploring the basic parameters of this evolutionary process and derive an analytical approximation for the expected waiting time to the cancer phenotype. Our results highlight the relative importance of selection over both the size of the cell population at risk and the mutation rate. The model predicts that the observed genetic diversity of cancer genomes can arise under a normal mutation rate if the average selective advantage per mutation is on the order of 1%. Increased mutation rates due to genetic instability would allow even smaller selective advantages during tumorigenesis. The complexity of cancer progression can be understood as the result of multiple sequential mutations, each of which has a relatively small but positive effect on net cell growth.'),
(83766, 2007, 'plos', 'Molecular basis for evolving modularity in the yeast protein interaction network', 'Fernández, Ariel', 'Department of Bioengineering, Rice University, Houston, Texas, United States of America. arifer@rice.edu', 'United States', 13, 'Base Sequence|Computer Simulation|Evolution, Molecular|Gene Expression Regulation|Models, Genetic|Molecular Sequence Data|Protein Interaction Mapping|Proteome|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030226', '17997598', 'Scale-free networks are generically defined by a power-law distribution of node connectivities. Vastly different graph topologies fit this law, ranging from the assortative, with frequent similar-degree node connections, to a modular structure. Using a metric to determine the extent of modularity, we examined the yeast protein network and found it to be significantly self-dissimilar. By orthologous node categorization, we established the evolutionary trend in the network, from an emerging assortative network to a present-day modular topology. The evolving topology fits a generic connectivity distribution but with a progressive enrichment in intramodule hubs that avoid each other. Primeval tolerance to random node failure is shown to evolve toward resilience to hub failure, thus removing the fragility often ascribed to scale-free networks. This trend is algorithmically reproduced by adopting a connectivity accretion law that disfavors like-degree connections for large-degree nodes. The selective advantage of this trend relates to the need to prevent a failed hub from inducing failure in an adjacent hub. The molecular basis for the evolutionary trend is likely rooted in the high-entropy penalty entailed in the association of two intramodular hubs.'),
(83767, 2007, 'plos', 'A dynamical systems hypothesis of schizophrenia', 'Loh, Marco|Rolls, Edmund T|Deco, Gustavo', 'Department of Technology, Universitas Pompeu Fabra, Barcelona, Spain.|Department of Technology, Universitas Pompeu Fabra, Barcelona, Spain.|Department of Technology, Universitas Pompeu Fabra, Barcelona, Spain.', 'Spain|Spain|Spain', 111, 'Action Potentials|Animals|Brain|Computer Simulation|Humans|Models, Neurological|Nerve Net|Receptors, GABA|Receptors, N-Methyl-D-Aspartate|Schizophrenia|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030228', '17997599', 'We propose a top-down approach to the symptoms of schizophrenia based on a statistical dynamical framework. We show that a reduced depth in the basins of attraction of cortical attractor states destabilizes the activity at the network level due to the constant statistical fluctuations caused by the stochastic spiking of neurons. In integrate-and-fire network simulations, a decrease in the NMDA receptor conductances, which reduces the depth of the attractor basins, decreases the stability of short-term memory states and increases distractibility. The cognitive symptoms of schizophrenia such as distractibility, working memory deficits, or poor attention could be caused by this instability of attractor states in prefrontal cortical networks. Lower firing rates are also produced, and in the orbitofrontal and anterior cingulate cortex could account for the negative symptoms, including a reduction of emotions. Decreasing the GABA as well as the NMDA conductances produces not only switches between the attractor states, but also jumps from spontaneous activity into one of the attractors. We relate this to the positive symptoms of schizophrenia, including delusions, paranoia, and hallucinations, which may arise because the basins of attraction are shallow and there is instability in temporal lobe semantic memory networks, leading thoughts to move too freely round the attractor energy landscape.'),
(83768, 2007, 'plos', 'Self-organizing mechanism for development of space-filling neuronal dendrites', 'Sugimura, Kaoru|Shimono, Kohei|Uemura, Tadashi|Mochizuki, Atsushi', 'Graduate School of Biostudies, Kyoto University, Kyoto, Japan. ksugimura@brain.riken.jp|Graduate School of Biostudies, Kyoto University, Kyoto, Japan. ksugimura@brain.riken.jp|Graduate School of Biostudies, Kyoto University, Kyoto, Japan. ksugimura@brain.riken.jp|Graduate School of Biostudies, Kyoto University, Kyoto, Japan. ksugimura@brain.riken.jp', 'Japan|Japan|Japan|Japan', 0, 'Animals|Cell Communication|Cell Enlargement|Cell Proliferation|Cell Size|Computer Simulation|Dendrites|Humans|Models, Biological|Neurons', 'Journal Article', '10.1371/journal.pcbi.0030212', '18020700', 'Neurons develop distinctive dendritic morphologies to receive and process information. Previous experiments showed that competitive dendro-dendritic interactions play critical roles in shaping dendrites of the space-filling type, which uniformly cover their receptive field. We incorporated this finding in constructing a new mathematical model, in which reaction dynamics of two chemicals (activator and suppressor) are coupled to neuronal dendrite growth. Our numerical analysis determined the conditions for dendritic branching and suggested that the self-organizing property of the proposed system can underlie dendritogenesis. Furthermore, we found a clear correlation between dendrite shape and the distribution of the activator, thus providing a morphological criterion to predict the in vivo distribution of the hypothetical molecular complexes responsible for dendrite elongation and branching.'),
(83769, 2007, 'plos', 'Control of membrane fusion mechanism by lipid composition: predictions from ensemble molecular dynamics', 'Kasson, Peter M|Pande, Vijay S', 'Department of Chemistry, Stanford University, Stanford, California, United States of America. kasson@stanford.edu|Department of Chemistry, Stanford University, Stanford, California, United States of America. kasson@stanford.edu', 'United States|United States', 77, 'Computer Simulation|Lipid Bilayers|Membrane Fluidity|Membrane Fusion|Membrane Lipids|Models, Chemical|Models, Molecular|Molecular Conformation', 'Journal Article', '10.1371/journal.pcbi.0030220', '18020701', 'Membrane fusion is critical to biological processes such as viral infection, endocrine hormone secretion, and neurotransmission, yet the precise mechanistic details of the fusion process remain unknown. Current experimental and computational model systems approximate the complex physiological membrane environment for fusion using one or a few protein and lipid species. Here, we report results of a computational model system for fusion in which the ratio of lipid components was systematically varied, using thousands of simulations of up to a microsecond in length to predict the effects of lipid composition on both fusion kinetics and mechanism. In our simulations, increased phosphatidylcholine content in vesicles causes increased activation energies for formation of the initial stalk-like intermediate for fusion and of hemifusion intermediates, in accordance with previous continuum-mechanics theoretical treatments. We also use our large simulation dataset to quantitatively compare the mechanism by which vesicles fuse at different lipid compositions, showing a significant difference in fusion kinetics and mechanism at different compositions simulated. As physiological membranes have different compositions in the inner and outer leaflets, we examine the effect of such asymmetry, as well as the effect of membrane curvature on fusion. These predicted effects of lipid composition on fusion mechanism both underscore the way in which experimental model system construction may affect the observed mechanism of fusion and illustrate a potential mechanism for cellular regulation of the fusion process by altering membrane composition.'),
(83770, 2007, 'plos', 'Phenotypic mutation rates and the abundance of abnormal proteins in yeast', 'Willensdorfer, Martin|Bürger, Reinhard|Nowak, Martin A', 'Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. ma.wi@gmx.at|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. ma.wi@gmx.at|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. ma.wi@gmx.at', 'United States|United States|United States', 0, 'Base Sequence|Computer Simulation|DNA Mutational Analysis|Evolution, Molecular|Genetic Variation|Genetics, Population|Models, Genetic|Molecular Sequence Data|Mutation|Phenotype|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.0030203', '18039025', 'Phenotypic mutations are errors that occur during protein synthesis. These errors lead to amino acid substitutions that give rise to abnormal proteins. Experiments suggest that such errors are quite common. We present a model to study the effect of phenotypic mutation rates on the amount of abnormal proteins in a cell. In our model, genes are regulated to synthesize a certain number of functional proteins. During this process, depending on the phenotypic mutation rate, abnormal proteins are generated. We use data on protein length and abundance in Saccharomyces cerevisiae to parametrize our model. We calculate that for small phenotypic mutation rates most abnormal proteins originate from highly expressed genes that are on average nearly twice as large as the average yeast protein. For phenotypic mutation rates much above 5 x 10(-4), the error-free synthesis of large proteins is nearly impossible and lowly expressed, very large proteins contribute more and more to the amount of abnormal proteins in a cell. This fact leads to a steep increase of the amount of abnormal proteins for phenotypic mutation rates above 5 x 10(-4). Simulations show that this property leads to an upper limit for the phenotypic mutation rate of approximately 2 x 10(-3) even if the costs for abnormal proteins are extremely low. We also consider the adaptation of individual proteins. Individual genes/proteins can decrease their phenotypic mutation rate by using preferred codons or by increasing their robustness against amino acid substitutions. We discuss the similarities and differences between the two mechanisms and show that they can only slow down but not prevent the rapid increase of the amount of abnormal proteins. Our work allows us to estimate the phenotypic mutation rate based on data on the fraction of abnormal proteins. For S. cerevisiae, we predict that the value for the phenotypic mutation rate is between 2 x 10(-4) and 6 x 10(-4).'),
(83771, 2007, 'plos', 'Where have all the interactions gone? Estimating the coverage of two-hybrid protein interaction maps', 'Huang, Hailiang|Jedynak, Bruno M|Bader, Joel S', 'Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States|United States', 90, 'Computer Simulation|Models, Biological|Protein Interaction Mapping|Reproducibility of Results|Sensitivity and Specificity|Two-Hybrid System Techniques', 'Evaluation Studies', '10.1371/journal.pcbi.0030214', '18039026', 'Yeast two-hybrid screens are an important method for mapping pairwise physical interactions between proteins. The fraction of interactions detected in independent screens can be very small, and an outstanding challenge is to determine the reason for the low overlap. Low overlap can arise from either a high false-discovery rate (interaction sets have low overlap because each set is contaminated by a large number of stochastic false-positive interactions) or a high false-negative rate (interaction sets have low overlap because each misses many true interactions). We extend capture-recapture theory to provide the first unified model for false-positive and false-negative rates for two-hybrid screens. Analysis of yeast, worm, and fly data indicates that 25% to 45% of the reported interactions are likely false positives. Membrane proteins have higher false-discovery rates on average, and signal transduction proteins have lower rates. The overall false-negative rate ranges from 75% for worm to 90% for fly, which arises from a roughly 50% false-negative rate due to statistical undersampling and a 55% to 85% false-negative rate due to proteins that appear to be systematically lost from the assays. Finally, statistical model selection conclusively rejects the Erdös-Rényi network model in favor of the power law model for yeast and the truncated power law for worm and fly degree distributions. Much as genome sequencing coverage estimates were essential for planning the human genome sequencing project, the coverage estimates developed here will be valuable for guiding future proteomic screens. All software and datasets are available in and , -, and -, and are also available from our Web site, http://www.baderzone.org.'),
(83772, 2007, 'plos', 'An evolutionary-network model reveals stratified interactions in the V3 loop of the HIV-1 envelope', 'Poon, Art F Y|Lewis, Fraser I|Pond, Sergei L Kosakovsky|Frost, Simon D W', 'Department of Pathology, University of California San Diego, La Jolla, California, United States of America. afpoon@ucsd.edu|Department of Pathology, University of California San Diego, La Jolla, California, United States of America. afpoon@ucsd.edu|Department of Pathology, University of California San Diego, La Jolla, California, United States of America. afpoon@ucsd.edu|Department of Pathology, University of California San Diego, La Jolla, California, United States of America. afpoon@ucsd.edu', 'United States|United States|United States|United States', 0, 'Evolution, Molecular|HIV-1|Models, Genetic|Phylogeny|Protein Conformation|Protein Structure, Tertiary|Sequence Analysis|Structure-Activity Relationship|Viral Envelope Proteins', 'Journal Article', '10.1371/journal.pcbi.0030231', '18039027', 'The third variable loop (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope is a principal determinant of antibody neutralization and progression to AIDS. Although it is undoubtedly an important target for vaccine research, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methods that exploit the abundance of sequence data can detect interactions between residues of rapidly evolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies have relied implicitly on two biologically unrealistic assumptions: (1) that founder effects in the evolutionary history of the sequences can be ignored, and, (2) that statistical associations between residues occur exclusively in pairs. We show that comparative methods that neglect the evolutionary history of extant sequences are susceptible to a high rate of false positives (20%-40%). Therefore, we propose a new method to detect interactions that relaxes both of these assumptions. First, we reconstruct the evolutionary history of extant sequences by maximum likelihood, shifting focus from extant sequence variation to the underlying substitution events. Second, we analyze the joint distribution of substitution events among positions in the sequence as a Bayesian graphical model, in which each branch in the phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a control case of known interactions in HIV-1 protease, and apply this method to detect interactions within V3 from a sample of 1,154 HIV-1 envelope sequences. Our method greatly reduces the number of false positives due to founder effects, while capturing several higher-order interactions among V3 residues. By mapping these interactions to a structural model of the V3 loop, we find that the loop is stratified into distinct evolutionary clusters. We extend our model to detect interactions between the V3 and C4 domains of the HIV-1 envelope, and account for the uncertainty in mapping substitutions to the tree with a parametric bootstrap.'),
(83773, 2007, 'plos', 'A universal mechanism ties genotype to phenotype in trinucleotide diseases', 'Kaplan, Shai|Itzkovitz, Shalev|Shapiro, Ehud', 'Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel', 0, 'Animals|Chromosome Disorders|Chromosome Fragile Sites|Computer Simulation|DNA|DNA Mutational Analysis|Genetic Predisposition to Disease|Genotype|Humans|Models, Genetic|Phenotype|Trinucleotide Repeat Expansion', 'Journal Article', '10.1371/journal.pcbi.0030235', '18039028', 'Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions, therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patients lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype-phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.'),
(83774, 2007, 'plos', 'A primer on python for life science researchers', 'Bassi, S', 'Universidad Nacional de Quilmes, Buenos Aires, Argentina. sbassi@genes.unq.edu.ar', 'Argentina', 33, 'Biological Science Disciplines|Computer Simulation|Models, Biological|Programming Languages|Research Design|Software|Software Design', 'Journal Article', '10.1371/journal.pcbi.0030199', '18052533', '-'),
(83775, 2007, 'plos', 'In silico elucidation of the molecular mechanism defining the adverse effect of selective estrogen receptor modulators', 'Xie, Lei|Wang, Jian|Bourne, Philip E', 'San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America.|San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America.|San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 0, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Protein Interaction Mapping|Receptors, Estrogen|Selective Estrogen Receptor Modulators|Sequence Analysis, Protein|Structure-Activity Relationship|Toxicity Tests', 'Journal Article', '10.1371/journal.pcbi.0030217', '18052534', 'Early identification of adverse effect of preclinical and commercial drugs is crucial in developing highly efficient therapeutics, since unexpected adverse drug effects account for one-third of all drug failures in drug development. To correlate protein-drug interactions at the molecule level with their clinical outcomes at the organism level, we have developed an integrated approach to studying protein-ligand interactions on a structural proteome-wide scale by combining protein functional site similarity search, small molecule screening, and protein-ligand binding affinity profile analysis. By applying this methodology, we have elucidated a possible molecular mechanism for the previously observed, but molecularly uncharacterized, side effect of selective estrogen receptor modulators (SERMs). The side effect involves the inhibition of the Sacroplasmic Reticulum Ca2+ ion channel ATPase protein (SERCA) transmembrane domain. The prediction provides molecular insight into reducing the adverse effect of SERMs and is supported by clinical and in vitro observations. The strategy used in this case study is being applied to discover off-targets for other commercially available pharmaceuticals. The process can be included in a drug discovery pipeline in an effort to optimize drug leads and reduce unwanted side effects.'),
(83776, 2007, 'plos', 'STDP in a bistable synapse model based on CaMKII and associated signaling pathways', 'Graupner, Michael|Brunel, Nicolas', 'Université Paris Descartes, Laboratoire de Neurophysique et Physiologie, Paris, France. michael.graupner@univ-paris5.fr|Université Paris Descartes, Laboratoire de Neurophysique et Physiologie, Paris, France. michael.graupner@univ-paris5.fr', 'France|France', 93, 'Action Potentials|Animals|Calcium-Calmodulin-Dependent Protein Kinase Type 2|Computer Simulation|Humans|Long-Term Potentiation|Long-Term Synaptic Depression|Memory|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Signal Transduction|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030221', '18052535', 'The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch. However, it is still unclear whether experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such a network. We present a detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentration, and high calcium transients can switch the system from the weakly phosphorylated (DOWN) to the highly phosphorylated (UP) state of the CaMKII (similar to a LTP event). We show here that increased CaMKII dephosphorylation activity at intermediate Ca(2+) concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). This can be achieved if protein phosphatase activity promoting CaMKII dephosphorylation activates at lower Ca(2+) levels than kinase activity. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. This shows that the CaMKII protein network can account for both induction, through LTP/LTD-like transitions, and storage, due to its bistability, of synaptic changes.'),
(83777, 2007, 'plos', 'Computational biology in Cuba: an opportunity to promote science in a developing country', 'Pons, Tirso|Montero, Luis A|Febles, Juan P', 'Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba. pons@fbio.uh.cu|Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba. pons@fbio.uh.cu|Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba. pons@fbio.uh.cu', 'Cuba|Cuba|Cuba', 5, 'Biotechnology|Computational Biology|Cuba|Developing Countries|Research|Science|Universities', 'Journal Article', '10.1371/journal.pcbi.0030227', '18052536', '-'),
(83778, 2007, 'plos', 'Ten simple rules for graduate students', 'Gu, Jenny|Bourne, Philip E', 'Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba. pons@fbio.uh.cu|Center for Protein Studies, Faculty of Biology, University of Havana, Havana, Cuba. pons@fbio.uh.cu', 'Cuba|Cuba', 0, 'Algorithms|Computational Biology|Decision Support Techniques|Education, Graduate|Students', 'Editorial', '10.1371/journal.pcbi.0030229', '18052537', '-'),
(83779, 2007, 'plos', 'Using likelihood-free inference to compare evolutionary dynamics of the protein networks of H pylori and P falciparum', 'Ratmann, Oliver|Jørgensen, Ole|Hinkley, Trevor|Stumpf, Michael|Richardson, Sylvia|Wiuf, Carsten', 'Department of Public Health and Epidemiology, Imperial College London, London, United Kingdom. oliver.ratmann@imperial.ac.uk|Department of Public Health and Epidemiology, Imperial College London, London, United Kingdom. oliver.ratmann@imperial.ac.uk|Department of Public Health and Epidemiology, Imperial College London, London, United Kingdom. oliver.ratmann@imperial.ac.uk|Department of Public Health and Epidemiology, Imperial College London, London, United Kingdom. oliver.ratmann@imperial.ac.uk|Department of Public Health and Epidemiology, Imperial College London, London, United Kingdom. oliver.ratmann@imperial.ac.uk|Department of Public Health and Epidemiology, Imperial College London, London, United Kingdom. oliver.ratmann@imperial.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 68, 'Animals|Bacterial Proteins|Biological Evolution|Evolution, Molecular|Gene Duplication|Genetic Variation|Helicobacter pylori|Likelihood Functions|Models, Genetic|Models, Statistical|Plasmodium falciparum|Protozoan Proteins|Signal Transduction', 'Comparative Study', '10.1371/journal.pcbi.0030230', '18052538', 'Gene duplication with subsequent interaction divergence is one of the primary driving forces in the evolution of genetic systems. Yet little is known about the precise mechanisms and the role of duplication divergence in the evolution of protein networks from the prokaryote and eukaryote domains. We developed a novel, model-based approach for Bayesian inference on biological network data that centres on approximate Bayesian computation, or likelihood-free inference. Instead of computing the intractable likelihood of the protein network topology, our method summarizes key features of the network and, based on these, uses a MCMC algorithm to approximate the posterior distribution of the model parameters. This allowed us to reliably fit a flexible mixture model that captures hallmarks of evolution by gene duplication and subfunctionalization to protein interaction network data of Helicobacter pylori and Plasmodium falciparum. The 80% credible intervals for the duplication-divergence component are [0.64, 0.98] for H. pylori and [0.87, 0.99] for P. falciparum. The remaining parameter estimates are not inconsistent with sequence data. An extensive sensitivity analysis showed that incompleteness of PIN data does not largely affect the analysis of models of protein network evolution, and that the degree sequence alone barely captures the evolutionary footprints of protein networks relative to other statistics. Our likelihood-free inference approach enables a fully Bayesian analysis of a complex and highly stochastic system that is otherwise intractable at present. Modelling the evolutionary history of PIN data, it transpires that only the simultaneous analysis of several global aspects of protein networks enables credible and consistent inference to be made from available datasets. Our results indicate that gene duplication has played a larger part in the network evolution of the eukaryote than in the prokaryote, and suggests that single gene duplications with immediate divergence alone may explain more than 60% of biological network data in both domains.'),
(83780, 2007, 'plos', 'CATHEDRAL: a fast and effective algorithm to predict folds and domain boundaries from multidomain protein structures', 'Redfern, Oliver C|Harrison, Andrew|Dallman, Tim|Pearl, Frances M G|Orengo, Christine A', 'Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ollie@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ollie@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ollie@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ollie@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ollie@biochem.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 63, 'Algorithms|Amino Acid Sequence|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Conformation|Protein Folding|Protein Structure, Tertiary|Proteins|Sequence Alignment|Sequence Analysis, Protein|Software', 'Journal Article', '10.1371/journal.pcbi.0030232', '18052539', 'We present CATHEDRAL, an iterative protocol for determining the location of previously observed protein folds in novel multidomain protein structures. CATHEDRAL builds on the features of a fast secondary-structure-based method (using graph theory) to locate known folds within a multidomain context and a residue-based, double-dynamic programming algorithm, which is used to align members of the target fold groups against the query protein structure to identify the closest relative and assign domain boundaries. To increase the fidelity of the assignments, a support vector machine is used to provide an optimal scoring scheme. Once a domain is verified, it is excised, and the search protocol is repeated in an iterative fashion until all recognisable domains have been identified. We have performed an initial benchmark of CATHEDRAL against other publicly available structure comparison methods using a consensus dataset of domains derived from the CATH and SCOP domain classifications. CATHEDRAL shows superior performance in fold recognition and alignment accuracy when compared with many equivalent methods. If a novel multidomain structure contains a known fold, CATHEDRAL will locate it in 90% of cases, with <1% false positives. For nearly 80% of assigned domains in a manually validated test set, the boundaries were correctly delineated within a tolerance of ten residues. For the remaining cases, previously classified domains were very remotely related to the query chain so that embellishments to the core of the fold caused significant differences in domain sizes and manual refinement of the boundaries was necessary. To put this performance in context, a well-established sequence method based on hidden Markov models was only able to detect 65% of domains, with 33% of the subsequent boundaries assigned within ten residues. Since, on average, 50% of newly determined protein structures contain more than one domain unit, and typically 90% or more of these domains are already classified in CATH, CATHEDRAL will considerably facilitate the automation of protein structure classification.'),
(83781, 2007, 'plos', 'Small regulatory RNAs may sharpen spatial expression patterns', 'Levine, Erel|McHale, Peter|Levine, Herbert', 'Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. hlevine@ucsd.edu|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. hlevine@ucsd.edu|Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America. hlevine@ucsd.edu', 'United States|United States|United States', 79, 'Animals|Biological Transport|Drosophila|Drosophila Proteins|Gene Expression Regulation, Developmental|Gene Targeting|Models, Genetic|Morphogenesis|Nuclear Proteins|RNA, Messenger|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030233', '18052540', 'The precise establishment of gene expression patterns is a crucial step in development. Formation of a sharp boundary between high and low spatial expression domains requires a genetic mechanism that exhibits sensitivity, yet is robust to fluctuations, a demand that may not be easily achieved by morphogens alone. Recently, it has been demonstrated that small RNAs (and, in particular, microRNAs) play many roles in embryonic development. Whereas some RNAs are essential for embryogenesis, others are limited to fine-tuning a predetermined gene expression pattern. Here, we explore the possibility that small RNAs participate in sharpening a gene expression profile that was crudely established by a morphogen. To this end, we study a model in which small RNAs interact with a target gene and diffusively move from cell to cell. Though diffusion generally smoothens spatial expression patterns, we find that intercellular mobility of small RNAs is actually critical in sharpening the interface between target expression domains in a robust manner. This sharpening occurs as small RNAs diffuse into regions of low mRNA expression and eliminate target molecules therein, but cannot affect regions of high mRNA levels. We discuss the applicability of our results, as examples, to the case of leaf polarity establishment in maize and Hox patterning in the early Drosophila embryo. Our findings point out the functional significance of some mechanistic properties, such as mobility of small RNAs and the irreversibility of their interactions. These properties are yet to be established directly for most classes of small RNAs. An indirect yet simple experimental test of the proposed mechanism is suggested in some detail.'),
(83782, 2007, 'plos', 'Gamma oscillations of spiking neural populations enhance signal discrimination', 'Masuda, Naoki|Doiron, Brent', 'Graduate School of Information Science and Technology, the University of Tokyo, Bunkyo, Tokyo, Japan. masuda@mist.i.u-tokyo.ac.jp|Graduate School of Information Science and Technology, the University of Tokyo, Bunkyo, Tokyo, Japan. masuda@mist.i.u-tokyo.ac.jp', 'Japan|Japan', 23, 'Action Potentials|Animals|Attention|Biological Clocks|Brain|Computer Simulation|Discriminant Analysis|Discrimination Learning|Electroencephalography|Humans|Models, Neurological|Nerve Net|Perception', 'Journal Article', '10.1371/journal.pcbi.0030236', '18052541', 'Selective attention is an important filter for complex environments where distractions compete with signals. Attention increases both the gamma-band power of cortical local field potentials and the spike-field coherence within the receptive field of an attended object. However, the mechanisms by which gamma-band activity enhances, if at all, the encoding of input signals are not well understood. We propose that gamma oscillations induce binomial-like spike-count statistics across noisy neural populations. Using simplified models of spiking neurons, we show how the discrimination of static signals based on the population spike-count response is improved with gamma induced binomial statistics. These results give an important mechanistic link between the neural correlates of attention and the discrimination tasks where attention is known to enhance performance. Further, they show how a rhythmicity of spike responses can enhance coding schemes that are not temporally sensitive.'),
(83783, 2007, 'plos', 'Predicting protein function with hierarchical phylogenetic profiles: the Gene3D Phylo-Tuner method applied to eukaryotic genomes', 'Ranea, Juan A G|Yeats, Corin|Grant, Alastair|Orengo, Christine A', 'Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ranea@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ranea@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ranea@biochem.ucl.ac.uk|Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom. ranea@biochem.ucl.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 41, 'Algorithms|Animals|Chromosome Mapping|Eukaryotic Cells|Gene Expression Profiling|Humans|Multigene Family|Phylogeny|Proteome|Software|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030237', '18052542', 'Phylogenetic profiling is based on the hypothesis that during evolution functionally or physically interacting genes are likely to be inherited or eliminated in a codependent manner. Creating presence-absence profiles of orthologous genes is now a common and powerful way of identifying functionally associated genes. In this approach, correctly determining orthology, as a means of identifying functional equivalence between two genes, is a critical and nontrivial step and largely explains why previous work in this area has mainly focused on using presence-absence profiles in prokaryotic species. Here, we demonstrate that eukaryotic genomes have a high proportion of multigene families whose phylogenetic profile distributions are poor in presence-absence information content. This feature makes them prone to orthology mis-assignment and unsuited to standard profile-based prediction methods. Using CATH structural domain assignments from the Gene3D database for 13 complete eukaryotic genomes, we have developed a novel modification of the phylogenetic profiling method that uses genome copy number of each domain superfamily to predict functional relationships. In our approach, superfamilies are subclustered at ten levels of sequence identity-from 30% to 100%-and phylogenetic profiles built at each level. All the profiles are compared using normalised Euclidean distances to identify those with correlated changes in their domain copy number. We demonstrate that two protein families will auto-tune with strong co-evolutionary signals when their profiles are compared at the similarity levels that capture their functional relationship. Our method finds functional relationships that are not detectable by the conventional presence-absence profile comparisons, and it does not require a priori any fixed criteria to define orthologous genes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83784, 2007, 'plos', 'Intragenomic matching reveals a huge potential for miRNA-mediated regulation in plants', 'Lindow, Morten|Jacobsen, Anders|Nygaard, Sanne|Mang, Yuan|Krogh, Anders', 'Bioinformatics Centre, Department of Molecular Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. morten@binf.ku.dk|Bioinformatics Centre, Department of Molecular Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. morten@binf.ku.dk|Bioinformatics Centre, Department of Molecular Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. morten@binf.ku.dk|Bioinformatics Centre, Department of Molecular Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. morten@binf.ku.dk|Bioinformatics Centre, Department of Molecular Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. morten@binf.ku.dk', 'Denmark|Denmark|Denmark|Denmark|Denmark', 49, 'Chromosome Mapping|Gene Expression Regulation, Plant|Genome, Plant|MicroRNAs|Phenotype|Plant Proteins|Plants|Sequence Analysis, RNA|Sequence Homology, Nucleic Acid|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.0030238', '18052543', 'microRNAs (miRNAs) are important post-transcriptional regulators, but the extent of this regulation is uncertain, both with regard to the number of miRNA genes and their targets. Using an algorithm based on intragenomic matching of potential miRNAs and their targets coupled with support vector machine classification of miRNA precursors, we explore the potential for regulation by miRNAs in three plant genomes: Arabidopsis thaliana, Populus trichocarpa, and Oryza sativa. We find that the intragenomic matching in conjunction with a supervised learning approach contains enough information to allow reliable computational prediction of miRNA candidates without requiring conservation across species. Using this method, we identify approximately 1,200, approximately 2,500, and approximately 2,100 miRNA candidate genes capable of extensive base-pairing to potential target mRNAs in A. thaliana, P. trichocarpa, and O. sativa, respectively. This is more than five times the number of currently annotated miRNAs in the plants. Many of these candidates are derived from repeat regions, yet they seem to contain the features necessary for correct processing by the miRNA machinery. Conservation analysis indicates that only a few of the candidates are conserved between the species. We conclude that there is a large potential for miRNA-mediated regulatory interactions encoded in the genomes of the investigated plants. We hypothesize that some of these interactions may be realized under special environmental conditions, while others can readily be recruited when organisms diverge and adapt to new niches.'),
(83785, 2007, 'plos', 'Predicting gene expression from sequence: a reexamination', 'Yuan, Yuan|Guo, Lei|Shen, Lei|Liu, Jun S', 'Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 46, 'Amino Acid Motifs|Base Sequence|Chromosome Mapping|DNA, Fungal|Gene Expression Regulation, Fungal|Molecular Sequence Data|Promoter Regions, Genetic|Reproducibility of Results|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Sensitivity and Specificity|Sequence Analysis, DNA', 'Comparative Study', '10.1371/journal.pcbi.0030243', '18052544', 'Although much of the information regarding genes expressions is encoded in the genome, deciphering such information has been very challenging. We reexamined Beer and Tavazoies (BT) approach to predict mRNA expression patterns of 2,587 genes in Saccharomyces cerevisiae from the information in their respective promoter sequences. Instead of fitting complex Bayesian network models, we trained naïve Bayes classifiers using only the sequence-motif matching scores provided by BT. Our simple models correctly predict expression patterns for 79% of the genes, based on the same criterion and the same cross-validation (CV) procedure as BT, which compares favorably to the 73% accuracy of BT. The fact that our approach did not use position and orientation information of the predicted binding sites but achieved a higher prediction accuracy, motivated us to investigate a few biological predictions made by BT. We found that some of their predictions, especially those related to motif orientations and positions, are at best circumstantial. For example, the combinatorial rules suggested by BT for the PAC and RRPE motifs are not unique to the cluster of genes from which the predictive model was inferred, and there are simpler rules that are statistically more significant than BTs ones. We also show that CV procedure used by BT to estimate their methods prediction accuracy is inappropriate and may have overestimated the prediction accuracy by about 10%.'),
(83786, 2007, 'plos', 'Direct inference of SNP heterozygosity rates and resolution of LOH detection', 'Li, Xiaohong|Self, Steven G|Galipeau, Patricia C|Paulson, Thomas G|Reid, Brian J', 'Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. xili@fhcrc.org|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. xili@fhcrc.org', 'United States|United States|United States|United States|United States', 17, 'Animals|Base Sequence|Chromosome Mapping|DNA Mutational Analysis|Humans|Loss of Heterozygosity|Molecular Sequence Data|Polymorphism, Single Nucleotide|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030244', '18052545', 'Single nucleotide polymorphisms (SNPs) have been increasingly utilized to investigate somatic genetic abnormalities in premalignancy and cancer. LOH is a common alteration observed during cancer development, and SNP assays have been used to identify LOH at specific chromosomal regions. The design of such studies requires consideration of the resolution for detecting LOH throughout the genome and identification of the number and location of SNPs required to detect genetic alterations in specific genomic regions. Our study evaluated SNP distribution patterns and used probability models, Monte Carlo simulation, and real human subject genotype data to investigate the relationships between the number of SNPs, SNP HET rates, and the sensitivity (resolution) for detecting LOH. We report that variances of SNP heterozygosity rate in dbSNP are high for a large proportion of SNPs. Two statistical methods proposed for directly inferring SNP heterozygosity rates require much smaller sample sizes (intermediate sizes) and are feasible for practical use in SNP selection or verification. Using HapMap data, we showed that a region of LOH greater than 200 kb can be reliably detected, with losses smaller than 50 kb having a substantially lower detection probability when using all SNPs currently in the HapMap database. Higher densities of SNPs may exist in certain local chromosomal regions that provide some opportunities for reliably detecting LOH of segment sizes smaller than 50 kb. These results suggest that the interpretation of the results from genome-wide scans for LOH using commercial arrays need to consider the relationships among inter-SNP distance, detection probability, and sample size for a specific study. New experimental designs for LOH studies would also benefit from considering the power of detection and sample sizes required to accomplish the proposed aims.'),
(83787, 2007, 'plos', 'Retinal wave behavior through activity-dependent refractory periods', 'Godfrey, Keith B|Swindale, Nicholas V', 'Department of Opthamology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada. aquilonis@earthlink.net|Department of Opthamology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada. aquilonis@earthlink.net', 'Canada|Canada', 32, 'Action Potentials|Animals|Biological Clocks|Computer Simulation|Excitatory Postsynaptic Potentials|Humans|Models, Neurological|Nerve Net|Refractory Period, Electrophysiological|Retinal Ganglion Cells', 'Journal Article', '10.1371/journal.pcbi.0030245', '18052546', 'In the developing mammalian visual system, spontaneous retinal ganglion cell (RGC) activity contributes to and drives several aspects of visual system organization. This spontaneous activity takes the form of spreading patches of synchronized bursting that slowly advance across portions of the retina. These patches are non-repeating and tile the retina in minutes. Several transmitter systems are known to be involved, but the basic mechanism underlying wave production is still not well-understood. We present a model for retinal waves that focuses on acetylcholine mediated waves but whose principles are adaptable to other developmental stages. Its assumptions are that a) spontaneous depolarizations of amacrine cells drive wave activity, b) amacrine cells are locally connected, and c) cells receiving more input during their depolarization are subsequently less responsive and have longer periods between spontaneous depolarizations. The resulting model produces waves with non-repeating borders and randomly distributed initiation points. The wave generation mechanism appears to be chaotic and does not require neural noise to produce this wave behavior. Variations in parameter settings allow the model to produce waves that are similar in size, frequency, and velocity to those observed in several species. Our results suggest that retinal wave behavior results from activity-dependent refractory periods and that the average velocity of retinal waves depends on the duration a cell is excitatory: longer periods of excitation result in slower waves. In contrast to previous studies, we find that a single layer of cells is sufficient for wave generation. The principles described here are very general and may be adaptable to the description of spontaneous wave activity in other areas of the nervous system.'),
(83788, 2007, 'plos', 'The modular organization of domain structures: insights into protein-protein binding', 'del Sol, Antonio|Carbonell, Pablo', 'Bioinformatics Research Unit, Research and Development Division, Fujirebio, Tokyo, Japan. ao-mesa@fujirebio.co.jp|Bioinformatics Research Unit, Research and Development Division, Fujirebio, Tokyo, Japan. ao-mesa@fujirebio.co.jp', 'Japan|Japan', 16, 'Amino Acid Sequence|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Interaction Mapping|Protein Structure, Tertiary|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030239', '18069884', 'Domains are the building blocks of proteins and play a crucial role in protein-protein interactions. Here, we propose a new approach for the analysis and prediction of domain-domain interfaces. Our method, which relies on the representation of domains as residue-interacting networks, finds an optimal decomposition of domain structures into modules. The resulting modules comprise highly cooperative residues, which exhibit few connections with other modules. We found that non-overlapping binding sites in a domain, involved in different domain-domain interactions, are generally contained in different modules. This observation indicates that our modular decomposition is able to separate protein domains into regions with specialized functions. Our results show that modules with high modularity values identify binding site regions, demonstrating the predictive character of modularity. Furthermore, the combination of modularity with other characteristics, such as sequence conservation or surface patches, was found to improve our predictions. In an attempt to give a physical interpretation to the modular architecture of domains, we analyzed in detail six examples of protein domains with available experimental binding data. The modular configuration of the TEM1-beta-lactamase binding site illustrates the energetic independence of hotspots located in different modules and the cooperativity of those sited within the same modules. The energetic and structural cooperativity between intramodular residues is also clearly shown in the example of the chymotrypsin inhibitor, where non-binding site residues have a synergistic effect on binding. Interestingly, the binding site of the T cell receptor beta chain variable domain 2.1 is contained in one module, which includes structurally distant hot regions displaying positive cooperativity. These findings support the idea that modules possess certain functional and energetic independence. A modular organization of binding sites confers robustness and flexibility to the performance of the functional activity, and facilitates the evolution of protein interactions.'),
(83789, 2007, 'plos', 'Neuraminidase inhibitor resistance in influenza: assessing the danger of its generation and spread', 'Handel, Andreas|Longini, Ira M|Antia, Rustom', 'Department of Biology, Emory University, Atlanta, Georgia, United States of America. ahandel@emory.edu|Department of Biology, Emory University, Atlanta, Georgia, United States of America. ahandel@emory.edu|Department of Biology, Emory University, Atlanta, Georgia, United States of America. ahandel@emory.edu', 'Georgia|Georgia|Georgia', 100, 'Antiviral Agents|Computer Simulation|Disease Outbreaks|Drug Resistance, Viral|Humans|Influenza A virus|Influenza, Human|Models, Biological|Models, Immunological|Neuraminidase|Risk Assessment|Risk Factors|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.0030240', '18069885', 'Neuraminidase Inhibitors (NI) are currently the most effective drugs against influenza. Recent cases of NI resistance are a cause for concern. To assess the danger of NI resistance, a number of studies have reported the fraction of treated patients from which resistant strains could be isolated. Unfortunately, those results strongly depend on the details of the experimental protocol. Additionally, knowing the fraction of patients harboring resistance is not too useful by itself. Instead, we want to know how likely it is that an infected patient can generate a resistant infection in a secondary host, and how likely it is that the resistant strain subsequently spreads. While estimates for these parameters can often be obtained from epidemiological data, such data is lacking for NI resistance in influenza. Here, we use an approach that does not rely on epidemiological data. Instead, we combine data from influenza infections of human volunteers with a mathematical framework that allows estimation of the parameters that govern the initial generation and subsequent spread of resistance. We show how these parameters are influenced by changes in drug efficacy, timing of treatment, fitness of the resistant strain, and details of virus and immune system dynamics. Our study provides estimates for parameters that can be directly used in mathematical and computational models to study how NI usage might lead to the emergence and spread of resistance in the population. We find that the initial generation of resistant cases is most likely lower than the fraction of resistant cases reported. However, we also show that the results depend strongly on the details of the within-host dynamics of influenza infections, and most importantly, the role the immune system plays. Better knowledge of the quantitative dynamics of the immune response during influenza infections will be crucial to further improve the results.'),
(83790, 2007, 'plos', 'Stereochemical criteria for prediction of the effects of proline mutations on protein stability', 'Bajaj, Kanika|Madhusudhan, M S|Adkar, Bharat V|Chakrabarti, Purbani|Ramakrishnan, C|Sali, Andrej|Varadarajan, Raghavan', 'Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.|Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.', 'India|India|India|India|India|India|India', 32, 'Amino Acid Sequence|Amino Acid Substitution|Bacterial Proteins|Bacterial Toxins|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Mutagenesis, Site-Directed|Mutation|Protein Conformation|Sequence Analysis, Protein|Stereoisomerism|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030241', '18069886', 'When incorporated into a polypeptide chain, proline (Pro) differs from all other naturally occurring amino acid residues in two important respects. The phi dihedral angle of Pro is constrained to values close to -65 degrees and Pro lacks an amide hydrogen. Consequently, mutations which result in introduction of Pro can significantly affect protein stability. In the present work, we describe a procedure to accurately predict the effect of Pro introduction on protein thermodynamic stability. Seventy-seven of the 97 non-Pro amino acid residues in the model protein, CcdB, were individually mutated to Pro, and the in vivo activity of each mutant was characterized. A decision tree to classify the mutation as perturbing or nonperturbing was created by correlating stereochemical properties of mutants to activity data. The stereochemical properties including main chain dihedral angle phi and main chain amide H-bonds (hydrogen bonds) were determined from 3D models of the mutant proteins built using MODELLER. We assessed the performance of the decision tree on a large dataset of 163 single-site Pro mutations of T4 lysozyme, 74 nsSNPs, and 52 other Pro substitutions from the literature. The overall accuracy of this algorithm was found to be 81% in the case of CcdB, 77% in the case of lysozyme, 76% in the case of nsSNPs, and 71% in the case of other Pro substitution data. The accuracy of Pro scanning mutagenesis for secondary structure assignment was also assessed and found to be at best 69%. Our prediction procedure will be useful in annotating uncharacterized nsSNPs of disease-associated proteins and for protein engineering and design.'),
(83791, 2007, 'plos', 'Getting started in probabilistic graphical models', 'Airoldi, Edoardo M', 'Lewis-Sigler Institute for Integrative Genomics and Computer Science Department, Princeton University, Princeton, New Jersey, United States of America. eairoldi@princeton.edu', 'Jersey', 28, 'Algorithms|Computer Graphics|Computer Simulation|Data Interpretation, Statistical|Models, Biological|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.0030252', '18069887', '-'),
(83792, 2007, 'plos', 'Coincidence detection of place and temporal context in a network model of spiking hippocampal neurons', 'Katz, Yael|Kath, William L|Spruston, Nelson|Hasselmo, Michael E', 'Interdepartmental Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America.|Interdepartmental Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America.|Interdepartmental Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America.|Interdepartmental Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America.', 'United States|United States|United States|United States', 0, 'Action Potentials|Algorithms|Animals|Computer Simulation|Hippocampus|Models, Neurological|Nerve Net|Neurons|Rats|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030234', '18085816', 'Recent advances in single-neuron biophysics have enhanced our understanding of information processing on the cellular level, but how the detailed properties of individual neurons give rise to large-scale behavior remains unclear. Here, we present a model of the hippocampal network based on observed biophysical properties of hippocampal and entorhinal cortical neurons. We assembled our model to simulate spatial alternation, a task that requires memory of the previous path through the environment for correct selection of the current path to a reward site. The convergence of inputs from entorhinal cortex and hippocampal region CA3 onto CA1 pyramidal cells make them potentially important for integrating information about place and temporal context on the network level. Our model shows how place and temporal context information might be combined in CA1 pyramidal neurons to give rise to splitter cells, which fire selectively based on a combination of place and temporal context. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical basis of information processing in the hippocampus.'),
(83793, 2007, 'plos', 'The Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism', 'Wilkins, A Katharina|Barton, Paul I|Tidor, Bruce', 'Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 20, 'Animals|Biological Clocks|Computer Simulation|Feedback|Humans|Models, Biological|Nuclear Proteins|Oscillometry|Period Circadian Proteins|Periodicity|Signal Transduction|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030242', '18085817', 'Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the Per2 loop, was uniquely identified as most responsible for setting the period of oscillation, none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases CK1delta and CK1varepsilon were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data.'),
(83794, 2007, 'plos', 'Comparative genomics search for losses of long-established genes on the human lineage', 'Zhu, Jingchun|Sanborn, J Zachary|Diekhans, Mark|Lowe, Craig B|Pringle, Tom H|Haussler, David', 'Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 75, 'Animals|Biological Evolution|Chromosome Mapping|DNA Mutational Analysis|Dogs|Evolution, Molecular|Gene Deletion|Genetic Variation|Genome, Human|Genomics|Humans|Mice|Pseudogenes', 'Journal Article', '10.1371/journal.pcbi.0030247', '18085818', 'Taking advantage of the complete genome sequences of several mammals, we developed a novel method to detect losses of well-established genes in the human genome through syntenic mapping of gene structures between the human, mouse, and dog genomes. Unlike most previous genomic methods for pseudogene identification, this analysis is able to differentiate losses of well-established genes from pseudogenes formed shortly after segmental duplication or generated via retrotransposition. Therefore, it enables us to find genes that were inactivated long after their birth, which were likely to have evolved nonredundant biological functions before being inactivated. The method was used to look for gene losses along the human lineage during the approximately 75 million years (My) since the common ancestor of primates and rodents (the euarchontoglire crown group). We identified 26 losses of well-established genes in the human genome that were all lost at least 50 My after their birth. Many of them were previously characterized pseudogenes in the human genome, such as GULO and UOX. Our methodology is highly effective at identifying losses of single-copy genes of ancient origin, allowing us to find a few well-known pseudogenes in the human genome missed by previous high-throughput genome-wide studies. In addition to confirming previously known gene losses, we identified 16 previously uncharacterized human pseudogenes that are definitive losses of long-established genes. Among them is ACYL3, an ancient enzyme present in archaea, bacteria, and eukaryotes, but lost approximately 6 to 8 Mya in the ancestor of humans and chimps. Although losses of well-established genes do not equate to adaptive gene losses, they are a useful proxy to use when searching for such genetic changes. This is especially true for adaptive losses that occurred more than 250,000 years ago, since any genetic evidence of the selective sweep indicative of such an event has been erased.'),
(83795, 2007, 'plos', 'Animal cell differentiation patterns suppress somatic evolution', 'Pepper, John W|Sprouffske, Kathleen|Maley, Carlo C', 'Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona, United States of America. jpepper1@email.arizona|Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona, United States of America. jpepper1@email.arizona|Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona, United States of America. jpepper1@email.arizona', 'United States|United States|United States', 48, 'Biological Evolution|Cell Communication|Cell Differentiation|Cell Division|Cell Proliferation|Cell Size|Cell Survival|Computer Simulation|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.0030250', '18085819', 'Cell differentiation in multicellular organisms has the obvious function during development of creating new cell types. However, in long-lived organisms with extensive cell turnover, cell differentiation often continues after new cell types are no longer needed or produced. Here, we address the question of why this is true. It is believed that multicellular organisms could not have arisen or been evolutionarily stable without possessing mechanisms to suppress somatic selection among cells within organisms, which would otherwise disrupt organismal integrity. Here, we propose that one such mechanism is a specific pattern of ongoing cell differentiation commonly found in metazoans with cell turnover, which we call serial differentiation. This pattern involves a sequence of differentiation stages, starting with self-renewing somatic stem cells and proceeding through several (non-self-renewing) transient amplifying cell stages before ending with terminally differentiated cells. To test the hypothesis that serial differentiation can suppress somatic evolution, we used an agent-based computer simulation of cell population dynamics and evolution within tissues. The results indicate that, relative to other, simpler patterns, tissues organized into serial differentiation experience lower rates of detrimental cell-level evolution. Self-renewing cell populations are susceptible to somatic evolution, while those that are not self-renewing are not. We find that a mutation disrupting differentiation can create a new self-renewing cell population that is vulnerable to somatic evolution. These results are relevant not only to understanding the evolutionary origins of multicellularity, but also the causes of pathologies such as cancer and senescence in extant metazoans, including humans.'),
(83796, 2007, 'plos', 'Operating regimes of signaling cycles: statics, dynamics, and noise filtering', 'Gomez-Uribe, Carlos|Verghese, George C|Mirny, Leonid A', 'Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 79, 'Adaptation, Physiological|Algorithms|Amino Acid Sequence|Animals|Biological Clocks|Computer Simulation|Feedback|Humans|Kinetics|Models, Biological|Models, Statistical|Molecular Sequence Data|Proteome|Signal Processing, Computer-Assisted|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030246', '18159939', 'A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylation in MAPK cascades). Our paper explores the kind of information processing and filtering that can be accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal (ultrasensitive) input-output characteristic in a certain steady-state regime. Here, we systematically study the cycles steady-state behavior and its response to time-varying stimuli. We demonstrate that the cycle can actually operate in four different regimes, each with its specific input-output characteristics. These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions. We invoke experimental data that suggest the possibility of signaling cycles operating in one of the new regimes. We then consider the cycles dynamic behavior, which has so far been relatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act--in all four regimes--as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover, the cutoff frequency can be adjusted by the cell. Numerical simulations show that our analytical results hold well even for noise of large amplitude. We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways.'),
(83797, 2007, 'plos', 'Determinants of protein abundance and translation efficiency in S cerevisiae', 'Tuller, Tamir|Kupiec, Martin|Ruppin, Eytan', 'School of Computer Science, Tel Aviv University, Tel Aviv, Israel. tamirtul@post.tau.ac.il|School of Computer Science, Tel Aviv University, Tel Aviv, Israel. tamirtul@post.tau.ac.il|School of Computer Science, Tel Aviv University, Tel Aviv, Israel. tamirtul@post.tau.ac.il', 'Israel|Israel|Israel', 92, 'Algorithms|Computer Simulation|Gene Expression Profiling|Models, Genetic|Protein Biosynthesis|RNA, Messenger|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.0030248', '18159940', 'The translation efficiency of most Saccharomyces cerevisiae genes remains fairly constant across poor and rich growth media. This observation has led us to revisit the available data and to examine the potential utility of a protein abundance predictor in reinterpreting existing mRNA expression data. Our predictor is based on large-scale data of mRNA levels, the tRNA adaptation index, and the evolutionary rate. It attains a correlation of 0.76 with experimentally determined protein abundance levels on unseen data and successfully cross-predicts protein abundance levels in another yeast species (Schizosaccharomyces pombe). The predicted abundance levels of proteins in known S. cerevisiae complexes, and of interacting proteins, are significantly more coherent than their corresponding mRNA expression levels. Analysis of gene expression measurement experiments using the predicted protein abundance levels yields new insights that are not readily discernable when clustering the corresponding mRNA expression levels. Comparing protein abundance levels across poor and rich media, we find a general trend for homeostatic regulation where transcription and translation change in a reciprocal manner. This phenomenon is more prominent near origins of replications. Our analysis shows that in parallel to the adaptation occurring at the tRNA level via the codon bias, proteins do undergo a complementary adaptation at the amino acid level to further increase their abundance.'),
(83798, 2007, 'plos', 'Spike correlations in a songbird agree with a simple markov population model', 'Weber, Andrea P|Hahnloser, Richard H R', 'Institute of Neuroinformatics UZH/ETH Zurich, Zurich, Switzerland.|Institute of Neuroinformatics UZH/ETH Zurich, Zurich, Switzerland.', 'Switzerland|Switzerland', 12, 'Action Potentials|Algorithms|Animals|Biological Clocks|Brain|Computer Simulation|Markov Chains|Models, Neurological|Models, Statistical|Nerve Net|Neurons|Sleep|Songbirds|Statistics as Topic|Synaptic Transmission|Vocalization, Animal', 'Journal Article', '10.1371/journal.pcbi.0030249', '18159941', 'The relationships between neural activity at the single-cell and the population levels are of central importance for understanding neural codes. In many sensory systems, collective behaviors in large cell groups can be described by pairwise spike correlations. Here, we test whether in a highly specialized premotor system of songbirds, pairwise spike correlations themselves can be seen as a simple corollary of an underlying random process. We test hypotheses on connectivity and network dynamics in the motor pathway of zebra finches using a high-level population model that is independent of detailed single-neuron properties. We assume that neural population activity evolves along a finite set of states during singing, and that during sleep population activity randomly switches back and forth between song states and a single resting state. Individual spike trains are generated by associating with each of the population states a particular firing mode, such as bursting or tonic firing. With an overall modification of one or two simple control parameters, the Markov model is able to reproduce observed firing statistics and spike correlations in different neuron types and behavioral states. Our results suggest that song- and sleep-related firing patterns are identical on short time scales and result from random sampling of a unique underlying theme. The efficiency of our population model may apply also to other neural systems in which population hypotheses can be tested on recordings from small neuron groups.'),
(83799, 2007, 'plos', 'The long and thorny road to publication in quality journals', 'Erren, Thomas C', 'Institute of Neuroinformatics UZH/ETH Zurich, Zurich, Switzerland.', 'Switzerland', 2, 'Editorial Policies|Peer Review, Research|Periodicals as Topic|Publishing|Research|Writing', 'Comment', '10.1371/journal.pcbi.0030251', '18166071', '-'),
(83800, 2007, 'plos', 'Social interactions in myxobacterial swarming', 'Wu, Yilin|Jiang, Yi|Kaiser, Dale|Alber, Mark', 'Department of Physics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Physics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Physics, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Physics, University of Notre Dame, Notre Dame, Indiana, United States of America.', 'India|India|India|India', 40, 'Bacterial Adhesion|Cell Communication|Chemotaxis|Computer Simulation|Models, Biological|Motion|Myxococcus', 'Journal Article', '10.1371/journal.pcbi.0030253', '18166072', 'Swarming, a collective motion of many thousands of cells, produces colonies that rapidly spread over surfaces. In this paper, we introduce a cell-based model to study how interactions between neighboring cells facilitate swarming. We chose to study Myxococcus xanthus, a species of myxobacteria, because it swarms rapidly and has well-defined cell-cell interactions mediated by type IV pili and by slime trails. The aim of this paper is to test whether the cell contact interactions, which are inherent in pili-based S motility and slime-based A motility, are sufficient to explain the observed expansion of wild-type swarms. The simulations yield a constant rate of swarm expansion, which has been observed experimentally. Also, the model is able to quantify the contributions of S motility and A motility to swarming. Some pathogenic bacteria spread over infected tissue by swarming. The model described here may shed some light on their colonization process.'),
(83801, 2007, 'plos', 'Analysis of sequence conservation at nucleotide resolution', 'Asthana, Saurabh|Roytberg, Mikhail|Stamatoyannopoulos, John|Sunyaev, Shamil', 'Division of Genetics, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 50, 'Base Pair Mismatch|Base Sequence|Chromosome Mapping|Conserved Sequence|Evolution, Molecular|Genome, Human|Humans|Molecular Sequence Data|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0030254', '18166073', 'One of the major goals of comparative genomics is to understand the evolutionary history of each nucleotide in the human genome sequence, and the degree to which it is under selective pressure. Ascertainment of selective constraint at nucleotide resolution is particularly important for predicting the functional significance of human genetic variation and for analyzing the sequence substructure of cis-regulatory sequences and other functional elements. Current methods for analysis of sequence conservation are focused on delineation of conserved regions comprising tens or even hundreds of consecutive nucleotides. We therefore developed a novel computational approach designed specifically for scoring evolutionary conservation at individual base-pair resolution. Our approach estimates the rate at which each nucleotide position is evolving, computes the probability of neutrality given this rate estimate, and summarizes the result in a Sequence CONservation Evaluation (SCONE) score. We computed SCONE scores in a continuous fashion across 1% of the human genome for which high-quality sequence information from up to 23 genomes are available. We show that SCONE scores are clearly correlated with the allele frequency of human polymorphisms in both coding and noncoding regions. We find that the majority of noncoding conserved nucleotides lie outside of longer conserved elements predicted by other conservation analyses, and are experiencing ongoing selection in modern humans as evident from the allele frequency spectrum of human polymorphism. We also applied SCONE to analyze the distribution of conserved nucleotides within functional regions. These regions are markedly enriched in individually conserved positions and short (<15 bp) conserved chunks. Our results collectively suggest that the majority of functionally important noncoding conserved positions are highly fragmented and reside outside of canonically defined long conserved noncoding sequences. A small subset of these fragmented positions may be identified with high confidence.'),
(83802, 2007, 'plos', 'Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model', 'Filipe, João A N|Riley, Eleanor M|Drakeley, Christopher J|Sutherland, Colin J|Ghani, Azra C', 'Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 106, 'Age Distribution|Aging|Computer Simulation|Disease Outbreaks|Disease Susceptibility|Gambia|Humans|Immunity, Innate|Malaria|Models, Immunological|Tanzania', 'Journal Article', '10.1371/journal.pcbi.0030255', '18166074', 'Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways (immunity functions): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data, a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.'),
(83803, 2007, 'plos', 'Density dependence triggers runaway selection of reduced senescence', 'Seymour, Robert M|Doncaster, C Patrick', 'Department of Mathematics, University College London, London, United Kingdom.|Department of Mathematics, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 15, 'Age Distribution|Aging|Animals|Computer Simulation|Humans|Longevity|Models, Biological|Mortality|Population Density|Population Dynamics|Selection, Genetic|Survival Rate', 'Journal Article', '10.1371/journal.pcbi.0030256', '18166075', 'In the presence of exogenous mortality risks, future reproduction by an individual is worth less than present reproduction to its fitness. Senescent aging thus results inevitably from transferring net fertility into younger ages. Some long-lived organisms appear to defy theory, however, presenting negligible senescence (e.g., hydra) and extended lifespans (e.g., Bristlecone Pine). Here, we investigate the possibility that the onset of vitality loss can be delayed indefinitely, even accepting the abundant evidence that reproduction is intrinsically costly to survival. For an environment with constant hazard, we establish that natural selection itself contributes to increasing density-dependent recruitment losses. We then develop a generalized model of accelerating vitality loss for analyzing fitness optima as a tradeoff between compression and spread in the age profile of net fertility. Across a realistic spectrum of senescent age profiles, density regulation of recruitment can trigger runaway selection for ever-reducing senescence. This novel prediction applies without requirement for special life-history characteristics such as indeterminate somatic growth or increasing fecundity with age. The evolution of nonsenescence from senescence is robust to the presence of exogenous adult mortality, which tends instead to increase the age-independent component of vitality loss. We simulate examples of runaway selection leading to negligible senescence and even intrinsic immortality.'),
(83804, 2007, 'plos', 'Computational biology in Argentina', 'Bassi, Sebastian|González, Virginia|Parisi, Gustavo', 'Universidad Nacional de Quilmes, Buenos Aires, Argentina. sbassi@genesdigitales.com|Universidad Nacional de Quilmes, Buenos Aires, Argentina. sbassi@genesdigitales.com|Universidad Nacional de Quilmes, Buenos Aires, Argentina. sbassi@genesdigitales.com', 'Argentina|Argentina|Argentina', 4, 'Argentina|Computational Biology|Genomics|Research|Universities', 'Journal Article', '10.1371/journal.pcbi.0030257', '18166076', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83805, 2008, 'plos', 'Chemotaxis in Escherichia coli: a molecular model for robust precise adaptation', 'Hansen, Clinton H|Endres, Robert G|Wingreen, Ned S', 'Department of Physics, Princeton University, Princeton, New Jersey, United States of America.|Department of Physics, Princeton University, Princeton, New Jersey, United States of America.|Department of Physics, Princeton University, Princeton, New Jersey, United States of America.', 'Jersey|Jersey|Jersey', 75, 'Adaptation, Physiological|Bacterial Proteins|Chemotaxis|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Methyltransferases|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.0040001', '18179279', 'The chemotaxis system in the bacterium Escherichia coli is remarkably sensitive to small relative changes in the concentrations of multiple chemical signals over a broad range of ambient concentrations. Interactions among receptors are crucial to this sensitivity as is precise adaptation, the return of chemoreceptor activity to prestimulus levels in a constant chemoeffector environment. Precise adaptation relies on methylation and demethylation of chemoreceptors by the enzymes CheR and CheB, respectively. Experiments indicate that when transiently bound to one receptor, these enzymes act on small assistance neighborhoods (AN) of five to seven receptor homodimers. In this paper, we model a strongly coupled complex of receptors including dynamic CheR and CheB acting on ANs. The model yields sensitive response and precise adaptation over several orders of magnitude of attractant concentrations and accounts for different responses to aspartate and serine. Within the model, we explore how the precision of adaptation is limited by small AN size as well as by CheR and CheB kinetics (including dwell times, saturation, and kinetic differences among modification sites) and how these kinetics contribute to noise in complex activity. The robustness of our dynamic model for precise adaptation is demonstrated by randomly varying biochemical parameters.'),
(83806, 2008, 'plos', 'Genes and (common) pathways underlying drug addiction', 'Li, Chuan-Yun|Mao, Xizeng|Wei, Liping', 'Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, Peoples Republic of China.|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, Peoples Republic of China.', 'China|China|China', 0, 'Biomarkers|Calcium-Calmodulin-Dependent Protein Kinase Type 2|Databases, Protein|Humans|Models, Biological|Proteome|Signal Transduction|Substance-Related Disorders', 'Journal Article', '10.1371/journal.pcbi.0040002', '18179280', 'Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction, however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.'),
(83807, 2008, 'plos', 'Noise propagation and signaling sensitivity in biological networks: a role for positive feedback', 'Hornung, Gil|Barkai, Naama', 'Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel', 126, 'Adaptation, Physiological|Computer Simulation|Feedback|Models, Biological|Models, Statistical|Proteome|Signal Transduction|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0040008', '18179281', 'Interactions between genes and proteins are crucial for efficient processing of internal or external signals, but this connectivity also amplifies stochastic fluctuations by propagating noise between components. Linear (unbranched) cascades were shown to exhibit an interplay between the sensitivity to changes in input signals and the ability to buffer noise. We searched for biological circuits that can maintain signaling sensitivity while minimizing noise propagation, focusing on cases where the noise is characterized by rapid fluctuations. Negative feedback can buffer this type of noise, but this buffering comes at the expense of an even greater reduction in signaling sensitivity. By systematically analyzing three-component circuits, we identify positive feedback as a central motif allowing for the buffering of propagated noise while maintaining sensitivity to long-term changes in input signals. We show analytically that noise reduction in the presence of positive feedback results from improved averaging of rapid fluctuations over time, and discuss in detail a particular implementation in the control of nutrient homeostasis in yeast. As the design of biological networks optimizes for multiple constraints, positive feedback can be used to improve sensitivity without a compromise in the ability to buffer propagated noise.'),
(83808, 2008, 'plos', 'A generic mechanism for adaptive growth rate regulation', 'Furusawa, Chikara|Kaneko, Kunihiko', 'Department of Bioinformatics Engineering, Graduate School of Information Science and Technology, Osaka University, Suita, Osaka, Japan. furusawa@ist.osaka-u.ac.jp|Department of Bioinformatics Engineering, Graduate School of Information Science and Technology, Osaka University, Suita, Osaka, Japan. furusawa@ist.osaka-u.ac.jp', 'Japan|Japan', 0, 'Cell Proliferation|Escherichia coli|Escherichia coli Proteins|Feedback|Gene Expression Regulation, Bacterial|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0040003', '18193939', 'How can a microorganism adapt to a variety of environmental conditions despite the existence of a limited number of signal transduction mechanisms? We show that for any growing cells whose gene expression fluctuate stochastically, the adaptive cellular state is inevitably selected by noise, even without a specific signal transduction network for it. In general, changes in protein concentration in a cell are given by its synthesis minus dilution and degradation, both of which are proportional to the rate of cell growth. In an adaptive state with a higher growth speed, both terms are large and balanced. Under the presence of noise in gene expression, the adaptive state is less affected by stochasticity since both the synthesis and dilution terms are large, while for a nonadaptive state both the terms are smaller so that cells are easily kicked out of the original state by noise. Hence, escape time from a cellular state and the cellular growth rate are negatively correlated. This leads to a selection of adaptive states with higher growth rates, and model simulations confirm this selection to take place in general. The results suggest a general form of adaptation that has never been brought to light--a process that requires no specific mechanisms for sensory adaptation. The present scheme may help explain a wide range of cellular adaptive responses including the metabolic flux optimization for maximal cell growth.'),
(83809, 2008, 'plos', 'Evolution and selection in yeast promoters: analyzing the combined effect of diverse transcription factor binding sites', 'Raijman, Daniela|Shamir, Ron|Tanay, Amos', 'School of Computer Science, Tel Aviv University, Ramat Aviv, Israel.|School of Computer Science, Tel Aviv University, Ramat Aviv, Israel.|School of Computer Science, Tel Aviv University, Ramat Aviv, Israel.', 'Israel|Israel|Israel', 0, 'Base Sequence|Binding Sites|Computer Simulation|Evolution, Molecular|Genetic Variation|Genome, Fungal|Models, Genetic|Molecular Sequence Data|Promoter Regions, Genetic|Protein Binding|Saccharomyces cerevisiae|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0040007', '18193940', 'In comparative genomics one analyzes jointly evolutionarily related species in order to identify conserved and diverged sequences and to infer their function. While such studies enabled the detection of conserved sequences in large genomes, the evolutionary dynamics of regulatory regions as a whole remain poorly understood. Here we present a probabilistic model for the evolution of promoter regions in yeast, combining the effects of regulatory interactions of many different transcription factors. The model expresses explicitly the selection forces acting on transcription factor binding sites in the context of a dynamic evolutionary process. We develop algorithms to compute likelihood and to learn de novo collections of transcription factor binding motifs and their selection parameters from alignments. Using the new techniques, we examine the evolutionary dynamics in Saccharomyces species promoters. Analyses of an evolutionary model constructed using all known transcription factor binding motifs and of a model learned from the data automatically reveal relatively weak selection on most binding sites. Moreover, according to our estimates, strong binding sites are constraining only a fraction of the yeast promoter sequence that is under selection. Our study demonstrates how complex evolutionary dynamics in noncoding regions emerges from formalization of the evolutionary consequences of known regulatory mechanisms.'),
(83810, 2008, 'plos', 'Matt: local flexibility aids protein multiple structure alignment', 'Menke, Matthew|Berger, Bonnie|Cowen, Lenore', 'Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 155, 'Algorithms|Amino Acid Sequence|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Software', 'Journal Article', '10.1371/journal.pcbi.0040010', '18193941', 'Even when there is agreement on what measure a protein multiple structure alignment should be optimizing, finding the optimal alignment is computationally prohibitive. One approach used by many previous methods is aligned fragment pair chaining, where short structural fragments from all the proteins are aligned against each other optimally, and the final alignment chains these together in geometrically consistent ways. Ye and Godzik have recently suggested that adding geometric flexibility may help better model protein structures in a variety of contexts. We introduce the program Matt (Multiple Alignment with Translations and Twists), an aligned fragment pair chaining algorithm that, in intermediate steps, allows local flexibility between fragments: small translations and rotations are temporarily allowed to bring sets of aligned fragments closer, even if they are physically impossible under rigid body transformations. After a dynamic programming assembly guided by these bent alignments, geometric consistency is restored in the final step before the alignment is output. Matt is tested against other recent multiple protein structure alignment programs on the popular Homstrad and SABmark benchmark datasets. Matts global performance is competitive with the other programs on Homstrad, but outperforms the other programs on SABmark, a benchmark of multiple structure alignments of proteins with more distant homology. On both datasets, Matt demonstrates an ability to better align the ends of alpha-helices and beta-strands, an important characteristic of any structure alignment program intended to help construct a structural template library for threading approaches to the inverse protein-folding problem. The related question of whether Matt alignments can be used to distinguish distantly homologous structure pairs from pairs of proteins that are not homologous is also considered. For this purpose, a p-value score based on the length of the common core and average root mean squared deviation (RMSD) of Matt alignments is shown to largely separate decoys from homologous protein structures in the SABmark benchmark dataset. We postulate that Matts strong performance comes from its ability to model proteins in different conformational states and, perhaps even more important, its ability to model backbone distortions in more distantly related proteins.'),
(83811, 2008, 'plos', 'In silico detection of sequence variations modifying transcriptional regulation', 'Andersen, Malin C|Engström, Pär G|Lithwick, Stuart|Arenillas, David|Eriksson, Per|Lenhard, Boris|Wasserman, Wyeth W|Odeberg, Jacob', 'Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.|Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 0, 'Algorithms|Binding Sites|Genetic Variation|Internet|Polymorphism, Single Nucleotide|Protein Binding|Regulatory Elements, Transcriptional|Sequence Analysis, DNA|Software|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0040005', '18208319', 'Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation.'),
(83812, 2008, 'plos', 'Neuronal firing sensitivity to morphologic and active membrane parameters', 'Weaver, Christina M|Wearne, Susan L', 'Laboratory of Biomathematics, Mount Sinai School of Medicine, New York, New York, United States of America. christina.weaver@mssm.edu|Laboratory of Biomathematics, Mount Sinai School of Medicine, New York, New York, United States of America. christina.weaver@mssm.edu', 'United States|United States', 50, 'Action Potentials|Animals|Cell Membrane|Computer Simulation|Differential Threshold|Goldfish|Membrane Potentials|Models, Neurological|Nerve Net|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0040011', '18208320', 'Both the excitability of a neurons membrane, driven by active ion channels, and dendritic morphology contribute to neuronal firing dynamics, but the relative importance and interactions between these features remain poorly understood. Recent modeling studies have shown that different combinations of active conductances can evoke similar firing patterns, but have neglected how morphology might contribute to homeostasis. Parameterizing the morphology of a cylindrical dendrite, we introduce a novel application of mathematical sensitivity analysis that quantifies how dendritic length, diameter, and surface area influence neuronal firing, and compares these effects directly against those of active parameters. The method was applied to a model of neurons from goldfish Area II. These neurons exhibit, and likely contribute to, persistent activity in eye velocity storage, a simple model of working memory. We introduce sensitivity landscapes, defined by local sensitivity analyses of firing rate and gain to each parameter, performed globally across the parameter space. Principal directions over which sensitivity to all parameters varied most revealed intrinsic currents that most controlled model output. We found domains where different groups of parameters had the highest sensitivities, suggesting that interactions within each group shaped firing behaviors within each specific domain. Application of our method, and its characterization of which models were sensitive to general morphologic features, will lead to advances in understanding how realistic morphology participates in functional homeostasis. Significantly, we can predict which active conductances, and how many of them, will compensate for a given age- or development-related structural change, or will offset a morphologic perturbation resulting from trauma or neurodegenerative disorder, to restore normal function. Our method can be adapted to analyze any computational model. Thus, sensitivity landscapes, and the quantitative predictions they provide, can give new insight into mechanisms of homeostasis in any biological system.'),
(83813, 2008, 'plos', 'Superhelical destabilization in regulatory regions of stress response genes', 'Wang, Huiquan|Benham, Craig J', 'UC Davis Genome Center, University of California Davis, Davis, California, United States of America.|UC Davis Genome Center, University of California Davis, Davis, California, United States of America.', 'United States|United States', 0, 'Computer Simulation|DNA Damage|DNA, Bacterial|DNA-Binding Proteins|Heat Shock Transcription Factors|Models, Chemical|Models, Genetic|Models, Molecular|Nucleic Acid Conformation|Regulatory Sequences, Nucleic Acid|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0040017', '18208321', 'Stress-induced DNA duplex destabilization (SIDD) analysis exploits the known structural and energetic properties of DNA to predict sites that are susceptible to strand separation under negative superhelical stress. When this approach was used to calculate the SIDD profile of the entire Escherichia coli K12 genome, it was found that strongly destabilized sites occur preferentially in intergenic regions that are either known or inferred to contain promoters, but rarely occur in coding regions. Here, we investigate whether the genes grouped in different functional categories have characteristic SIDD properties in their upstream flanks. We report that strong SIDD sites in the E. coli K12 genome are statistically significantly overrepresented in the upstream regions of genes encoding transcriptional regulators. In particular, the upstream regions of genes that directly respond to physiological and environmental stimuli are more destabilized than are those regions of genes that are not involved in these responses. Moreover, if a pathway is controlled by a transcriptional regulator whose gene has a destabilized 5 flank, then the genes (operons) in that pathway also usually contain strongly destabilized SIDD sites in their 5 flanks. We observe this statistically significant association of SIDD sites with upstream regions of genes functioning in transcription in 38 of 43 genomes of free-living bacteria, but in only four of 18 genomes of endosymbionts or obligate parasitic bacteria. These results suggest that strong SIDD sites 5 to participating genes may be involved in transcriptional responses to environmental changes, which are known to transiently alter superhelicity. We propose that these SIDD sites are active and necessary participants in superhelically mediated regulatory mechanisms governing changes in the global pattern of gene expression in prokaryotes in response to physiological or environmental changes.'),
(83814, 2008, 'plos', 'A quantitative study of the division cycle of Caulobacter crescentus stalked cells', 'Li, Shenghua|Brazhnik, Paul|Sobral, Bruno|Tyson, John J', 'Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.|Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.', 'United States|United States|United States|United States', 37, 'Caulobacter crescentus|Cell Cycle|Cell Cycle Proteins|Computer Simulation|Models, Biological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0040009', '18225942', 'Progression of a cell through the division cycle is tightly controlled at different steps to ensure the integrity of genome replication and partitioning to daughter cells. From published experimental evidence, we propose a molecular mechanism for control of the cell division cycle in Caulobacter crescentus. The mechanism, which is based on the synthesis and degradation of three master regulator proteins (CtrA, GcrA, and DnaA), is converted into a quantitative model, in order to study the temporal dynamics of these and other cell cycle proteins. The model accounts for important details of the physiology, biochemistry, and genetics of cell cycle control in stalked C. crescentus cell. It reproduces protein time courses in wild-type cells, mimics correctly the phenotypes of many mutant strains, and predicts the phenotypes of currently uncharacterized mutants. Since many of the proteins involved in regulating the cell cycle of C. crescentus are conserved among many genera of alpha-proteobacteria, the proposed mechanism may be applicable to other species of importance in agriculture and medicine.'),
(83815, 2008, 'plos', 'Genomic sequence is highly predictive of local nucleosome depletion', 'Yuan, Guo-Cheng|Liu, Jun S', 'Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu', 'United States|United States', 0, 'Chromosome Mapping|Computer Simulation|Conserved Sequence|Genome|Humans|Models, Genetic|Models, Statistical|Nucleosomes|Regulatory Sequences, Nucleic Acid|Saccharomyces cerevisiae|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0040013', '18225943', 'The regulation of DNA accessibility through nucleosome positioning is important for transcription control. Computational models have been developed to predict genome-wide nucleosome positions from DNA sequences, but these models consider only nucleosome sequences, which may have limited their power. We developed a statistical multi-resolution approach to identify a sequence signature, called the N-score, that distinguishes nucleosome binding DNA from non-nucleosome DNA. This new approach has significantly improved the prediction accuracy. The sequence information is highly predictive for local nucleosome enrichment or depletion, whereas predictions of the exact positions are only modestly more accurate than a null model, suggesting the importance of other regulatory factors in fine-tuning the nucleosome positions. The N-score in promoter regions is negatively correlated with gene expression levels. Regulatory elements are enriched in low N-score regions. While our model is derived from yeast data, the N-score pattern computed from this model agrees well with recent high-resolution protein-binding data in human.'),
(83816, 2008, 'plos', 'Coping with viral diversity in HIV vaccine design: a response to Nickle et al', 'Fischer, Will|Liao, H X|Haynes, Barton F|Letvin, Norman L|Korber, Bette', 'Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America. gcyuan@jimmy.harvard.edu', 'United States|United States|United States|United States|United States', 0, 'AIDS Vaccines|Antigenic Variation|Drug Design|Epitope Mapping|Ethanolamines|Gene Products, nef|Genetic Variation|nef Gene Products, Human Immunodeficiency Virus', 'Comment', '10.1371/journal.pcbi.0040015', '18225944', '-'),
(83817, 2008, 'plos', 'Mechanics of channel gating of the nicotinic acetylcholine receptor', 'Liu, Xinli|Xu, Yechun|Li, Honglin|Wang, Xicheng|Jiang, Hualiang|Barrantes, Francisco J', 'Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.|Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.|Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.|Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.|Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.|Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.', 'China|China|China|China|China|China', 0, '1,2-Dipalmitoylphosphatidylcholine|Biomechanical Phenomena|Computer Simulation|Ion Channel Gating|Lipid Bilayers|Membrane Fluidity|Models, Chemical|Models, Molecular|Motion|Porosity|Protein Conformation|Receptors, Nicotinic', 'Journal Article', '10.1371/journal.pcbi.0040019', '18225945', 'The nicotinic acetylcholine receptor (nAChR) is a key molecule involved in the propagation of signals in the central nervous system and peripheral synapses. Although numerous computational and experimental studies have been performed on this receptor, the structural dynamics of the receptor underlying the gating mechanism is still unclear. To address the mechanical fundamentals of nAChR gating, both conventional molecular dynamics (CMD) and steered rotation molecular dynamics (SRMD) simulations have been conducted on the cryo-electron microscopy (cryo-EM) structure of nAChR embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer and water molecules. A 30-ns CMD simulation revealed a collective motion amongst C-loops, M1, and M2 helices. The inward movement of C-loops accompanying the shrinking of acetylcholine (ACh) binding pockets induced an inward and upward motion of the outer beta-sheet composed of beta9 and beta10 strands, which in turn causes M1 and M2 to undergo anticlockwise motions around the pore axis. Rotational motion of the entire receptor around the pore axis and twisting motions among extracellular (EC), transmembrane (TM), and intracellular MA domains were also detected by the CMD simulation. Moreover, M2 helices undergo a local twisting motion synthesized by their bending vibration and rotation. The hinge of either twisting motion or bending vibration is located at the middle of M2, possibly the gate of the receptor. A complementary twisting-to-open motion throughout the receptor was detected by a normal mode analysis (NMA). To mimic the pulsive action of ACh binding, nonequilibrium MD simulations were performed by using the SRMD method developed in one of our laboratories. The result confirmed all the motions derived from the CMD simulation and NMA. In addition, the SRMD simulation indicated that the channel may undergo an open-close (O <--> C) motion. The present MD simulations explore the structural dynamics of the receptor under its gating process and provide a new insight into the gating mechanism of nAChR at the atomic level.'),
(83818, 2008, 'plos', 'Getting started in text mining', 'Cohen, K Bretonnel|Hunter, Lawrence', 'University of Colorado School of Medicine, Center for Computational Pharmacology, UCHSC at Fitzsimons, Department of Pharmacology, Aurora, Colorado, United States of America. kevin.cohen@gmail.com|University of Colorado School of Medicine, Center for Computational Pharmacology, UCHSC at Fitzsimons, Department of Pharmacology, Aurora, Colorado, United States of America. kevin.cohen@gmail.com', 'United States|United States', 144, 'Algorithms|Artificial Intelligence|Database Management Systems|Databases, Bibliographic|Information Storage and Retrieval|Natural Language Processing|Periodicals as Topic', 'Journal Article', '10.1371/journal.pcbi.0040020', '18225946', '-'),
(83819, 2008, 'plos', 'Strategies for identifying RNA splicing regulatory motifs and predicting alternative splicing events', 'Holste, Dirk|Ohler, Uwe', 'Research Institute of Molecular Pathology, Austrian Academy of Sciences, Vienna, Austria. holste@imp.ac.at|Research Institute of Molecular Pathology, Austrian Academy of Sciences, Vienna, Austria. holste@imp.ac.at', 'Austria|Austria', 15, 'Algorithms|Models, Genetic|RNA Splice Sites|RNA, Messenger|Regulatory Sequences, Ribonucleic Acid|Sequence Analysis, RNA|Sequence Homology, Nucleic Acid|Software|Systems Integration|Untranslated Regions', 'Journal Article', '10.1371/journal.pcbi.0040021', '18225947', '-'),
(83820, 2008, 'plos', 'Co-regulation of metabolic genes is better explained by flux coupling than by network distance', 'Notebaart, Richard A|Teusink, Bas|Siezen, Roland J|Papp, Balázs', 'Center for Molecular and Biomolecular Informatics (NCMLS), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.|Center for Molecular and Biomolecular Informatics (NCMLS), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.|Center for Molecular and Biomolecular Informatics (NCMLS), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.|Center for Molecular and Biomolecular Informatics (NCMLS), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Computer Simulation|Escherichia coli|Escherichia coli Proteins|Gene Expression Regulation, Bacterial|Models, Biological|Multigene Family|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0040026', '18225949', 'To what extent can modes of gene regulation be explained by systems-level properties of metabolic networks? Prior studies on co-regulation of metabolic genes have mainly focused on graph-theoretical features of metabolic networks and demonstrated a decreasing level of co-expression with increasing network distance, a naïve, but widely used, topological index. Others have suggested that static graph representations can poorly capture dynamic functional associations, e.g., in the form of dependence of metabolic fluxes across genes in the network. Here, we systematically tested the relative importance of metabolic flux coupling and network position on gene co-regulation, using a genome-scale metabolic model of Escherichia coli. After validating the computational method with empirical data on flux correlations, we confirm that genes coupled by their enzymatic fluxes not only show similar expression patterns, but also share transcriptional regulators and frequently reside in the same operon. In contrast, we demonstrate that network distance per se has relatively minor influence on gene co-regulation. Moreover, the type of flux coupling can explain refined properties of the regulatory network that are ignored by simple graph-theoretical indices. Our results underline the importance of studying functional states of cellular networks to define physiologically relevant associations between genes and should stimulate future developments of novel functional genomic tools.'),
(83821, 2008, 'plos', 'Why is real-world visual object recognition hard?', 'Pinto, Nicolas|Cox, David D|DiCarlo, James J', 'McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 0, 'Artificial Intelligence|Biomimetics|Computer Simulation|Humans|Image Interpretation, Computer-Assisted|Models, Biological|Pattern Recognition, Visual', 'Journal Article', '10.1371/journal.pcbi.0040027', '18225950', 'Progress in understanding the brain mechanisms underlying vision requires the construction of computational models that not only emulate the brains anatomy and physiology, but ultimately match its performance on visual tasks. In recent years, natural images have become popular in the study of vision and have been used to show apparently impressive progress in building such models. Here, we challenge the use of uncontrolled natural images in guiding that progress. In particular, we show that a simple V1-like model--a neuroscientists null model, which should perform poorly at real-world visual object recognition tasks--outperforms state-of-the-art object recognition systems (biologically inspired and otherwise) on a standard, ostensibly natural image recognition test. As a counterpoint, we designed a simpler recognition test to better span the real-world variation in object pose, position, and scale, and we show that this test correctly exposes the inadequacy of the V1-like model. Taken together, these results demonstrate that tests based on uncontrolled natural images can be seriously misleading, potentially guiding progress in the wrong direction. Instead, we reexamine what it means for images to be natural and argue for a renewed focus on the core problem of object recognition--real-world image variation.'),
(83822, 2007, 'plos', 'Brightness and darkness as perceptual dimensions', 'Vladusich, Tony|Lucassen, Marcel P|Cornelissen, Frans W', 'Laboratory of Experimental Ophthalmology & BCN NeuroImaging Centre, School of Behavioural and Cognitive Neurosciences, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. thevlad@bu.edu|Laboratory of Experimental Ophthalmology & BCN NeuroImaging Centre, School of Behavioural and Cognitive Neurosciences, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. thevlad@bu.edu|Laboratory of Experimental Ophthalmology & BCN NeuroImaging Centre, School of Behavioural and Cognitive Neurosciences, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. thevlad@bu.edu', 'Netherlands|Netherlands|Netherlands', 24, 'Adult|Contrast Sensitivity|Darkness|Female|Humans|Light|Male|Models, Neurological|Perceptual Closure|Photic Stimulation|Task Performance and Analysis|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.0030179', '18237226', 'A common-sense assumption concerning visual perception states that brightness and darkness cannot coexist at a given spatial location. One corollary of this assumption is that achromatic colors, or perceived grey shades, are contained in a one-dimensional (1-D) space varying from bright to dark. The results of many previous psychophysical studies suggest, by contrast, that achromatic colors are represented as points in a color space composed of two or more perceptual dimensions. The nature of these perceptual dimensions, however, presently remains unclear. Here we provide direct evidence that brightness and darkness form the dimensions of a two-dimensional (2-D) achromatic color space. This color space may play a role in the representation of object surfaces viewed against natural backgrounds, which simultaneously induce both brightness and darkness signals. Our 2-D model generalizes to the chromatic dimensions of color perception, indicating that redness and greenness (blueness and yellowness) also form perceptual dimensions. Collectively, these findings suggest that human color space is composed of six dimensions, rather than the conventional three.'),
(83823, 2008, 'plos', 'Serotonin, inhibition, and negative mood', 'Dayan, Peter|Huys, Quentin J M', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Brain|Depression|Humans|Inhibition (Psychology)|Learning|Models, Neurological|Models, Psychological|Serotonin', 'Journal Article', '10.1371/journal.pcbi.0040004', '18248087', 'Pavlovian predictions of future aversive outcomes lead to behavioral inhibition, suppression, and withdrawal. There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two. In the context of a highly simplified model of chains of affectively charged thoughts, we interpret the combined effects of serotonin in terms of pruning a tree of possible decisions, (i.e., eliminating those choices that have low or negative expected outcomes). We show how a drop in behavioral inhibition, putatively resulting from an experimentally or psychiatrically influenced drop in serotonin, could result in unexpectedly large negative prediction errors and a significant aversive shift in reinforcement statistics. We suggest an interpretation of this finding that helps dissolve the apparent contradiction between the fact that inhibition of serotonin reuptake is the first-line treatment of depression, although serotonin itself is most strongly linked with aversive rather than appetitive outcomes and predictions.'),
(83824, 2008, 'plos', 'Predicting the receptive range of olfactory receptors', 'Haddad, Rafi|Carmel, Liran|Sobel, Noam|Harel, David', 'Department of Computer Science and Applied Mathematics, The Weizmann Institute of Science, Rehovot, Israel. rhaddad@weizmann.ac.il|Department of Computer Science and Applied Mathematics, The Weizmann Institute of Science, Rehovot, Israel. rhaddad@weizmann.ac.il|Department of Computer Science and Applied Mathematics, The Weizmann Institute of Science, Rehovot, Israel. rhaddad@weizmann.ac.il|Department of Computer Science and Applied Mathematics, The Weizmann Institute of Science, Rehovot, Israel. rhaddad@weizmann.ac.il', 'Israel|Israel|Israel|Israel', 11, 'Animals|Computer Simulation|Humans|Models, Neurological|Odorants|Olfactory Receptor Neurons|Receptors, Odorant|Sensory Thresholds|Smell', 'Journal Article', '10.1371/journal.pcbi.0040018', '18248088', 'Although the family of genes encoding for olfactory receptors was identified more than 15 years ago, the difficulty of functionally expressing these receptors in an heterologous system has, with only some exceptions, rendered the receptive range of given olfactory receptors largely unknown. Furthermore, even when successfully expressed, the task of probing such a receptor with thousands of odors/ligands remains daunting. Here we provide proof of concept for a solution to this problem. Using computational methods, we tune an electronic nose to the receptive range of an olfactory receptor. We then use this electronic nose to predict the receptors response to other odorants. Our method can be used to identify the receptive range of olfactory receptors, and can also be applied to other questions involving receptor-ligand interactions in non-olfactory settings.'),
(83825, 2008, 'plos', 'Evolution of complex modular biological networks', 'Hintze, Arend|Adami, Christoph', 'Keck Graduate Institute of Applied Life Sciences, Claremont, California, USA.|Keck Graduate Institute of Applied Life Sciences, Claremont, California, USA.', 'United States|United States', 110, 'Animals|Computer Simulation|Evolution, Molecular|Genetic Variation|Humans|Models, Genetic|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0040023', '18266463', 'Biological networks have evolved to be highly functional within uncertain environments while remaining extremely adaptable. One of the main contributors to the robustness and evolvability of biological networks is believed to be their modularity of function, with modules defined as sets of genes that are strongly interconnected but whose function is separable from those of other modules. Here, we investigate the in silico evolution of modularity and robustness in complex artificial metabolic networks that encode an increasing amount of information about their environment while acquiring ubiquitous features of biological, social, and engineering networks, such as scale-free edge distribution, small-world property, and fault-tolerance. These networks evolve in environments that differ in their predictability, and allow us to study modularity from topological, information-theoretic, and gene-epistatic points of view using new tools that do not depend on any preconceived notion of modularity. We find that for our evolved complex networks as well as for the yeast protein-protein interaction network, synthetic lethal gene pairs consist mostly of redundant genes that lie close to each other and therefore within modules, while knockdown suppressor gene pairs are farther apart and often straddle modules, suggesting that knockdown rescue is mediated by alternative pathways or modules. The combination of network modularity tools together with genetic interaction data constitutes a powerful approach to study and dissect the role of modularity in the evolution and function of biological networks.'),
(83826, 2008, 'plos', 'Computational and experimental analysis of redundancy in the central metabolism of Geobacter sulfurreducens', 'Segura, Daniel|Mahadevan, Radhakrishnan|Juárez, Katy|Lovley, Derek R', 'Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA.|Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA.|Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA.|Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA.', 'United States|United States|United States|United States', 0, 'Bacterial Proteins|Base Sequence|Computer Simulation|Gene Expression Regulation, Bacterial|Geobacter|Models, Biological|Molecular Sequence Data|Multienzyme Complexes|Signal Transduction', 'Comparative Study', '10.1371/journal.pcbi.0040036', '18266464', 'Previous model-based analysis of the metabolic network of Geobacter sulfurreducens suggested the existence of several redundant pathways. Here, we identified eight sets of redundant pathways that included redundancy for the assimilation of acetate, and for the conversion of pyruvate into acetyl-CoA. These equivalent pathways and two other sub-optimal pathways were studied using 5 single-gene deletion mutants in those pathways for the evaluation of the predictive capacity of the model. The growth phenotypes of these mutants were studied under 12 different conditions of electron donor and acceptor availability. The comparison of the model predictions with the resulting experimental phenotypes indicated that pyruvate ferredoxin oxidoreductase is the only activity able to convert pyruvate into acetyl-CoA. However, the results and the modeling showed that the two acetate activation pathways present are not only active, but needed due to the additional role of the acetyl-CoA transferase in the TCA cycle, probably reflecting the adaptation of these bacteria to acetate utilization. In other cases, the data reconciliation suggested additional capacity constraints that were confirmed with biochemical assays. The results demonstrate the need to experimentally verify the activity of key enzymes when developing in silico models of microbial physiology based on sequence-based reconstruction of metabolic networks.'),
(83827, 2008, 'plos', 'Filling-in and suppression of visual perception from context: a Bayesian account of perceptual biases by contextual influences', 'Zhaoping, Li|Jingling, Li', 'Department of Computer Science, University College London, United Kingdom. z.li@ucl.ac.uk|Department of Computer Science, University College London, United Kingdom. z.li@ucl.ac.uk', 'United Kingdom|United Kingdom', 14, 'Artifacts|Bayes Theorem|Computer Simulation|Cues|Discrimination (Psychology)|Humans|Models, Neurological|Neural Inhibition|Visual Cortex|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.0040014', '18282080', 'Visual object recognition and sensitivity to image features are largely influenced by contextual inputs. We study influences by contextual bars on the bias to perceive or infer the presence of a target bar, rather than on the sensitivity to image features. Human observers judged from a briefly presented stimulus whether a target bar of a known orientation and shape is present at the center of a display, given a weak or missing input contrast at the target location with or without a context of other bars. Observers are more likely to perceive a target when the context has a weaker rather than stronger contrast. When the context can perceptually group well with the would-be target, weak contrast contextual bars bias the observers to perceive a target relative to the condition without contexts, as if to fill in the target. Meanwhile, high-contrast contextual bars, regardless of whether they group well with the target, bias the observers to perceive no target. A Bayesian model of visual inference is shown to account for the data well, illustrating that the context influences the perception in two ways: (1) biasing observers prior belief that a target should be present according to visual grouping principles, and (2) biasing observers internal model of the likely input contrasts caused by a target bar. According to this model, our data suggest that the context does not influence the perceived target contrast despite its influence on the bias to perceive the targets presence, thereby suggesting that cortical areas beyond the primary visual cortex are responsible for the visual inferences.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83828, 2008, 'plos', 'Microarray based diagnosis profits from better documentation of gene expression signatures', 'Kostka, Dennis|Spang, Rainer', 'Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. dkostka@ucdavis.edu|Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. dkostka@ucdavis.edu', 'Germany|Germany', 17, 'Algorithms|Biomarkers, Tumor|Diagnosis, Computer-Assisted|Documentation|Gene Expression Profiling|Humans|Neoplasm Proteins|Neoplasms|Oligonucleotide Array Sequence Analysis|Reproducibility of Results|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.0040022', '18282081', 'Microarray gene expression signatures hold great promise to improve diagnosis and prognosis of disease. However, current documentation standards of such signatures do not allow for an unambiguous application to study-external patients. This hinders independent evaluation, effectively delaying the use of signatures in clinical practice. Data from eight publicly available clinical microarray studies were analyzed and the consistency of study-internal with study-external diagnoses was evaluated. Study-external classifications were based on documented information only. Documenting a signature is conceptually different from reporting a list of genes. We show that even the exact quantitative specification of a classification rule alone does not define a signature unambiguously. We found that discrepancy between study-internal and study-external diagnoses can be as frequent as 30% (worst case) and 18% (median). By using the proposed documentation by value strategy, which documents quantitative preprocessing information, the median discrepancy was reduced to 1%. The process of evaluating microarray gene expression diagnostic signatures and bringing them to clinical practice can be substantially improved and made more reliable by better documentation of the signatures.'),
(83829, 2008, 'plos', 'How force might activate talins vinculin binding sites: SMD reveals a structural mechanism', 'Hytönen, Vesa P|Vogel, Viola', 'Laboratory of Biologically Oriented Materials, Department of Materials, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zürich, Switzerland.|Laboratory of Biologically Oriented Materials, Department of Materials, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zürich, Switzerland.', 'Switzerland|Switzerland', 0, 'Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Motor Proteins|Motion|Protein Binding|Protein Conformation|Stress, Mechanical|Talin|Vinculin', 'Journal Article', '10.1371/journal.pcbi.0040024', '18282082', 'Upon cell adhesion, talin physically couples the cytoskeleton via integrins to the extracellular matrix, and subsequent vinculin recruitment is enhanced by locally applied tensile force. Since the vinculin binding (VB) sites are buried in the talin rod under equilibrium conditions, the structural mechanism of how vinculin binding to talin is force-activated remains unknown. Taken together with experimental data, a biphasic vinculin binding model, as derived from steered molecular dynamics, provides high resolution structural insights how tensile mechanical force applied to the talin rod fragment (residues 486-889 constituting helices H1-H12) might activate the VB sites. Fragmentation of the rod into three helix subbundles is prerequisite to the sequential exposure of VB helices to water. Finally, unfolding of a VB helix into a completely stretched polypeptide might inhibit further binding of vinculin. The first events in fracturing the H1-H12 rods of talin1 and talin2 in subbundles are similar. The proposed force-activated alpha-helix swapping mechanism by which vinculin binding sites in talin rods are exposed works distinctly different from that of other force-activated bonds, including catch bonds.'),
(83830, 2008, 'plos', 'Modeling cancer progression via pathway dependencies', 'Edelman, Elena J|Guinney, Justin|Chi, Jen-Tsan|Febbo, Phillip G|Mukherjee, Sayan', 'Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA.', 'United States|United States|United States|United States|United States', 56, 'Computer Simulation|Disease Progression|Gene Expression Regulation, Neoplastic|Humans|Male|Melanoma|Models, Biological|Neoplasm Proteins|Prostatic Neoplasms|Signal Transduction', 'Evaluation Studies', '10.1371/journal.pcbi.0040028', '18282083', 'Cancer is a heterogeneous disease often requiring a complexity of alterations to drive a normal cell to a malignancy and ultimately to a metastatic state. Certain genetic perturbations have been implicated for initiation and progression. However, to a great extent, underlying mechanisms often remain elusive. These genetic perturbations are most likely reflected by the altered expression of sets of genes or pathways, rather than individual genes, thus creating a need for models of deregulation of pathways to help provide an understanding of the mechanisms of tumorigenesis. We introduce an integrative hierarchical analysis of tumor progression that discovers which a priori defined pathways are relevant either throughout or in particular steps of progression. Pathway interaction networks are inferred for these relevant pathways over the steps in progression. This is followed by the refinement of the relevant pathways to those genes most differentially expressed in particular disease stages. The final analysis infers a gene interaction network for these refined pathways. We apply this approach to model progression in prostate cancer and melanoma, resulting in a deeper understanding of the mechanisms of tumorigenesis. Our analysis supports previous findings for the deregulation of several pathways involved in cell cycle control and proliferation in both cancer types. A novel finding of our analysis is a connection between ErbB4 and primary prostate cancer.'),
(83831, 2008, 'plos', 'Selective adaptation in networks of heterogeneous populations: model, simulation, and experiment', 'Wallach, Avner|Eytan, Danny|Marom, Shimon|Meir, Ron', 'Faculty of Electrical Engineering, Technion Israel Institute of Technology, Haifa, Israel. avnerw@tx.technion.ac.il|Faculty of Electrical Engineering, Technion Israel Institute of Technology, Haifa, Israel. avnerw@tx.technion.ac.il|Faculty of Electrical Engineering, Technion Israel Institute of Technology, Haifa, Israel. avnerw@tx.technion.ac.il|Faculty of Electrical Engineering, Technion Israel Institute of Technology, Haifa, Israel. avnerw@tx.technion.ac.il', 'Israel|Israel|Israel|Israel', 9, 'Action Potentials|Adaptation, Physiological|Animals|Computer Simulation|Humans|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0040029', '18282084', 'Biological systems often change their responsiveness when subject to persistent stimulation, a phenomenon termed adaptation. In neural systems, this process is often selective, allowing the system to adapt to one stimulus while preserving its sensitivity to another. In some studies, it has been shown that adaptation to a frequent stimulus increases the systems sensitivity to rare stimuli. These phenomena were explained in previous work as a result of complex interactions between the various subpopulations of the network. A formal description and analysis of neuronal systems, however, is hindered by the networks heterogeneity and by the multitude of processes taking place at different time-scales. Viewing neural networks as populations of interacting elements, we develop a framework that facilitates a formal analysis of complex, structured, heterogeneous networks. The formulation developed is based on an analysis of the availability of activity dependent resources, and their effects on network responsiveness. This approach offers a simple mechanistic explanation for selective adaptation, and leads to several predictions that were corroborated in both computer simulations and in cultures of cortical neurons developing in vitro. The framework is sufficiently general to apply to different biological systems, and was demonstrated in two different cases.'),
(83832, 2008, 'plos', 'Stimulus design for model selection and validation in cell signaling', 'Apgar, Joshua F|Toettcher, Jared E|Endy, Drew|White, Forest M|Tidor, Bruce', '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, 'Computer Simulation|Models, Biological|Protein Interaction Mapping|Proteome|Research Design|Signal Transduction', 'Evaluation Studies', '10.1371/journal.pcbi.0040030', '18282085', 'Mechanism-based chemical kinetic models are increasingly being used to describe biological signaling. Such models serve to encapsulate current understanding of pathways and to enable insight into complex biological processes. One challenge in model development is that, with limited experimental data, multiple models can be consistent with known mechanisms and existing data. Here, we address the problem of model ambiguity by providing a method for designing dynamic stimuli that, in stimulus-response experiments, distinguish among parameterized models with different topologies, i.e., reaction mechanisms, in which only some of the species can be measured. We develop the approach by presenting two formulations of a model-based controller that is used to design the dynamic stimulus. In both formulations, an input signal is designed for each candidate model and parameterization so as to drive the model outputs through a target trajectory. The quality of a model is then assessed by the ability of the corresponding controller, informed by that model, to drive the experimental system. We evaluated our method on models of antibody-ligand binding, mitogen-activated protein kinase (MAPK) phosphorylation and de-phosphorylation, and larger models of the epidermal growth factor receptor (EGFR) pathway. For each of these systems, the controller informed by the correct model is the most successful at designing a stimulus to produce the desired behavior. Using these stimuli we were able to distinguish between models with subtle mechanistic differences or where input and outputs were multiple reactions removed from the model differences. An advantage of this method of model discrimination is that it does not require novel reagents, or altered measurement techniques, the only change to the experiment is the time course of stimulation. Taken together, these results provide a strong basis for using designed input stimuli as a tool for the development of cell signaling models.'),
(83833, 2008, 'plos', 'The peri-saccadic perception of objects and space', 'Hamker, Fred H|Zirnsak, Marc|Calow, Dirk|Lappe, Markus', 'Institute of Psychology, Westfälische Wilhelms-Universität Münster, Münster, Germany. fhamker@uni-muenster.de|Institute of Psychology, Westfälische Wilhelms-Universität Münster, Münster, Germany. fhamker@uni-muenster.de|Institute of Psychology, Westfälische Wilhelms-Universität Münster, Münster, Germany. fhamker@uni-muenster.de|Institute of Psychology, Westfälische Wilhelms-Universität Münster, Münster, Germany. fhamker@uni-muenster.de', 'Germany|Germany|Germany|Germany', 84, 'Computer Simulation|Humans|Models, Neurological|Nerve Net|Pattern Recognition, Visual|Saccades|Space Perception|Visual Cortex|Visual Fields', 'Journal Article', '10.1371/journal.pcbi.0040031', '18282086', 'Eye movements affect object localization and object recognition. Around saccade onset, briefly flashed stimuli appear compressed towards the saccade target, receptive fields dynamically change position, and the recognition of objects near the saccade target is improved. These effects have been attributed to different mechanisms. We provide a unifying account of peri-saccadic perception explaining all three phenomena by a quantitative computational approach simulating cortical cell responses on the population level. Contrary to the common view of spatial attention as a spotlight, our model suggests that oculomotor feedback alters the receptive field structure in multiple visual areas at an intermediate level of the cortical hierarchy to dynamically recruit cells for processing a relevant part of the visual field. The compression of visual space occurs at the expense of this locally enhanced processing capacity.'),
(83834, 2008, 'plos', 'Synaptic plasticity can produce and enhance direction selectivity', 'Carver, Sean|Roth, Eatai|Cowan, Noah J|Fortune, Eric S', 'Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland, USA. sean.carver@jhu.edu|Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland, USA. sean.carver@jhu.edu|Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland, USA. sean.carver@jhu.edu|Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland, USA. sean.carver@jhu.edu', 'United States|United States|United States|United States', 0, 'Action Potentials|Animals|Electric Fish|Motion Perception|Nerve Net|Neuronal Plasticity|Neurons|Sensitivity and Specificity|Sensory Thresholds|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0040032', '18282087', 'The discrimination of the direction of movement of sensory images is critical to the control of many animal behaviors. We propose a parsimonious model of motion processing that generates direction selective responses using short-term synaptic depression and can reproduce salient features of direction selectivity found in a population of neurons in the midbrain of the weakly electric fish Eigenmannia virescens. The model achieves direction selectivity with an elementary Reichardt motion detector: information from spatially separated receptive fields converges onto a neuron via dynamically different pathways. In the model, these differences arise from convergence of information through distinct synapses that either exhibit or do not exhibit short-term synaptic depression--short-term depression produces phase-advances relative to nondepressing synapses. Short-term depression is modeled using two state-variables, a fast process with a time constant on the order of tens to hundreds of milliseconds, and a slow process with a time constant on the order of seconds to tens of seconds. These processes correspond to naturally occurring time constants observed at synapses that exhibit short-term depression. Inclusion of the fast process is sufficient for the generation of temporal disparities that are necessary for direction selectivity in the elementary Reichardt circuit. The addition of the slow process can enhance direction selectivity over time for stimuli that are sustained for periods of seconds or more. Transient (i.e., short-duration) stimuli do not evoke the slow process and therefore do not elicit enhanced direction selectivity. The addition of a sustained global, synchronous oscillation in the gamma frequency range can, however, drive the slow process and enhance direction selectivity to transient stimuli. This enhancement effect does not, however, occur for all combinations of model parameters. The ratio of depressing and nondepressing synapses determines the effects of the addition of the global synchronous oscillation on direction selectivity. These ingredients, short-term depression, spatial convergence, and gamma-band oscillations, are ubiquitous in sensory systems and may be used in Reichardt-style circuits for the generation and enhancement of a variety of biologically relevant spatiotemporal computations.'),
(83835, 2008, 'plos', 'On the process of becoming a great scientist', 'Giddings, Morgan C', 'Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland, USA. sean.carver@jhu.edu', 'United States', 4, 'Biomedical Research|Computational Biology|Creativity|Humans|Philosophy|Professional Competence|Science', 'Comment', '10.1371/journal.pcbi.0040033', '18282088', '-'),
(83836, 2008, 'plos', 'Modeling an evolutionary conserved circadian cis-element', 'Paquet, Eric R|Rey, Guillaume|Naef, Felix', 'Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.', 'Switzerland|Switzerland|Switzerland', 23, 'ARNTL Transcription Factors|Animals|Basic Helix-Loop-Helix Transcription Factors|CLOCK Proteins|Chromosome Mapping|Circadian Rhythm|Computer Simulation|Conserved Sequence|Drosophila Proteins|Drosophila melanogaster|Evolution, Molecular|Models, Genetic|Regulatory Sequences, Nucleic Acid|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0040038', '18282089', 'Circadian oscillator networks rely on a transcriptional activator called CLOCK/CYCLE (CLK/CYC) in insects and CLOCK/BMAL1 or NPAS2/BMAL1 in mammals. Identifying the targets of this heterodimeric basic-helix-loop-helix (bHLH) transcription factor poses challenges and it has been difficult to decipher its specific sequence affinity beyond a canonical E-box motif, except perhaps for some flanking bases contributing weakly to the binding energy. Thus, no good computational model presently exists for predicting CLK/CYC, CLOCK/BMAL1, or NPAS2/BMAL1 targets. Here, we use a comparative genomics approach and first study the conservation properties of the best-known circadian enhancer: a 69-bp element upstream of the Drosophila melanogaster period gene. This fragment shows a signal involving the presence of two closely spaced E-box-like motifs, a configuration that we can also detect in the other four prominent CLK/CYC target genes in flies: timeless, vrille, Pdp1, and cwo. This allows for the training of a probabilistic sequence model that we test using functional genomics datasets. We find that the predicted sequences are overrepresented in promoters of genes induced in a recent study by a glucocorticoid receptor-CLK fusion protein. We then scanned the mouse genome with the fly model and found that many known CLOCK/BMAL1 targets harbor sequences matching our consensus. Moreover, the phase of predicted cyclers in liver agreed with known CLOCK/BMAL1 regulation. Taken together, we built a predictive model for CLK/CYC or CLOCK/BMAL1-bound cis-enhancers through the integration of comparative and functional genomics data. Finally, a deeper phylogenetic analysis reveals that the link between the CLOCK/BMAL1 complex and the circadian cis-element dates back to before insects and vertebrates diverged.'),
(83837, 2008, 'plos', 'Control of cation permeation through the nicotinic receptor channel', 'Wang, Hai-Long|Cheng, Xiaolin|Taylor, Palmer|McCammon, J Andrew|Sine, Steven M', 'Receptor Biology Laboratory, Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. hwang@mayo.edu|Receptor Biology Laboratory, Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. hwang@mayo.edu|Receptor Biology Laboratory, Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. hwang@mayo.edu|Receptor Biology Laboratory, Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. hwang@mayo.edu|Receptor Biology Laboratory, Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. hwang@mayo.edu', 'United States|United States|United States|United States|United States', 0, 'Cations|Computer Simulation|Electromagnetic Fields|Ion Channel Gating|Lipid Bilayers|Models, Chemical|Models, Molecular|Motion|Permeability|Receptors, Nicotinic', 'Journal Article', '10.1371/journal.pcbi.0040041', '18282090', 'We used molecular dynamics (MD) simulations to explore the transport of single cations through the channel of the muscle nicotinic acetylcholine receptor (nAChR). Four MD simulations of 16 ns were performed at physiological and hyperpolarized membrane potentials, with and without restraints of the structure, but all without bound agonist. With the structure unrestrained and a potential of -100 mV, one cation traversed the channel during a transient period of channel hydration, at -200 mV, the channel was continuously hydrated and two cations traversed the channel. With the structure restrained, however, cations did not traverse the channel at either membrane potential, even though the channel was continuously hydrated. The overall results show that cation selective transport through the nAChR channel is governed by electrostatic interactions to achieve charge selectivity, but ion translocation relies on channel hydration, facilitated by a trans-membrane field, coupled with dynamic fluctuations of the channel structure.'),
(83838, 2008, 'plos', 'Accurate structural correlations from maximum likelihood superpositions', 'Theobald, Douglas L|Wuttke, Deborah S', 'Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA. dtheobald@brandeis.edu|Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA. dtheobald@brandeis.edu', 'United States|United States', 62, 'Computer Simulation|Crystallography|Likelihood Functions|Models, Chemical|Models, Molecular|Models, Statistical|Protein Conformation|Proteins|Reproducibility of Results|Sensitivity and Specificity|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.0040043', '18282091', 'The cores of globular proteins are densely packed, resulting in complicated networks of structural interactions. These interactions in turn give rise to dynamic structural correlations over a wide range of time scales. Accurate analysis of these complex correlations is crucial for understanding biomolecular mechanisms and for relating structure to function. Here we report a highly accurate technique for inferring the major modes of structural correlation in macromolecules using likelihood-based statistical analysis of sets of structures. This method is generally applicable to any ensemble of related molecules, including families of nuclear magnetic resonance (NMR) models, different crystal forms of a protein, and structural alignments of homologous proteins, as well as molecular dynamics trajectories. Dominant modes of structural correlation are determined using principal components analysis (PCA) of the maximum likelihood estimate of the correlation matrix. The correlations we identify are inherently independent of the statistical uncertainty and dynamic heterogeneity associated with the structural coordinates. We additionally present an easily interpretable method (PCA plots) for displaying these positional correlations by color-coding them onto a macromolecular structure. Maximum likelihood PCA of structural superpositions, and the structural PCA plots that illustrate the results, will facilitate the accurate determination of dynamic structural correlations analyzed in diverse fields of structural biology.'),
(83839, 2008, 'plos', 'Robustness of learning that is based on covariance-driven synaptic plasticity', 'Loewenstein, Yonatan', 'Department of Neurobiology, Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. yonatan@huji.ac.il', 'Israel', 20, 'Action Potentials|Brain|Computer Simulation|Decision Making|Learning|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000007', '18369414', 'It is widely believed that learning is due, at least in part, to long-lasting modifications of the strengths of synapses in the brain. Theoretical studies have shown that a family of synaptic plasticity rules, in which synaptic changes are driven by covariance, is particularly useful for many forms of learning, including associative memory, gradient estimation, and operant conditioning. Covariance-based plasticity is inherently sensitive. Even a slight mistuning of the parameters of a covariance-based plasticity rule is likely to result in substantial changes in synaptic efficacies. Therefore, the biological relevance of covariance-based plasticity models is questionable. Here, we study the effects of mistuning parameters of the plasticity rule in a decision making model in which synaptic plasticity is driven by the covariance of reward and neural activity. An exact covariance plasticity rule yields Herrnsteins matching law. We show that although the effect of slight mistuning of the plasticity rule on the synaptic efficacies is large, the behavioral effect is small. Thus, matching behavior is robust to mistuning of the parameters of the covariance-based plasticity rule. Furthermore, the mistuned covariance rule results in undermatching, which is consistent with experimentally observed behavior. These results substantiate the hypothesis that approximate covariance-based synaptic plasticity underlies operant conditioning. However, we show that the mistuning of the mean subtraction makes behavior sensitive to the mistuning of the properties of the decision making network. Thus, there is a tradeoff between the robustness of matching behavior to changes in the plasticity rule and its robustness to changes in the properties of the decision making network.'),
(83840, 2008, 'plos', 'Entropy measures quantify global splicing disorders in cancer', 'Ritchie, William|Granjeaud, Samuel|Puthier, Denis|Gautheret, Daniel', 'Université de Méditerranée, INSERM ERM 206, Technologies Avancées pour le Génome et Clinique, Marseille, France.|Université de Méditerranée, INSERM ERM 206, Technologies Avancées pour le Génome et Clinique, Marseille, France.|Université de Méditerranée, INSERM ERM 206, Technologies Avancées pour le Génome et Clinique, Marseille, France.|Université de Méditerranée, INSERM ERM 206, Technologies Avancées pour le Génome et Clinique, Marseille, France.', 'France|France|France|France', 0, 'Alternative Splicing|Biomarkers, Tumor|Computer Simulation|Entropy|Gene Expression Regulation, Neoplastic|Gene Targeting|Genetic Predisposition to Disease|Genetic Variation|Humans|Models, Genetic|Models, Statistical|Mutation|Neoplasm Proteins|Neoplasms|Protein Splicing', 'Journal Article', '10.1371/journal.pcbi.1000011', '18369415', 'Most mammalian genes are able to express several splice variants in a phenomenon known as alternative splicing. Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of cancer-specific splice variants as potential therapeutic targets. Here, we examine instead the bulk of non-specific transcript isoforms and analyze their level of disorder using a measure of uncertainty called Shannons entropy. We compare isoform expression entropy in normal and cancer tissues from the same anatomical site for different classes of transcript variations: alternative splicing, polyadenylation, and transcription initiation. Whereas alternative initiation and polyadenylation show no significant gain or loss of entropy between normal and cancer tissues, alternative splicing shows highly significant entropy gains for 13 of the 27 cancers studied. This entropy gain is characterized by a flattening in the expression profile of normal isoforms and is correlated to the level of estimated cellular proliferation in the cancer tissue. Interestingly, the genes that present the highest entropy gain are enriched in splicing factors. We provide here the first quantitative estimate of splicing disruption in cancer. The expression of normal splice variants is widely and significantly disrupted in at least half of the cancers studied. We postulate that such splicing disorders may develop in part from splicing alteration in key splice factors, which in turn significantly impact multiple target genes.'),
(83841, 2008, 'plos', 'Representing where along with what information in a model of a cortical patch', 'Roudi, Yasser|Treves, Alessandro', 'Gatsby Computational Neuroscience Unit, UCL, United Kingdom. yasser@gatsby.ucl.ac.uk|Gatsby Computational Neuroscience Unit, UCL, United Kingdom. yasser@gatsby.ucl.ac.uk', 'United Kingdom|United Kingdom', 30, 'Action Potentials|Animals|Computer Simulation|Evoked Potentials, Visual|Humans|Information Storage and Retrieval|Memory|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Pattern Recognition, Visual|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.1000012', '18369416', 'Behaving in the real world requires flexibly combining and maintaining information about both continuous and discrete variables. In the visual domain, several lines of evidence show that neurons in some cortical networks can simultaneously represent information about the position and identity of objects, and maintain this combined representation when the object is no longer present. The underlying network mechanism for this combined representation is, however, unknown. In this paper, we approach this issue through a theoretical analysis of recurrent networks. We present a model of a cortical network that can retrieve information about the identity of objects from incomplete transient cues, while simultaneously representing their spatial position. Our results show that two factors are important in making this possible: A) a metric organisation of the recurrent connections, and B) a spatially localised change in the linear gain of neurons. Metric connectivity enables a localised retrieval of information about object identity, while gain modulation ensures localisation in the correct position. Importantly, we find that the amount of information that the network can retrieve and retain about identity is strongly affected by the amount of information it maintains about position. This balance can be controlled by global signals that change the neuronal gain. These results show that anatomical and physiological properties, which have long been known to characterise cortical networks, naturally endow them with the ability to maintain a conjunctive representation of the identity and location of objects.'),
(83842, 2008, 'plos', 'Intrinsically disordered proteins display no preference for chaperone binding in vivo', 'Hegyi, Hedi|Tompa, Peter', 'Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.', 'Hungary|Hungary', 0, 'Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Chaperones|Protein Binding|Protein Interaction Mapping|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000017', '18369417', 'Intrinsically disordered/unstructured proteins (IDPs) are extremely sensitive to proteolysis in vitro, but show no enhanced degradation rates in vivo. Their existence and functioning may be explained if IDPs are preferentially associated with chaperones in the cell, which may offer protection against degradation by proteases. To test this inference, we took pairwise interaction data from high-throughput interaction studies and analyzed to see if predicted disorder correlates with the tendency of chaperone binding by proteins. Our major finding is that disorder predicted by the IUPred algorithm actually shows negative correlation with chaperone binding in E. coli, S. cerevisiae, and metazoa species. Since predicted disorder positively correlates with the tendency of partner binding in the interactome, the difference between the disorder of chaperone-binding and non-binding proteins is even more pronounced if normalized to their overall tendency to be involved in pairwise protein-protein interactions. We argue that chaperone binding is primarily required for folding of globular proteins, as reflected in an increased preference for chaperones of proteins in which at least one Pfam domain exists. In terms of the functional consequences of chaperone binding of mostly disordered proteins, we suggest that its primary reason is not the assistance of folding, but promotion of assembly with partners. In support of this conclusion, we show that IDPs that bind chaperones also tend to bind other proteins.'),
(83843, 2008, 'plos', 'Evolutionary patterns in the sequence and structure of transfer RNA: early origins of archaea and viruses', 'Sun, Feng-Jie|Caetano-Anollés, Gustavo', 'Department of Crop Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America.|Department of Crop Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America.', 'United States|United States', 34, 'Base Sequence|Biological Evolution|Evolution, Molecular|Genetic Variation|Models, Genetic|Molecular Sequence Data|Pattern Recognition, Automated|RNA, Archaeal|RNA, Transfer|RNA, Viral|Sequence Alignment|Sequence Analysis, RNA', 'Journal Article', '10.1371/journal.pcbi.1000018', '18369418', 'Transfer RNAs (tRNAs) are ancient molecules that are central to translation. Since they probably carry evolutionary signatures that were left behind when the living world diversified, we reconstructed phylogenies directly from the sequence and structure of tRNA using well-established phylogenetic methods. The trees placed tRNAs with long variable arms charging Sec, Tyr, Ser, and Leu consistently at the base of the rooted phylogenies, but failed to reveal groupings that would indicate clear evolutionary links to organismal origin or molecular functions. In order to uncover evolutionary patterns in the trees, we forced tRNAs into monophyletic groups using constraint analyses to generate timelines of organismal diversification and test competing evolutionary hypotheses. Remarkably, organismal timelines showed Archaea was the most ancestral superkingdom, followed by viruses, then superkingdoms Eukarya and Bacteria, in that order, supporting conclusions from recent phylogenomic studies of protein architecture. Strikingly, constraint analyses showed that the origin of viruses was not only ancient, but was linked to Archaea. Our findings have important implications. They support the notion that the archaeal lineage was very ancient, resulted in the first organismal divide, and predated diversification of tRNA function and specificity. Results are also consistent with the concept that viruses contributed to the development of the DNA replication machinery during the early diversification of the living world.'),
(83844, 2008, 'plos', 'Modeling the effects of cell cycle M-phase transcriptional inhibition on circadian oscillation', 'Kang, Bin|Li, Yuan-Yuan|Chang, Xiao|Liu, Lei|Li, Yi-Xue', 'Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Laboratory of Systems Biology [corrected] Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.', 'China|China|China|China|China', 9, 'Animals|Biological Clocks|Cell Cycle Proteins|Cell Division|Circadian Rhythm|Computer Simulation|Feedback|Gene Expression Regulation|Humans|Models, Biological|Transcription Factors|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1000019', '18369419', 'Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.'),
(83845, 2008, 'plos', 'Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics', 'Ramsey, Stephen A|Klemm, Sandy L|Zak, Daniel E|Kennedy, Kathleen A|Thorsson, Vesteinn|Li, Bin|Gilchrist, Mark|Gold, Elizabeth S|Johnson, Carrie D|Litvak, Vladimir|Navarro, Garnet|Roach, Jared C|Rosenberger, Carrie M|Rust, Alistair G|Yudkovsky, Natalya|Aderem, Alan|Shmulevich, Ilya', 'Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org|Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Amino Acid Motifs|Animals|Computer Simulation|Gene Expression Regulation|Humans|Kinetics|Macrophage Activation|Macrophages|Models, Biological|Signal Transduction|Structure-Activity Relationship|Systems Integration|Toll-Like Receptors|Transcription Factors|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1000021', '18369420', 'Macrophages are versatile immune cells that can detect a variety of pathogen-associated molecular patterns through their Toll-like receptors (TLRs). In response to microbial challenge, the TLR-stimulated macrophage undergoes an activation program controlled by a dynamically inducible transcriptional regulatory network. Mapping a complex mammalian transcriptional network poses significant challenges and requires the integration of multiple experimental data types. In this work, we inferred a transcriptional network underlying TLR-stimulated murine macrophage activation. Microarray-based expression profiling and transcription factor binding site motif scanning were used to infer a network of associations between transcription factor genes and clusters of co-expressed target genes. The time-lagged correlation was used to analyze temporal expression data in order to identify potential causal influences in the network. A novel statistical test was developed to assess the significance of the time-lagged correlation. Several associations in the resulting inferred network were validated using targeted ChIP-on-chip experiments. The network incorporates known regulators and gives insight into the transcriptional control of macrophage activation. Our analysis identified a novel regulator (TGIF1) that may have a role in macrophage activation.'),
(83846, 2008, 'plos', 'Structure of spontaneous UP and DOWN transitions self-organizing in a cortical network model', 'Kang, Siu|Kitano, Katsunori|Fukai, Tomoki', 'Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Wako, Japan.|Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Wako, Japan.|Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Wako, Japan.', 'Japan|Japan|Japan', 0, 'Action Potentials|Animals|Biological Clocks|Cerebral Cortex|Computer Simulation|Feedback|Humans|Models, Neurological|Nerve Net|Neural Inhibition|Neuronal Plasticity|Neurons', 'Journal Article', '10.1371/journal.pcbi.1000022', '18369421', 'Synaptic plasticity is considered to play a crucial role in the experience-dependent self-organization of local cortical networks. In the absence of sensory stimuli, cerebral cortex exhibits spontaneous membrane potential transitions between an UP and a DOWN state. To reveal how cortical networks develop spontaneous activity, or conversely, how spontaneous activity structures cortical networks, we analyze the self-organization of a recurrent network model of excitatory and inhibitory neurons, which is realistic enough to replicate UP-DOWN states, with spike-timing-dependent plasticity (STDP). The individual neurons in the self-organized network exhibit a variety of temporal patterns in the two-state transitions. In addition, the model develops a feed-forward network-like structure that produces a diverse repertoire of precise sequences of the UP state. Our model shows that the self-organized activity well resembles the spontaneous activity of cortical networks if STDP is accompanied by the pruning of weak synapses. These results suggest that the two-state membrane potential transitions play an active role in structuring local cortical circuits.'),
(83847, 2008, 'plos', 'A continuum model for metabolic gas exchange in pear fruit', 'Ho, Q Tri|Verboven, Pieter|Verlinden, Bert E|Lammertyn, Jeroen|Vandewalle, Stefan|Nicolaï, Bart M', 'BIOSYST-MeBioS, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Leuven, Belgium.|BIOSYST-MeBioS, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Leuven, Belgium.|BIOSYST-MeBioS, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Leuven, Belgium.|BIOSYST-MeBioS, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Leuven, Belgium.|BIOSYST-MeBioS, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Leuven, Belgium.|BIOSYST-MeBioS, Faculty of Bioscience Engineering, Katholieke Universiteit Leuven, Leuven, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 0, 'Biological Transport, Active|Carbon Dioxide|Cell Respiration|Computer Simulation|Diffusion|Fruit|Models, Biological|Oxygen|Plant Leaves|Pyrus', 'Journal Article', '10.1371/journal.pcbi.1000023', '18369422', 'Exchange of O(2) and CO(2) of plants with their environment is essential for metabolic processes such as photosynthesis and respiration. In some fruits such as pears, which are typically stored under a controlled atmosphere with reduced O(2) and increased CO(2) levels to extend their commercial storage life, anoxia may occur, eventually leading to physiological disorders. In this manuscript we have developed a mathematical model to predict the internal gas concentrations, including permeation, diffusion, and respiration and fermentation kinetics. Pear fruit has been selected as a case study. The model has been used to perform in silico experiments to evaluate the effect of, for example, fruit size or ambient gas concentration on internal O(2) and CO(2) levels. The model incorporates the actual shape of the fruit and was solved using fluid dynamics software. Environmental conditions such as temperature and gas composition have a large effect on the internal distribution of oxygen and carbon dioxide in fruit. Also, the fruit size has a considerable effect on local metabolic gas concentrations, hence, depending on the size, local anaerobic conditions may result, which eventually may lead to physiological disorders. The model developed in this manuscript is to our knowledge the most comprehensive model to date to simulate gas exchange in plant tissue. It can be used to evaluate the effect of environmental stresses on fruit via in silico experiments and may lead to commercial applications involving long-term storage of fruit under controlled atmospheres.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83848, 2008, 'plos', 'Neural coding of natural stimuli: information at sub-millisecond resolution', 'Nemenman, Ilya|Lewen, Geoffrey D|Bialek, William|de Ruyter van Steveninck, Rob R', 'Computer, Computational, and Statistical Sciences Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. nemenman@lanl.gov|Computer, Computational, and Statistical Sciences Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. nemenman@lanl.gov|Computer, Computational, and Statistical Sciences Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. nemenman@lanl.gov|Computer, Computational, and Statistical Sciences Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. nemenman@lanl.gov', 'Mexico|Mexico|Mexico|Mexico', 83, 'Action Potentials|Algorithms|Animals|Computer Simulation|Diptera|Evoked Potentials, Visual|Models, Neurological|Motion Perception|Photic Stimulation|Photoreceptor Cells', 'Journal Article', '10.1371/journal.pcbi.1000025', '18369423', 'Sensory information about the outside world is encoded by neurons in sequences of discrete, identical pulses termed action potentials or spikes. There is persistent controversy about the extent to which the precise timing of these spikes is relevant to the function of the brain. We revisit this issue, using the motion-sensitive neurons of the fly visual system as a test case. Our experimental methods allow us to deliver more nearly natural visual stimuli, comparable to those which flies encounter in free, acrobatic flight. New mathematical methods allow us to draw more reliable conclusions about the information content of neural responses even when the set of possible responses is very large. We find that significant amounts of visual information are represented by details of the spike train at millisecond and sub-millisecond precision, even though the sensory input has a correlation time of approximately 55 ms, different patterns of spike timing represent distinct motion trajectories, and the absolute timing of spikes points to particular features of these trajectories with high precision. Finally, the efficiency of our entropy estimator makes it possible to uncover features of neural coding relevant for natural visual stimuli: first, the systems information transmission rate varies with natural fluctuations in light intensity, resulting from varying cloud cover, such that marginal increases in information rate thus occur even when the individual photoreceptors are counting on the order of one million photons per second. Secondly, we see that the system exploits the relatively slow dynamics of the stimulus to remove coding redundancy and so generate a more efficient neural code.'),
(83849, 2008, 'plos', 'The evolution of robust development and homeostasis in artificial organisms', 'Basanta, David|Miodownik, Mark|Baum, Buzz', 'Materials Research Group, Engineering Division, Kings College London, London, United Kingdom.|Materials Research Group, Engineering Division, Kings College London, London, United Kingdom.|Materials Research Group, Engineering Division, Kings College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Biological Evolution|Biomimetics|Cell Communication|Cell Physiological Phenomena|Computer Simulation|Homeostasis|Humans|Models, Biological|Morphogenesis|Regeneration', 'Journal Article', '10.1371/journal.pcbi.1000030', '18369424', 'During embryogenesis, multicellular animals are shaped via cell proliferation, cell rearrangement, and apoptosis. At the end of development, tissue architecture is then maintained through balanced rates of cell proliferation and loss. Here, we take an in silico approach to look for generic systems features of morphogenesis in multicellular animals that arise as a consequence of the evolution of development. Using artificial evolution, we evolved cellular automata-based digital organisms that have distinct embryonic and homeostatic phases of development. Although these evolved organisms use a variety of strategies to maintain their form over time, organisms of different types were all found to rapidly recover from environmental damage in the form of wounds. This regenerative response was most robust in an organism with a stratified tissue-like architecture. An evolutionary analysis revealed that evolution itself contributed to the ability of this organism to maintain its form in the face of genetic and environmental perturbation, confirming the results of previous studies. In addition, the exceptional robustness of this organism to surface injury was found to result from an upward flux of cells, driven in part by cell divisions with a stable niche at the tissue base. Given the general nature of the model, our results lead us to suggest that many of the robust systems properties observed in real organisms, including scar-free wound-healing in well-protected embryos and the layered tissue architecture of regenerating epithelial tissues, may be by-products of the evolution of morphogenesis, rather than the direct result of selection.'),
(83850, 2008, 'plos', 'Plant classification from bat-like echolocation signals', 'Yovel, Yossi|Franz, Matthias Otto|Stilz, Peter|Schnitzler, Hans-Ulrich', 'Animal Physiology, Zoological Institute, University of Tuebingen, Tuebingen, Germany.|Animal Physiology, Zoological Institute, University of Tuebingen, Tuebingen, Germany.|Animal Physiology, Zoological Institute, University of Tuebingen, Tuebingen, Germany.|Animal Physiology, Zoological Institute, University of Tuebingen, Tuebingen, Germany.', 'Germany|Germany|Germany|Germany', 55, 'Algorithms|Animals|Artificial Intelligence|Chiroptera|Echolocation|Pattern Recognition, Automated|Plant Physiological Phenomena|Plants|Sound Spectrography', 'Journal Article', '10.1371/journal.pcbi.1000032', '18369425', 'Classification of plants according to their echoes is an elementary component of bat behavior that plays an important role in spatial orientation and food acquisition. Vegetation echoes are, however, highly complex stochastic signals: from an acoustical point of view, a plant can be thought of as a three-dimensional array of leaves reflecting the emitted bat call. The received echo is therefore a superposition of many reflections. In this work we suggest that the classification of these echoes might not be such a troublesome routine for bats as formerly thought. We present a rather simple approach to classifying signals from a large database of plant echoes that were created by ensonifying plants with a frequency-modulated bat-like ultrasonic pulse. Our algorithm uses the spectrogram of a single echo from which it only uses features that are undoubtedly accessible to bats. We used a standard machine learning algorithm (SVM) to automatically extract suitable linear combinations of time and frequency cues from the spectrograms such that classification with high accuracy is enabled. This demonstrates that ultrasonic echoes are highly informative about the species membership of an ensonified plant, and that this information can be extracted with rather simple, biologically plausible analysis. Thus, our findings provide a new explanatory basis for the poorly understood observed abilities of bats in classifying vegetation and other complex objects.'),
(83851, 2008, 'plos', 'Chromophore protonation state controls photoswitching of the fluoroprotein asFP595', 'Schäfer, Lars V|Groenhof, Gerrit|Boggio-Pasqua, Martial|Robb, Michael A|Grubmüller, Helmut', 'Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.|Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.|Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.|Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.|Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.', 'Germany|Germany|Germany|Germany|Germany', 78, 'Computer Simulation|Dose-Response Relationship, Drug|Isomerism|Light|Luminescent Proteins|Models, Chemical|Models, Molecular|Photochemistry|Protein Conformation|Protons|Radiation Dosage', 'Journal Article', '10.1371/journal.pcbi.1000034', '18369426', 'Fluorescent proteins have been widely used as genetically encodable fusion tags for biological imaging. Recently, a new class of fluorescent proteins was discovered that can be reversibly light-switched between a fluorescent and a non-fluorescent state. Such proteins can not only provide nanoscale resolution in far-field fluorescence optical microscopy much below the diffraction limit, but also hold promise for other nanotechnological applications, such as optical data storage. To systematically exploit the potential of such photoswitchable proteins and to enable rational improvements to their properties requires a detailed understanding of the molecular switching mechanism, which is currently unknown. Here, we have studied the photoswitching mechanism of the reversibly switchable fluoroprotein asFP595 at the atomic level by multiconfigurational ab initio (CASSCF) calculations and QM/MM excited state molecular dynamics simulations with explicit surface hopping. Our simulations explain measured quantum yields and excited state lifetimes, and also predict the structures of the hitherto unknown intermediates and of the irreversibly fluorescent state. Further, we find that the proton distribution in the active site of the asFP595 controls the photochemical conversion pathways of the chromophore in the protein matrix. Accordingly, changes in the protonation state of the chromophore and some proximal amino acids lead to different photochemical states, which all turn out to be essential for the photoswitching mechanism. These photochemical states are (i) a neutral chromophore, which can trans-cis photoisomerize, (ii) an anionic chromophore, which rapidly undergoes radiationless decay after excitation, and (iii) a putative fluorescent zwitterionic chromophore. The overall stability of the different protonation states is controlled by the isomeric state of the chromophore. We finally propose that radiation-induced decarboxylation of the glutamic acid Glu215 blocks the proton transfer pathways that enable the deactivation of the zwitterionic chromophore and thus leads to irreversible fluorescence. We have identified the tight coupling of trans-cis isomerization and proton transfers in photoswitchable proteins to be essential for their function and propose a detailed underlying mechanism, which provides a comprehensive picture that explains the available experimental data. The structural similarity between asFP595 and other fluoroproteins of interest for imaging suggests that this coupling is a quite general mechanism for photoswitchable proteins. These insights can guide the rational design and optimization of photoswitchable proteins.'),
(83852, 2008, 'plos', 'Electrotonic signals along intracellular membranes may interconnect dendritic spines and nucleus', 'Shemer, Isaac|Brinne, Björn|Tegnér, Jesper|Grillner, Sten', 'Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se', 'Sweden|Sweden|Sweden|Sweden', 19, 'Action Potentials|Animals|Cell Nucleus|Computer Simulation|Dendritic Spines|Endoplasmic Reticulum|Humans|Intracellular Membranes|Models, Neurological|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000036', '18369427', 'Synapses on dendritic spines of pyramidal neurons show a remarkable ability to induce phosphorylation of transcription factors at the nuclear level with a short latency, incompatible with a diffusion process from the dendritic spines to the nucleus. To account for these findings, we formulated a novel extension of the classical cable theory by considering the fact that the endoplasmic reticulum (ER) is an effective charge separator, forming an intrinsic compartment that extends from the spine to the nuclear membrane. We use realistic parameters to show that an electrotonic signal may be transmitted along the ER from the dendritic spines to the nucleus. We found that this type of signal transduction can additionally account for the remarkable ability of the cell nucleus to differentiate between depolarizing synaptic signals that originate from the dendritic spines and back-propagating action potentials. This study considers a novel computational role for dendritic spines, and sheds new light on how spines and ER may jointly create an additional level of processing within the single neuron.'),
(83853, 2008, 'plos', 'Open access: taking full advantage of the content', 'Bourne, Philip E|Fink, J Lynn|Gerstein, Mark', 'Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se|Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Isaac.Shemer@ki.se', 'Sweden|Sweden|Sweden', 11, 'Abstracting and Indexing as Topic|Authorship|Information Dissemination|Internet|Natural Language Processing|Periodicals as Topic|PubMed|Publishing|United States', 'Editorial', '10.1371/journal.pcbi.1000037', '18369428', '-'),
(83854, 2008, 'plos', 'Statistical modeling of transcription factor binding affinities predicts regulatory interactions', 'Manke, Thomas|Roider, Helge G|Vingron, Martin', 'Max Planck Institute for Molecular Genetics, Berlin, Germany. manke@molgen.mpg.de|Max Planck Institute for Molecular Genetics, Berlin, Germany. manke@molgen.mpg.de|Max Planck Institute for Molecular Genetics, Berlin, Germany. manke@molgen.mpg.de', 'Germany|Germany|Germany', 34, 'Algorithms|Base Sequence|Binding Sites|Computer Simulation|DNA|Data Interpretation, Statistical|Models, Genetic|Models, Statistical|Molecular Sequence Data|Protein Binding|Regulatory Elements, Transcriptional|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000039', '18369429', 'Recent experimental and theoretical efforts have highlighted the fact that binding of transcription factors to DNA can be more accurately described by continuous measures of their binding affinities, rather than a discrete description in terms of binding sites. While the binding affinities can be predicted from a physical model, it is often desirable to know the distribution of binding affinities for specific sequence backgrounds. In this paper, we present a statistical approach to derive the exact distribution for sequence models with fixed GC content. We demonstrate that the affinity distribution of almost all known transcription factors can be effectively parametrized by a class of generalized extreme value distributions. Moreover, this parameterization also describes the affinity distribution for sequence backgrounds with variable GC content, such as human promoter sequences. Our approach is applicable to arbitrary sequences and all transcription factors with known binding preferences that can be described in terms of a motif matrix. The statistical treatment also provides a proper framework to directly compare transcription factors with very different affinity distributions. This is illustrated by our analysis of human promoters with known binding sites, for many of which we could identify the known regulators as those with the highest affinity. The combination of physical model and statistical normalization provides a quantitative measure which ranks transcription factors for a given sequence, and which can be compared directly with large-scale binding data. Its successful application to human promoter sequences serves as an encouraging example of how the method can be applied to other sequences.'),
(83855, 2008, 'plos', 'Computational biology in Costa Rica: the role of a small country in the global context of bioinformatics', 'Moreno, Edgardo|Lomonte, Bruno|Gutiérrez, José-María', 'Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Heredia, Costa Rica. emoreno@medvet.una.ac.cr|Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Heredia, Costa Rica. emoreno@medvet.una.ac.cr|Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Heredia, Costa Rica. emoreno@medvet.una.ac.cr', 'Costa Rica|Costa Rica|Costa Rica', 6, 'Biological Science Disciplines|Computational Biology|Costa Rica|Developing Countries|Genomics|Internationality', 'Journal Article', '10.1371/journal.pcbi.1000040', '18369430', '-'),
(83856, 2008, 'plos', 'A hidden feedback in signaling cascades is revealed', 'Ventura, Alejandra C|Sepulchre, Jacques-A|Merajver, Sofía D', 'Department of Internal Medicine, Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Internal Medicine, Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Internal Medicine, Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States', 69, 'Computer Simulation|Feedback|Models, Biological|Multienzyme Complexes|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000041', '18369431', 'Cycles involving covalent modification of proteins are key components of the intracellular signaling machinery. Each cycle is comprised of two interconvertable forms of a particular protein. A classic signaling pathway is structured by a chain or cascade of basic cycle units in such a way that the activated protein in one cycle promotes the activation of the next protein in the chain, and so on. Starting from a mechanistic kinetic description and using a careful perturbation analysis, we have derived, to our knowledge for the first time, a consistent approximation of the chain with one variable per cycle. The model we derive is distinct from the one that has been in use in the literature for several years, which is a phenomenological extension of the Goldbeter-Koshland biochemical switch. Even though much has been done regarding the mathematical modeling of these systems, our contribution fills a gap between existing models and, in doing so, we have unveiled critical new properties of this type of signaling cascades. A key feature of our new model is that a negative feedback emerges naturally, exerted between each cycle and its predecessor. Due to this negative feedback, the system displays damped temporal oscillations under constant stimulation and, most important, propagates perturbations both forwards and backwards. This last attribute challenges the widespread notion of unidirectionality in signaling cascades. Concrete examples of applications to MAPK cascades are discussed. All these properties are shared by the complete mechanistic description and our simplified model, but not by previously derived phenomenological models of signaling cascades.'),
(83857, 2008, 'plos', 'Shaping embodied neural networks for adaptive goal-directed behavior', 'Chao, Zenas C|Bakkum, Douglas J|Potter, Steve M', 'Laboratory for Neuroengineering, Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, United States of America.|Laboratory for Neuroengineering, Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, United States of America.|Laboratory for Neuroengineering, Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia, United States of America.', 'Georgia|Georgia|Georgia', 44, 'Action Potentials|Adaptation, Physiological|Animals|Behavior, Animal|Brain|Computer Simulation|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Reward', 'Journal Article', '10.1371/journal.pcbi.1000042', '18369432', 'The acts of learning and memory are thought to emerge from the modifications of synaptic connections between neurons, as guided by sensory feedback during behavior. However, much is unknown about how such synaptic processes can sculpt and are sculpted by neuronal population dynamics and an interaction with the environment. Here, we embodied a simulated network, inspired by dissociated cortical neuronal cultures, with an artificial animal (an animat) through a sensory-motor loop consisting of structured stimuli, detailed activity metrics incorporating spatial information, and an adaptive training algorithm that takes advantage of spike timing dependent plasticity. By using our design, we demonstrated that the network was capable of learning associations between multiple sensory inputs and motor outputs, and the animat was able to adapt to a new sensory mapping to restore its goal behavior: move toward and stay within a user-defined area. We further showed that successful learning required proper selections of stimuli to encode sensory inputs and a variety of training stimuli with adaptive selection contingent on the animats behavior. We also found that an individual network had the flexibility to achieve different multi-task goals, and the same goal behavior could be exhibited with different sets of network synaptic strengths. While lacking the characteristic layered structure of in vivo cortical tissue, the biologically inspired simulated networks could tune their activity in behaviorally relevant manners, demonstrating that leaky integrate-and-fire neural networks have an innate ability to process information. This closed-loop hybrid system is a useful tool to study the network properties intermediating synaptic plasticity and behavioral adaptation. The training algorithm provides a stepping stone towards designing future control systems, whether with artificial neural networks or biological animats themselves.'),
(83858, 2008, 'plos', 'Prediction of human disease genes by human-mouse conserved coexpression analysis', 'Ala, Ugo|Piro, Rosario Michael|Grassi, Elena|Damasco, Christian|Silengo, Lorenzo|Oti, Martin|Provero, Paolo|Di Cunto, Ferdinando', 'Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.|Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.', 'Italy|Italy|Italy|Italy|Italy|Italy|Italy|Italy', 92, 'Algorithms|Animals|Biomarkers|Chromosome Mapping|Conserved Sequence|Diagnosis, Computer-Assisted|Gene Expression Profiling|Genetic Diseases, Inborn|Genetic Predisposition to Disease|Humans|Mice|Proteome', 'Evaluation Studies', '10.1371/journal.pcbi.1000043', '18369433', 'Even in the post-genomic era, the identification of candidate genes within loci associated with human genetic diseases is a very demanding task, because the critical region may typically contain hundreds of positional candidates. Since genes implicated in similar phenotypes tend to share very similar expression profiles, high throughput gene expression data may represent a very important resource to identify the best candidates for sequencing. However, so far, gene coexpression has not been used very successfully to prioritize positional candidates.'),
(83859, 2008, 'plos', 'A semi-supervised method for predicting transcription factor-gene interactions in Escherichia coli', 'Ernst, Jason|Beg, Qasim K|Kay, Krin A|Balázsi, Gábor|Oltvai, Zoltán N|Bar-Joseph, Ziv', 'Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Artificial Intelligence|Base Sequence|Escherichia coli|Escherichia coli Proteins|Gene Expression Profiling|Gene Expression Regulation, Bacterial|Molecular Sequence Data|Pattern Recognition, Automated|Protein Interaction Mapping|Sequence Analysis, DNA|Transcription Factors', 'Evaluation Studies', '10.1371/journal.pcbi.1000044', '18369434', 'While Escherichia coli has one of the most comprehensive datasets of experimentally verified transcriptional regulatory interactions of any organism, it is still far from complete. This presents a problem when trying to combine gene expression and regulatory interactions to model transcriptional regulatory networks. Using the available regulatory interactions to predict new interactions may lead to better coverage and more accurate models. Here, we develop SEREND (SEmi-supervised REgulatory Network Discoverer), a semi-supervised learning method that uses a curated database of verified transcriptional factor-gene interactions, DNA sequence binding motifs, and a compendium of gene expression data in order to make thousands of new predictions about transcription factor-gene interactions, including whether the transcription factor activates or represses the gene. Using genome-wide binding datasets for several transcription factors, we demonstrate that our semi-supervised classification strategy improves the prediction of targets for a given transcription factor. To further demonstrate the utility of our inferred interactions, we generated a new microarray gene expression dataset for the aerobic to anaerobic shift response in E. coli. We used our inferred interactions with the verified interactions to reconstruct a dynamic regulatory network for this response. The network reconstructed when using our inferred interactions was better able to correctly identify known regulators and suggested additional activators and repressors as having important roles during the aerobic-anaerobic shift interface.'),
(83860, 2008, 'plos', 'The dynamics of human body weight change', 'Chow, Carson C|Hall, Kevin D', 'Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. carsonc@mail.nih.gov|Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America. carsonc@mail.nih.gov', 'United States|United States', 86, 'Body Composition|Computer Simulation|Eating|Energy Metabolism|Humans|Kinetics|Models, Biological|Obesity|Weight Gain|Weight Loss', 'Journal Article', '10.1371/journal.pcbi.1000045', '18369435', 'An imbalance between energy intake and energy expenditure will lead to a change in body weight (mass) and body composition (fat and lean masses). A quantitative understanding of the processes involved, which currently remains lacking, will be useful in determining the etiology and treatment of obesity and other conditions resulting from prolonged energy imbalance. Here, we show that a mathematical model of the macronutrient flux balances can capture the long-term dynamics of human weight change, all previous models are special cases of this model. We show that the generic dynamic behavior of body composition for a clamped diet can be divided into two classes. In the first class, the body composition and mass are determined uniquely. In the second class, the body composition can exist at an infinite number of possible states. Surprisingly, perturbations of dietary energy intake or energy expenditure can give identical responses in both model classes, and existing data are insufficient to distinguish between these two possibilities. Nevertheless, this distinction has important implications for the efficacy of clinical interventions that alter body composition and mass.'),
(83861, 2008, 'plos', 'Neurobiological models of two-choice decision making can be reduced to a one-dimensional nonlinear diffusion equation', 'Roxin, Alex|Ledberg, Anders', 'Computational Neuroscience, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain. alexander.roxin@upf.edu|Computational Neuroscience, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain. alexander.roxin@upf.edu', 'Spain|Spain', 83, 'Animals|Brain|Choice Behavior|Computer Simulation|Haplorhini|Humans|Models, Neurological|Nerve Net|Neurobiology|Neurons', 'Journal Article', '10.1371/journal.pcbi.1000046', '18369436', 'The response behaviors in many two-alternative choice tasks are well described by so-called sequential sampling models. In these models, the evidence for each one of the two alternatives accumulates over time until it reaches a threshold, at which point a response is made. At the neurophysiological level, single neuron data recorded while monkeys are engaged in two-alternative choice tasks are well described by winner-take-all network models in which the two choices are represented in the firing rates of separate populations of neurons. Here, we show that such nonlinear network models can generally be reduced to a one-dimensional nonlinear diffusion equation, which bears functional resemblance to standard sequential sampling models of behavior. This reduction gives the functional dependence of performance and reaction-times on external inputs in the original system, irrespective of the system details. What is more, the nonlinear diffusion equation can provide excellent fits to behavioral data from two-choice decision making tasks by varying these external inputs. This suggests that changes in behavior under various experimental conditions, e.g. changes in stimulus coherence or response deadline, are driven by internal modulation of afferent inputs to putative decision making circuits in the brain. For certain model systems one can analytically derive the nonlinear diffusion equation, thereby mapping the original system parameters onto the diffusion equation coefficients. Here, we illustrate this with three model systems including coupled rate equations and a network of spiking neurons.'),
(83862, 2008, 'plos', 'Src kinase conformational activation: thermodynamics, pathways, and mechanisms', 'Yang, Sichun|Roux, Benoît', 'Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, Chicago, Illinois, United States of America.|Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States', 77, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Kinetics|Models, Chemical|Models, Molecular|Molecular Sequence Data|Motion|Protein Binding|Protein Conformation|Sequence Analysis, Protein|Structure-Activity Relationship|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1000047', '18369437', 'Tyrosine kinases of the Src-family are large allosteric enzymes that play a key role in cellular signaling. Conversion of the kinase from an inactive to an active state is accompanied by substantial structural changes. Here, we construct a coarse-grained model of the catalytic domain incorporating experimental structures for the two stable states, and simulate the dynamics of conformational transitions in kinase activation. We explore the transition energy landscapes by constructing a structural network among clusters of conformations from the simulations. From the structural network, two major ensembles of pathways for the activation are identified. In the first transition pathway, we find a coordinated switching mechanism of interactions among the alphaC helix, the activation-loop, and the beta strands in the N-lobe of the catalytic domain. In a second pathway, the conformational change is coupled to a partial unfolding of the N-lobe region of the catalytic domain. We also characterize the switching mechanism for the alphaC helix and the activation-loop in detail. Finally, we test the performance of a Markov model and its ability to account for the structural kinetics in the context of Src conformational changes. Taken together, these results provide a broad framework for understanding the main features of the conformational transition taking place upon Src activation.'),
(83863, 2008, 'plos', 'A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach', 'Wang, Peng|Sidney, John|Dow, Courtney|Mothé, Bianca|Sette, Alessandro|Peters, Bjoern', 'La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.|La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 454, 'Algorithms|Amino Acid Sequence|Binding Sites|Epitope Mapping|Genes, MHC Class II|HLA-D Antigens|Molecular Sequence Data|Peptides|Protein Binding|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000048', '18389056', 'The identification of MHC class II restricted peptide epitopes is an important goal in immunological research. A number of computational tools have been developed for this purpose, but there is a lack of large-scale systematic evaluation of their performance. Herein, we used a comprehensive dataset consisting of more than 10,000 previously unpublished MHC-peptide binding affinities, 29 peptide/MHC crystal structures, and 664 peptides experimentally tested for CD4+ T cell responses to systematically evaluate the performances of publicly available MHC class II binding prediction tools. While in selected instances the best tools were associated with AUC values up to 0.86, in general, class II predictions did not perform as well as historically noted for class I predictions. It appears that the ability of MHC class II molecules to bind variable length peptides, which requires the correct assignment of peptide binding cores, is a critical factor limiting the performance of existing prediction tools. To improve performance, we implemented a consensus prediction approach that combines methods with top performances. We show that this consensus approach achieved best overall performance. Finally, we make the large datasets used publicly available as a benchmark to facilitate further development of MHC class II binding peptide prediction methods.'),
(83864, 2008, 'plos', 'The statistical neuroanatomy of frontal networks in the macaque', 'Averbeck, Bruno B|Seo, Moonsang', 'Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom. b.averbeck@ion.ucl.ac.uk|Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom. b.averbeck@ion.ucl.ac.uk', 'United Kingdom|United Kingdom', 65, 'Animals|Computer Simulation|Data Interpretation, Statistical|Frontal Lobe|Macaca|Models, Anatomic|Models, Neurological|Models, Statistical|Nerve Net|Neural Pathways|Neuroanatomy', 'Journal Article', '10.1371/journal.pcbi.1000050', '18389057', 'We were interested in gaining insight into the functional properties of frontal networks based upon their anatomical inputs. We took a neuroinformatics approach, carrying out maximum likelihood hierarchical cluster analysis on 25 frontal cortical areas based upon their anatomical connections, with 68 input areas representing exterosensory, chemosensory, motor, limbic, and other frontal inputs. The analysis revealed a set of statistically robust clusters. We used these clusters to divide the frontal areas into 5 groups, including ventral-lateral, ventral-medial, dorsal-medial, dorsal-lateral, and caudal-orbital groups. Each of these groups was defined by a unique set of inputs. This organization provides insight into the differential roles of each group of areas and suggests a gradient by which orbital and ventral-medial areas may be responsible for decision-making processes based on emotion and primary reinforcers, and lateral frontal areas are more involved in integrating affective and rational information into a common framework.'),
(83865, 2008, 'plos', 'Genome-wide prediction of SH2 domain targets using structural information and the FoldX algorithm', 'Sánchez, Ignacio E|Beltrao, Pedro|Stricher, Francois|Schymkowitz, Joost|Ferkinghoff-Borg, Jesper|Rousseau, Frederic|Serrano, Luis', 'European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 34, 'Algorithms|Amino Acid Sequence|Binding Sites|Chromosome Mapping|Molecular Sequence Data|Protein Binding|Protein Interaction Mapping|Sequence Analysis, Protein|Software|src Homology Domains|src-Family Kinases', 'Journal Article', '10.1371/journal.pcbi.1000052', '18389064', 'Current experiments likely cover only a fraction of all protein-protein interactions. Here, we developed a method to predict SH2-mediated protein-protein interactions using the structure of SH2-phosphopeptide complexes and the FoldX algorithm. We show that our approach performs similarly to experimentally derived consensus sequences and substitution matrices at predicting known in vitro and in vivo targets of SH2 domains. We use our method to provide a set of high-confidence interactions for human SH2 domains with known structure filtered on secondary structure and phosphorylation state. We validated the predictions using literature-derived SH2 interactions and a probabilistic score obtained from a naive Bayes integration of information on coexpression, conservation of the interaction in other species, shared interaction partners, and functions. We show how our predictions lead to a new hypothesis for the role of SH2 domains in signaling.'),
(83866, 2008, 'plos', 'Dimensionality and dynamics in the behavior of C elegans', 'Stephens, Greg J|Johnson-Kerner, Bethany|Bialek, William|Ryu, William S', 'Lewis-Sigler Institute for Integrative Genomics, Princeton, New Jersey, United States of America. gstephen@princeton.edu|Lewis-Sigler Institute for Integrative Genomics, Princeton, New Jersey, United States of America. gstephen@princeton.edu|Lewis-Sigler Institute for Integrative Genomics, Princeton, New Jersey, United States of America. gstephen@princeton.edu|Lewis-Sigler Institute for Integrative Genomics, Princeton, New Jersey, United States of America. gstephen@princeton.edu', 'Jersey|Jersey|Jersey|Jersey', 213, 'Animals|Behavior, Animal|Caenorhabditis elegans|Computer Simulation|Gait|Locomotion|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000028', '18389066', 'A major challenge in analyzing animal behavior is to discover some underlying simplicity in complex motor actions. Here, we show that the space of shapes adopted by the nematode Caenorhabditis elegans is low dimensional, with just four dimensions accounting for 95% of the shape variance. These dimensions provide a quantitative description of worm behavior, and we partially reconstruct equations of motion for the dynamics in this space. These dynamics have multiple attractors, and we find that the worm visits these in a rapid and almost completely deterministic response to weak thermal stimuli. Stimulus-dependent correlations among the different modes suggest that one can generate more reliable behaviors by synchronizing stimuli to the state of the worm in shape space. We confirm this prediction, effectively steering the worm in real time.'),
(83867, 2008, 'plos', 'Biosynthetic potentials of metabolites and their hierarchical organization', 'Matthäus, Franziska|Salazar, Carlos|Ebenhöh, Oliver', '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', 13, 'Algorithms|Computer Simulation|Energy Metabolism|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000049', '18392147', 'A major challenge in systems biology is to understand how complex and highly connected metabolic networks are organized. The structure of these networks is investigated here by identifying sets of metabolites that have a similar biosynthetic potential. We measure the biosynthetic potential of a particular compound by determining all metabolites than can be produced from it and, following a terminology introduced previously, call this set the scope of the compound. To identify groups of compounds with similar scopes, we apply a hierarchical clustering method. We find that compounds within the same cluster often display similar chemical structures and appear in the same metabolic pathway. For each cluster we define a consensus scope by determining a set of metabolites that is most similar to all scopes within the cluster. This allows for a generalization from scopes of single compounds to scopes of a chemical family. We observe that most of the resulting consensus scopes overlap or are fully contained in others, revealing a hierarchical ordering of metabolites according to their biosynthetic potential. Our investigations show that this hierarchy is not only determined by the chemical complexity of the metabolites, but also strongly by their biological function. As a general tendency, metabolites which are necessary for essential cellular processes exhibit a larger biosynthetic potential than those involved in secondary metabolism. A central result is that chemically very similar substances with different biological functions may differ significantly in their biosynthetic potentials. Our studies provide an important step towards understanding fundamental design principles of metabolic networks determined by the structural and functional complexity of metabolites.'),
(83868, 2008, 'plos', 'Statistical resolution of ambiguous HLA typing data', 'Listgarten, Jennifer|Brumme, Zabrina|Kadie, Carl|Xiaojiang, Gao|Walker, Bruce|Carrington, Mary|Goulder, Philip|Heckerman, David', 'Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com|Microsoft Research, Redmond, Washington, United States of America. jennl@microsoft.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 40, 'Algorithms|Alleles|Data Interpretation, Statistical|Gene Frequency|Genetics, Population|HLA-A Antigens|Haplotypes|Histocompatibility Testing|Humans|Polymorphism, Single Nucleotide|Reproducibility of Results|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.1000016', '18392148', 'High-resolution HLA typing plays a central role in many areas of immunology, such as in identifying immunogenetic risk factors for disease, in studying how the genomes of pathogens evolve in response to immune selection pressures, and also in vaccine design, where identification of HLA-restricted epitopes may be used to guide the selection of vaccine immunogens. Perhaps one of the most immediate applications is in direct medical decisions concerning the matching of stem cell transplant donors to unrelated recipients. However, high-resolution HLA typing is frequently unavailable due to its high cost or the inability to re-type historical data. In this paper, we introduce and evaluate a method for statistical, in silico refinement of ambiguous and/or low-resolution HLA data. Our method, which requires an independent, high-resolution training data set drawn from the same population as the data to be refined, uses linkage disequilibrium in HLA haplotypes as well as four-digit allele frequency data to probabilistically refine HLA typings. Central to our approach is the use of haplotype inference. We introduce new methodology to this area, improving upon the Expectation-Maximization (EM)-based approaches currently used within the HLA community. Our improvements are achieved by using a parsimonious parameterization for haplotype distributions and by smoothing the maximum likelihood (ML) solution. These improvements make it possible to scale the refinement to a larger number of alleles and loci in a more computationally efficient and stable manner. We also show how to augment our method in order to incorporate ethnicity information (as HLA allele distributions vary widely according to race/ethnicity as well as geographic area), and demonstrate the potential utility of this experimentally. A tool based on our approach is freely available for research purposes at http://microsoft.com/science.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83869, 2008, 'plos', 'Evaluation of paired-end sequencing strategies for detection of genome rearrangements in cancer', 'Bashir, Ali|Volik, Stanislav|Collins, Colin|Bafna, Vineet|Raphael, Benjamin J', 'Bioinformatics Graduate Program, University of California San Diego, San Diego, California, United States of America. abashir@ucsd.edu|Bioinformatics Graduate Program, University of California San Diego, San Diego, California, United States of America. abashir@ucsd.edu|Bioinformatics Graduate Program, University of California San Diego, San Diego, California, United States of America. abashir@ucsd.edu|Bioinformatics Graduate Program, University of California San Diego, San Diego, California, United States of America. abashir@ucsd.edu|Bioinformatics Graduate Program, University of California San Diego, San Diego, California, United States of America. abashir@ucsd.edu', 'United States|United States|United States|United States|United States', 55, 'Algorithms|Base Sequence|Breast Neoplasms|Chromosome Mapping|Female|Gene Rearrangement|Humans|Molecular Sequence Data|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000051', '18404202', 'Paired-end sequencing is emerging as a key technique for assessing genome rearrangements and structural variation on a genome-wide scale. This technique is particularly useful for detecting copy-neutral rearrangements, such as inversions and translocations, which are common in cancer and can produce novel fusion genes. We address the question of how much sequencing is required to detect rearrangement breakpoints and to localize them precisely using both theoretical models and simulation. We derive a formula for the probability that a fusion gene exists in a cancer genome given a collection of paired-end sequences from this genome. We use this formula to compute fusion gene probabilities in several breast cancer samples, and we find that we are able to accurately predict fusion genes in these samples with a relatively small number of fragments of large size. We further demonstrate how the ability to detect fusion genes depends on the distribution of gene lengths, and we evaluate how different parameters of a sequencing strategy impact breakpoint detection, breakpoint localization, and fusion gene detection, even in the presence of errors that suggest false rearrangements. These results will be useful in calibrating future cancer sequencing efforts, particularly large-scale studies of many cancer genomes that are enabled by next-generation sequencing technologies.'),
(83870, 2008, 'plos', 'The role of elastic stresses on leaf venation morphogenesis', 'Laguna, Maria F|Bohn, Steffen|Jagla, Eduardo A', 'Centro Atómico Bariloche, Comisión Nacional de Energía Atómica, Bariloche, Argentina. lagunaf@cab.cnea.gov.ar|Centro Atómico Bariloche, Comisión Nacional de Energía Atómica, Bariloche, Argentina. lagunaf@cab.cnea.gov.ar|Centro Atómico Bariloche, Comisión Nacional de Energía Atómica, Bariloche, Argentina. lagunaf@cab.cnea.gov.ar', 'Argentina|Argentina|Argentina', 42, 'Computer Simulation|Elasticity|Mechanotransduction, Cellular|Models, Biological|Morphogenesis|Plant Leaves|Stress, Mechanical', 'Journal Article', '10.1371/journal.pcbi.1000055', '18404203', 'We explore the possible role of elastic mismatch between epidermis and mesophyll as a driving force for the development of leaf venation. The current prevalent canalization hypothesis for the formation of veins claims that the transport of the hormone auxin out of the leaves triggers cell differentiation to form veins. Although there is evidence that auxin plays a fundamental role in vein formation, the simple canalization mechanism may not be enough to explain some features observed in the vascular system of leaves, in particular, the abundance of vein loops. We present a model based on the existence of mechanical instabilities that leads very naturally to hierarchical patterns with a large number of closed loops. When applied to the structure of high-order veins, the numerical results show the same qualitative features as actual venation patterns and, furthermore, have the same statistical properties. We argue that the agreement between actual and simulated patterns provides strong evidence for the role of mechanical effects on venation development.'),
(83871, 2008, 'plos', 'A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains', 'Kornev, Alexandr P|Taylor, Susan S|Ten Eyck, Lynn F', 'San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America.|San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America.|San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 42, 'Binding Sites|Computer Simulation|Cyclic AMP|Models, Chemical|Models, Molecular|Protein Binding|Protein Structure, Tertiary|Regulatory Sequences, Nucleic Acid|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000056', '18404204', 'Cyclic nucleotides (cAMP and cGMP) regulate multiple intracellular processes and are thus of a great general interest for molecular and structural biologists. To study the allosteric mechanism of different cyclic nucleotide binding (CNB) domains, we compared cAMP-bound and cAMP-free structures (PKA, Epac, and two ionic channels) using a new bioinformatics method: local spatial pattern alignment. Our analysis highlights four major conserved structural motifs: 1) the phosphate binding cassette (PBC), which binds the cAMP ribose-phosphate, 2) the hinge, a flexible helix, which contacts the PBC, 3) the beta(2,3) loop, which provides precise positioning of an invariant arginine from the PBC, and 4) a conserved structural element consisting of an N-terminal helix, an eight residue loop and the A-helix (N3A-motif). The PBC and the hinge were included in the previously reported allosteric model, whereas the definition of the beta(2,3) loop and the N3A-motif as conserved elements is novel. The N3A-motif is found in all cis-regulated CNB domains, and we present a model for an allosteric mechanism in these domains. Catabolite gene activator protein (CAP) represents a trans-regulated CNB domain family: it does not contain the N3A-motif, and its long range allosteric interactions are substantially different from the cis-regulated CNB domains.'),
(83872, 2008, 'plos', 'Estimating cell depth from somatic mutations', 'Wasserstrom, Adam|Frumkin, Dan|Adar, Rivka|Itzkovitz, Shalev|Stern, Tomer|Kaplan, Shai|Shefer, Gabi|Shur, Irena|Zangi, Lior|Reizel, Yitzhak|Harmelin, Alon|Dor, Yuval|Dekel, Nava|Reisner, Yair|Benayahu, Dafna|Tzahor, Eldad|Segal, Eran|Shapiro, Ehud', 'Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Israel|Is', 24, 'Animals|B-Lymphocytes|Base Sequence|Cells, Cultured|Cellular Senescence|DNA Mutational Analysis|Hybrid Cells|Mice|Microsatellite Repeats|Molecular Sequence Data|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000058', '18404205', 'The depth of a cell of a multicellular organism is the number of cell divisions it underwent since the zygote, and knowing this basic cell property would help address fundamental problems in several areas of biology. At present, the depths of the vast majority of human and mouse cell types are unknown. Here, we show a method for estimating the depth of a cell by analyzing somatic mutations in its microsatellites, and provide to our knowledge for the first time reliable depth estimates for several cells types in mice. According to our estimates, the average depth of oocytes is 29, consistent with previous estimates. The average depth of B cells ranges from 34 to 79, linearly related to the mouse age, suggesting a rate of one cell division per day. In contrast, various types of adult stem cells underwent on average fewer cell divisions, supporting the notion that adult stem cells are relatively quiescent. Our method for depth estimation opens a window for revealing tissue turnover rates in animals, including humans, which has important implications for our knowledge of the body under physiological and pathological conditions.'),
(83873, 2008, 'plos', 'The emergence and fate of horizontally acquired genes in Escherichia coli', 'van Passel, Mark W J|Marri, Pradeep Reddy|Ochman, Howard', 'Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona, United States of America. Mark.vanPassel@wur.nl|Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona, United States of America. Mark.vanPassel@wur.nl|Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona, United States of America. Mark.vanPassel@wur.nl', 'United States|United States|United States', 53, 'Bacterial Proteins|Escherichia coli|Evolution, Molecular|Gene Transfer, Horizontal|Genetic Variation|Genomic Instability|Shigella', 'Journal Article', '10.1371/journal.pcbi.1000059', '18404206', 'Bacterial species, and even strains within species, can vary greatly in their gene contents and metabolic capabilities. We examine the evolution of this diversity by assessing the distribution and ancestry of each gene in 13 sequenced isolates of Escherichia coli and Shigella. We focus on the emergence and demise of two specific classes of genes, ORFans (genes with no homologs in present databases) and HOPs (genes with distant homologs), since these genes, in contrast to most conserved ancestral sequences, are known to be a major source of the novel features in each strain. We find that the rates of gain and loss of these genes vary greatly among strains as well as through time, and that ORFans and HOPs show very different behavior with respect to their emergence and demise. Although HOPs, which mostly represent gene acquisitions from other bacteria, originate more frequently, ORFans are much more likely to persist. This difference suggests that many adaptive traits are conferred by completely novel genes that do not originate in other bacterial genomes. With respect to the demise of these acquired genes, we find that strains of Shigella lose genes, both by disruption events and by complete removal, at accelerated rates.'),
(83874, 2008, 'plos', 'Binding-induced folding of a natively unstructured transcription factor', 'Turjanski, Adrian Gustavo|Gutkind, J Silvio|Best, Robert B|Hummer, Gerhard', 'Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.|Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.|Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.|Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.', 'United States|United States|United States|United States', 0, 'Amino Acid Sequence|Binding Sites|CREB-Binding Protein|Computer Simulation|Humans|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Protein Folding|Protein Structure, Tertiary|Sequence Analysis, Protein|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000060', '18404207', 'Transcription factors are central components of the intracellular regulatory networks that control gene expression. An increasingly recognized phenomenon among human transcription factors is the formation of structure upon target binding. Here, we study the folding and binding of the pKID domain of CREB to the KIX domain of the co-activator CBP. Our simulations of a topology-based Gxc5x8d-type model predict a coupled folding and binding mechanism, and the existence of partially bound intermediates. From transition-path and Phi-value analyses, we find that the binding transition state resembles the unstructured state in solution, implying that CREB becomes structured only after committing to binding. A change of structure following binding is reminiscent of an induced-fit mechanism and contrasts with models in which binding occurs to pre-structured conformations that exist in the unbound state at equilibrium. Interestingly, increasing the amount of structure in the unbound pKID reduces the rate of binding, suggesting a fly-casting-like process. We find that the inclusion of attractive non-native interactions results in the formation of non-specific encounter complexes that enhance the on-rate of binding, but do not significantly change the binding mechanism. Our study helps explain how being unstructured can confer an advantage in protein target recognition. The simulations are in general agreement with the results of a recently reported nuclear magnetic resonance study, and aid in the interpretation of the experimental binding kinetics.'),
(83875, 2008, 'plos', 'Predicting co-complexed protein pairs from heterogeneous data', 'Qiu, Jian|Noble, William Stafford', 'Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.|Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.', 'United States|United States', 0, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Databases, Protein|Information Storage and Retrieval|Models, Chemical|Models, Molecular|Molecular Sequence Data|Multiprotein Complexes|Protein Binding|Protein Conformation|Protein Interaction Mapping|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000054', '18421371', 'Proteins do not carry out their functions alone. Instead, they often act by participating in macromolecular complexes and play different functional roles depending on the other members of the complex. It is therefore interesting to identify co-complex relationships. Although protein complexes can be identified in a high-throughput manner by experimental technologies such as affinity purification coupled with mass spectrometry (APMS), these large-scale datasets often suffer from high false positive and false negative rates. Here, we present a computational method that predicts co-complexed protein pair (CCPP) relationships using kernel methods from heterogeneous data sources. We show that a diffusion kernel based on random walks on the full network topology yields good performance in predicting CCPPs from protein interaction networks. In the setting of direct ranking, a diffusion kernel performs much better than the mutual clustering coefficient. In the setting of SVM classifiers, a diffusion kernel performs much better than a linear kernel. We also show that combination of complementary information improves the performance of our CCPP recognizer. A summation of three diffusion kernels based on two-hybrid, APMS, and genetic interaction networks and three sequence kernels achieves better performance than the sequence kernels or diffusion kernels alone. Inclusion of additional features achieves a still better ROC(50) of 0.937. Assuming a negative-to-positive ratio of 600ratio1, the final classifier achieves 89.3% coverage at an estimated false discovery rate of 10%. Finally, we applied our prediction method to two recently described APMS datasets. We find that our predicted positives are highly enriched with CCPPs that are identified by both datasets, suggesting that our method successfully identifies true CCPPs. An SVM classifier trained from heterogeneous data sources provides accurate predictions of CCPPs in yeast. This computational method thereby provides an inexpensive method for identifying protein complexes that extends and complements high-throughput experimental data.'),
(83876, 2008, 'plos', 'Investigations of oligonucleotide usage variance within and between prokaryotes', 'Bohlin, Jon|Skjerve, Eystein|Ussery, David W', 'Norwegian School of Veterinary Science, Oslo, Norway.|Norwegian School of Veterinary Science, Oslo, Norway.|Norwegian School of Veterinary Science, Oslo, Norway.', 'Norway|Norway|Norway', 38, 'Base Composition|Base Sequence|Chromosome Mapping|Computer Simulation|DNA, Archaeal|DNA, Bacterial|Evolution, Molecular|Genetic Variation|Models, Genetic|Molecular Sequence Data|Sequence Analysis, DNA|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000057', '18421372', 'Oligonucleotide usage in archaeal and bacterial genomes can be linked to a number of properties, including codon usage (trinucleotides), DNA base-stacking energy (dinucleotides), and DNA structural conformation (di- to tetranucleotides). We wanted to assess the statistical information potential of different DNA word-sizes and explore how oligonucleotide frequencies differ in coding and non-coding regions. In addition, we used oligonucleotide frequencies to investigate DNA composition and how DNA sequence patterns change within and between prokaryotic organisms. Among the results found was that prokaryotic chromosomes can be described by hexanucleotide frequencies, suggesting that prokaryotic DNA is predominantly short range correlated, i.e., information in prokaryotic genomes is encoded in short oligonucleotides. Oligonucleotide usage varied more within AT-rich and host-associated genomes than in GC-rich and free-living genomes, and this variation was mainly located in non-coding regions. Bias (selectional pressure) in tetranucleotide usage correlated with GC content, and coding regions were more biased than non-coding regions. Non-coding regions were also found to be approximately 5.5% more AT-rich than coding regions, on average, in the 402 chromosomes examined. Pronounced DNA compositional differences were found both within and between AT-rich and GC-rich genomes. GC-rich genomes were more similar and biased in terms of tetranucleotide usage in non-coding regions than AT-rich genomes. The differences found between AT-rich and GC-rich genomes may possibly be attributed to lifestyle, since tetranucleotide usage within host-associated bacteria was, on average, more dissimilar and less biased than free-living archaea and bacteria.'),
(83877, 2008, 'plos', 'Synaptic learning rules and sparse coding in a model sensory system', 'Finelli, Luca A|Haney, Seth|Bazhenov, Maxim|Stopfer, Mark|Sejnowski, Terrence J', 'Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. lfinelli@salk.edu|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. lfinelli@salk.edu|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. lfinelli@salk.edu|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. lfinelli@salk.edu|Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. lfinelli@salk.edu', 'United States|United States|United States|United States|United States', 0, 'Action Potentials|Adaptation, Physiological|Animals|Biological Clocks|Computer Simulation|Grasshoppers|Learning|Models, Neurological|Nerve Net|Neuronal Plasticity|Olfactory Receptor Neurons|Smell|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000062', '18421373', 'Neural circuits exploit numerous strategies for encoding information. Although the functional significance of individual coding mechanisms has been investigated, ways in which multiple mechanisms interact and integrate are not well understood. The locust olfactory system, in which dense, transiently synchronized spike trains across ensembles of antenna lobe (AL) neurons are transformed into a sparse representation in the mushroom body (MB, a region associated with memory), provides a well-studied preparation for investigating the interaction of multiple coding mechanisms. Recordings made in vivo from the insect MB demonstrated highly specific responses to odors in Kenyon cells (KCs). Typically, only a few KCs from the recorded population of neurons responded reliably when a specific odor was presented. Different odors induced responses in different KCs. Here, we explored with a biologically plausible model the possibility that a form of plasticity may control and tune synaptic weights of inputs to the mushroom body to ensure the specificity of KCs responses to familiar or meaningful odors. We found that plasticity at the synapses between the AL and the MB efficiently regulated the delicate tuning necessary to selectively filter the intense AL oscillatory output and condense it to a sparse representation in the MB. Activity-dependent plasticity drove the observed specificity, reliability, and expected persistence of odor representations, suggesting a role for plasticity in information processing and making a testable prediction about synaptic plasticity at AL-MB synapses.'),
(83878, 2008, 'plos', 'Functional maps of protein complexes from quantitative genetic interaction data', 'Bandyopadhyay, Sourav|Kelley, Ryan|Krogan, Nevan J|Ideker, Trey', 'Program in Bioinformatics, University of California San Diego, La Jolla, California, United States of America.|Program in Bioinformatics, University of California San Diego, La Jolla, California, United States of America.|Program in Bioinformatics, University of California San Diego, La Jolla, California, United States of America.|Program in Bioinformatics, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States', 108, 'Binding Sites|Chromosome Mapping|Computer Simulation|Models, Biological|Protein Binding|Protein Interaction Mapping|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000065', '18421374', 'Recently, a number of advanced screening technologies have allowed for the comprehensive quantification of aggravating and alleviating genetic interactions among gene pairs. In parallel, TAP-MS studies (tandem affinity purification followed by mass spectroscopy) have been successful at identifying physical protein interactions that can indicate proteins participating in the same molecular complex. Here, we propose a method for the joint learning of protein complexes and their functional relationships by integration of quantitative genetic interactions and TAP-MS data. Using 3 independent benchmark datasets, we demonstrate that this method is >50% more accurate at identifying functionally related protein pairs than previous approaches. Application to genes involved in yeast chromosome organization identifies a functional map of 91 multimeric complexes, a number of which are novel or have been substantially expanded by addition of new subunits. Interestingly, we find that complexes that are enriched for aggravating genetic interactions (i.e., synthetic lethality) are more likely to contain essential genes, linking each of these interactions to an underlying mechanism. These results demonstrate the importance of both large-scale genetic and physical interaction data in mapping pathway architecture and function.'),
(83879, 2008, 'plos', 'Performance and scalability of discriminative metrics for comparative gene identification in 12 Drosophila genomes', 'Lin, Michael F|Deoras, Ameya N|Rasmussen, Matthew D|Kellis, Manolis', 'Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, United States of America.|Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, United States of America.|Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, United States of America.|Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|Base Sequence|Chromosome Mapping|Discriminant Analysis|Drosophila|Drosophila Proteins|Genetic Variation|Molecular Sequence Data|Open Reading Frames|Reproducibility of Results|Sensitivity and Specificity|Sequence Analysis, DNA|Species Specificity', 'Comparative Study', '10.1371/journal.pcbi.1000067', '18421375', 'Comparative genomics of multiple related species is a powerful methodology for the discovery of functional genomic elements, and its power should increase with the number of species compared. Here, we use 12 Drosophila genomes to study the power of comparative genomics metrics to distinguish between protein-coding and non-coding regions. First, we study the relative power of different comparative metrics and their relationship to single-species metrics. We find that even relatively simple multi-species metrics robustly outperform advanced single-species metrics, especially for shorter exons (< or =240 nt), which are common in animal genomes. Moreover, the two capture largely independent features of protein-coding genes, with different sensitivity/specificity trade-offs, such that their combinations lead to even greater discriminatory power. In addition, we study how discovery power scales with the number and phylogenetic distance of the genomes compared. We find that species at a broad range of distances are comparably effective informants for pairwise comparative gene identification, but that these are surpassed by multi-species comparisons at similar evolutionary divergence. In particular, while pairwise discovery power plateaued at larger distances and never outperformed the most advanced single-species metrics, multi-species comparisons continued to benefit even from the most distant species with no apparent saturation. Last, we find that genes in functional categories typically considered fast-evolving can nonetheless be recovered at very high rates using comparative methods. Our results have implications for comparative genomics analyses in any species, including the human.'),
(83880, 2008, 'plos', 'Ten simple rules for aspiring scientists in a low-income country', 'Moreno, Edgardo|Gutiérrez, José-María', 'Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Heredia, Costa Rica. emoreno@medvet.una.ac.cr|Programa de Investigación en Enfermedades Tropicales, Escuela de Medicina Veterinaria, Universidad Nacional, Heredia, Costa Rica. emoreno@medvet.una.ac.cr', 'Costa Rica|Costa Rica', 10, 'Algorithms|Career Mobility|Cooperative Behavior|Developed Countries|Research|Science', 'Journal Article', '10.1371/journal.pcbi.1000024', '18437198', '-'),
(83881, 2008, 'plos', 'An AP endonuclease 1-DNA polymerase beta complex: theoretical prediction of interacting surfaces', 'Abyzov, Alexej|Uzun, Alper|Strauss, Phyllis R|Ilyin, Valentin A', 'Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Biology, Northeastern University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 15, 'Binding Sites|Computer Simulation|DNA|DNA Polymerase beta|DNA-(Apurinic or Apyrimidinic Site) Lyase|Enzyme Activation|Models, Chemical|Models, Molecular|Nucleic Acid Conformation|Protein Binding|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.1000066', '18437203', 'Abasic (AP) sites in DNA arise through both endogenous and exogenous mechanisms. Since AP sites can prevent replication and transcription, the cell contains systems for their identification and repair. AP endonuclease (APEX1) cleaves the phosphodiester backbone 5 to the AP site. The cleavage, a key step in the base excision repair pathway, is followed by nucleotide insertion and removal of the downstream deoxyribose moiety, performed most often by DNA polymerase beta (pol-beta). While yeast two-hybrid studies and electrophoretic mobility shift assays provide evidence for interaction of APEX1 and pol-beta, the specifics remain obscure. We describe a theoretical study designed to predict detailed interacting surfaces between APEX1 and pol-beta based on published co-crystal structures of each enzyme bound to DNA. Several potentially interacting complexes were identified by sliding the protein molecules along DNA: two with pol-beta located downstream of APEX1 (3 to the damaged site) and three with pol-beta located upstream of APEX1 (5 to the damaged site). Molecular dynamics (MD) simulations, ensuring geometrical complementarity of interfaces, enabled us to predict interacting residues and calculate binding energies, which in two cases were sufficient (approximately -10.0 kcal/mol) to form a stable complex and in one case a weakly interacting complex. Analysis of interface behavior during MD simulation and visual inspection of interfaces allowed us to conclude that complexes with pol-beta at the 3-side of APEX1 are those most likely to occur in vivo. Additional multiple sequence analyses of APEX1 and pol-beta in related organisms identified a set of correlated mutations of specific residues at the predicted interfaces. Based on these results, we propose that pol-beta in the open or closed conformation interacts and makes a stable interface with APEX1 bound to a cleaved abasic site on the 3 side. The method described here can be used for analysis in any DNA-metabolizing pathway where weak interactions are the principal mode of cross-talk among participants and co-crystal structures of the individual components are available.'),
(83882, 2008, 'plos', 'Bioinformatics in China: a personal perspective', 'Wei, Liping|Yu, Jun', 'Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, Peoples Republic of China. weilp@mail.cbi.pku.edu.cn|Center for Bioinformatics, National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing, Peoples Republic of China. weilp@mail.cbi.pku.edu.cn', 'China|China', 0, 'Biology|China|Computational Biology|Genomics|Research', 'Journal Article', '10.1371/journal.pcbi.1000020', '18437216', '-'),
(83883, 2008, 'plos', 'Efficient olfactory coding in the pheromone receptor neuron of a moth', 'Kostal, Lubomir|Lansky, Petr|Rospars, Jean-Pierre', 'Institute of Physiology, Academy of Sciences, Prague, Czech Republic.|Institute of Physiology, Academy of Sciences, Prague, Czech Republic.|Institute of Physiology, Academy of Sciences, Prague, Czech Republic.', '-|-|-', 27, 'Action Potentials|Animals|Computer Simulation|Female|Male|Models, Neurological|Moths|Olfactory Pathways|Olfactory Receptor Neurons|Sex Attractants|Smell', 'Journal Article', '10.1371/journal.pcbi.1000053', '18437217', 'The concept of coding efficiency holds that sensory neurons are adapted, through both evolutionary and developmental processes, to the statistical characteristics of their natural stimulus. Encouraged by the successful invocation of this principle to predict how neurons encode natural auditory and visual stimuli, we attempted its application to olfactory neurons. The pheromone receptor neuron of the male moth Antheraea polyphemus, for which quantitative properties of both the natural stimulus and the reception processes are available, was selected. We predicted several characteristics that the pheromone plume should possess under the hypothesis that the receptors perform optimally, i.e., transfer as much information on the stimulus per unit time as possible. Our results demonstrate that the statistical characteristics of the predicted stimulus, e.g., the probability distribution function of the stimulus concentration, the spectral density function of the stimulation course, and the intermittency, are in good agreement with those measured experimentally in the field. These results should stimulate further quantitative studies on the evolutionary adaptation of olfactory nervous systems to odorant plumes and on the plume characteristics that are most informative for the sniffer. Both aspects are relevant to the design of olfactory sensors for odour-tracking robots.'),
(83884, 2008, 'plos', 'A coarse-grained biophysical model of E coli and its application to perturbation of the rRNA operon copy number', 'Tadmor, Arbel D|Tlusty, Tsvi', 'Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.|Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel', 0, 'Biophysics|Cell Proliferation|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Gene Dosage|Models, Genetic|rRNA Operon', 'Journal Article', '10.1371/journal.pcbi.1000038', '18437222', 'We propose a biophysical model of Escherichia coli that predicts growth rate and an effective cellular composition from an effective, coarse-grained representation of its genome. We assume that E. coli is in a state of balanced exponential steady-state growth, growing in a temporally and spatially constant environment, rich in resources. We apply this model to a series of past measurements, where the growth rate and rRNA-to-protein ratio have been measured for seven E. coli strains with an rRNA operon copy number ranging from one to seven (the wild-type copy number). These experiments show that growth rate markedly decreases for strains with fewer than six copies. Using the model, we were able to reproduce these measurements. We show that the model that best fits these data suggests that the volume fraction of macromolecules inside E. coli is not fixed when the rRNA operon copy number is varied. Moreover, the model predicts that increasing the copy number beyond seven results in a cytoplasm densely packed with ribosomes and proteins. Assuming that under such overcrowded conditions prolonged diffusion times tend to weaken binding affinities, the model predicts that growth rate will not increase substantially beyond the wild-type growth rate, as indicated by other experiments. Our model therefore suggests that changing the rRNA operon copy number of wild-type E. coli cells growing in a constant rich environment does not substantially increase their growth rate. Other observations regarding strains with an altered rRNA operon copy number, such as nucleoid compaction and the rRNA operon feedback response, appear to be qualitatively consistent with this model. In addition, we discuss possible design principles suggested by the model and propose further experiments to test its validity.'),
(83885, 2008, 'plos', 'Discovering sequence motifs with arbitrary insertions and deletions', 'Frith, Martin C|Saunders, Neil F W|Kobe, Bostjan|Bailey, Timothy L', 'Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan. martin@cbrc.jp|Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan. martin@cbrc.jp|Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan. martin@cbrc.jp|Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan. martin@cbrc.jp', 'Japan|Japan|Japan|Japan', 191, 'Algorithms|Amino Acid Motifs|Amino Acid Sequence|Base Sequence|Chromosome Mapping|DNA Transposable Elements|Gene Deletion|Molecular Sequence Data|Sequence Alignment|Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.1000071', '18437229', 'BIOLOGY IS ENCODED IN MOLECULAR SEQUENCES: deciphering this encoding remains a grand scientific challenge. Functional regions of DNA, RNA, and protein sequences often exhibit characteristic but subtle motifs, thus, computational discovery of motifs in sequences is a fundamental and much-studied problem. However, most current algorithms do not allow for insertions or deletions (indels) within motifs, and the few that do have other limitations. We present a method, GLAM2 (Gapped Local Alignment of Motifs), for discovering motifs allowing indels in a fully general manner, and a companion method GLAM2SCAN for searching sequence databases using such motifs. glam2 is a generalization of the gapless Gibbs sampling algorithm. It re-discovers variable-width protein motifs from the PROSITE database significantly more accurately than the alternative methods PRATT and SAM-T2K. Furthermore, it usefully refines protein motifs from the ELM database: in some cases, the refined motifs make orders of magnitude fewer overpredictions than the original ELM regular expressions. GLAM2 performs respectably on the BAliBASE multiple alignment benchmark, and may be superior to leading multiple alignment methods for motif-like alignments with N- and C-terminal extensions. Finally, we demonstrate the use of GLAM2 to discover protein kinase substrate motifs and a gapped DNA motif for the LIM-only transcriptional regulatory complex: using GLAM2SCAN, we identify promising targets for the latter. GLAM2 is especially promising for short protein motifs, and it should improve our ability to identify the protein cleavage sites, interaction sites, post-translational modification attachment sites, etc., that underlie much of biology. It may be equally useful for arbitrarily gapped motifs in DNA and RNA, although fewer examples of such motifs are known at present. GLAM2 is public domain software, available for download at http://bioinformatics.org.au/glam2.'),
(83886, 2008, 'plos', 'Viral population estimation using pyrosequencing', 'Eriksson, Nicholas|Pachter, Lior|Mitsuya, Yumi|Rhee, Soo-Yon|Wang, Chunlin|Gharizadeh, Baback|Ronaghi, Mostafa|Shafer, Robert W|Beerenwinkel, Niko', 'Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu|Department of Statistics, University of Chicago, Chicago, Illinois, United States of America. eriksson@galton.uchicago.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 158, 'Algorithms|Base Sequence|Chromosome Mapping|DNA, Viral|Genetic Variation|HIV|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000074', '18437230', 'The diversity of virus populations within single infected hosts presents a major difficulty for the natural immune response as well as for vaccine design and antiviral drug therapy. Recently developed pyrophosphate-based sequencing technologies (pyrosequencing) can be used for quantifying this diversity by ultra-deep sequencing of virus samples. We present computational methods for the analysis of such sequence data and apply these techniques to pyrosequencing data obtained from HIV populations within patients harboring drug-resistant virus strains. Our main result is the estimation of the population structure of the sample from the pyrosequencing reads. This inference is based on a statistical approach to error correction, followed by a combinatorial algorithm for constructing a minimal set of haplotypes that explain the data. Using this set of explaining haplotypes, we apply a statistical model to infer the frequencies of the haplotypes in the population via an expectation-maximization (EM) algorithm. We demonstrate that pyrosequencing reads allow for effective population reconstruction by extensive simulations and by comparison to 165 sequences obtained directly from clonal sequencing of four independent, diverse HIV populations. Thus, pyrosequencing can be used for cost-effective estimation of the structure of virus populations, promising new insights into viral evolutionary dynamics and disease control strategies.'),
(83887, 2008, 'plos', 'A quick guide for computer-assisted instruction in computational biology and bioinformatics', 'Costa, Manuel João|Galembeck, Eduardo|Marson, Guilherme A|Torres, Bayardo B', 'Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Gualtar Campus, Braga, Portugal. mmcosta@ecsaude.uminho.pt|Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Gualtar Campus, Braga, Portugal. mmcosta@ecsaude.uminho.pt|Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Gualtar Campus, Braga, Portugal. mmcosta@ecsaude.uminho.pt|Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Gualtar Campus, Braga, Portugal. mmcosta@ecsaude.uminho.pt', 'Portugal|Portugal|Portugal|Portugal', 0, 'Biological Science Disciplines|Computational Biology|Computer-Assisted Instruction|Curriculum|Guidelines as Topic', 'Journal Article', '10.1371/journal.pcbi.1000035', '18437234', '-'),
(83888, 2008, 'plos', 'Distinct timing mechanisms produce discrete and continuous movements', 'Huys, Raoul|Studenka, Breanna E|Rheaume, Nicole L|Zelaznik, Howard N|Jirsa, Viktor K', 'Theoretical Neuroscience Group, UMR 6152 Institut des Sciences du Mouvement, CNRS and Université de Méditerranée, Marseille, France. raoul.huys@univmed.fr|Theoretical Neuroscience Group, UMR 6152 Institut des Sciences du Mouvement, CNRS and Université de Méditerranée, Marseille, France. raoul.huys@univmed.fr|Theoretical Neuroscience Group, UMR 6152 Institut des Sciences du Mouvement, CNRS and Université de Méditerranée, Marseille, France. raoul.huys@univmed.fr|Theoretical Neuroscience Group, UMR 6152 Institut des Sciences du Mouvement, CNRS and Université de Méditerranée, Marseille, France. raoul.huys@univmed.fr|Theoretical Neuroscience Group, UMR 6152 Institut des Sciences du Mouvement, CNRS and Université de Méditerranée, Marseille, France. raoul.huys@univmed.fr', 'France|France|France|France|France', 87, 'Animals|Computer Simulation|Humans|Models, Biological|Motor Skills|Movement|Task Performance and Analysis|Time Factors', 'Journal Article', '10.1371/journal.pcbi.1000061', '18437236', 'The differentiation of discrete and continuous movement is one of the pillars of motor behavior classification. Discrete movements have a definite beginning and end, whereas continuous movements do not have such discriminable end points. In the past decade there has been vigorous debate whether this classification implies different control processes. This debate up until the present has been empirically based. Here, we present an unambiguous non-empirical classification based on theorems in dynamical system theory that sets discrete and continuous movements apart. Through computational simulations of representative modes of each class and topological analysis of the flow in state space, we show that distinct control mechanisms underwrite discrete and fast rhythmic movements. In particular, we demonstrate that discrete movements require a time keeper while fast rhythmic movements do not. We validate our computational findings experimentally using a behavioral paradigm in which human participants performed finger flexion-extension movements at various movement paces and under different instructions. Our results demonstrate that the human motor system employs different timing control mechanisms (presumably via differential recruitment of neural subsystems) to accomplish varying behavioral functions such as speed constraints.'),
(83889, 2008, 'plos', 'Translational systems biology of inflammation', 'Vodovotz, Yoram|Csete, Marie|Bartels, John|Chang, Steven|An, Gary', 'Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. vodovotzy@upmc.edu|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. vodovotzy@upmc.edu|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. vodovotzy@upmc.edu|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. vodovotzy@upmc.edu|Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. vodovotzy@upmc.edu', 'United States|United States|United States|United States|United States', 0, 'Animals|Computer Simulation|Cytokines|Humans|Immunity, Innate|Immunologic Factors|Inflammation|Models, Immunological|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000014', '18437239', 'Inflammation is a complex, multi-scale biologic response to stress that is also required for repair and regeneration after injury. Despite the repository of detailed data about the cellular and molecular processes involved in inflammation, including some understanding of its pathophysiology, little progress has been made in treating the severe inflammatory syndrome of sepsis. To address the gap between basic science knowledge and therapy for sepsis, a community of biologists and physicians is using systems biology approaches in hopes of yielding basic insights into the biology of inflammation. Systems biology is a discipline that combines experimental discovery with mathematical modeling to aid in the understanding of the dynamic global organization and function of a biologic system (cell to organ to organism). We propose the term translational systems biology for the application of similar tools and engineering principles to biologic systems with the primary goal of optimizing clinical practice. We describe the efforts to use translational systems biology to develop an integrated framework to gain insight into the problem of acute inflammation. Progress in understanding inflammation using translational systems biology tools highlights the promise of this multidisciplinary field. Future advances in understanding complex medical problems are highly dependent on methodological advances and integration of the computational systems biology community with biologists and clinicians.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83890, 2008, 'plos', 'Implementing arithmetic and other analytic operations by transcriptional regulation', 'Cory, Sean M|Perkins, Theodore J', 'Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada', 0, 'Algorithms|Computer Simulation|Computers, Molecular|Gene Expression Regulation|Mathematics|Models, Genetic|Signal Processing, Computer-Assisted|Transcription Factors|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.1000064', '18437243', 'The transcriptional regulatory machinery of a gene can be viewed as a computational device, with transcription factor concentrations as inputs and expression level as the output. This view begs the question: what kinds of computations are possible? We show that different parameterizations of a simple chemical kinetic model of transcriptional regulation are able to approximate all four standard arithmetic operations: addition, subtraction, multiplication, and division, as well as various equality and inequality operations. This contrasts with other studies that emphasize logical or digital notions of computation in biological networks. We analyze the accuracy and precision of these approximations, showing that they depend on different sets of parameters, and are thus independently tunable. We demonstrate that networks of these arithmetic genes can be combined to accomplish yet more complicated computations by designing and simulating a network that detects statistically significant elevations in a time-varying signal. We also consider the much more general problem of approximating analytic functions, showing that this can be achieved by allowing multiple transcription factor binding sites on the promoter. These observations are important for the interpretation of naturally occurring networks and imply new possibilities for the design of synthetic networks.'),
(83891, 2008, 'plos', 'An allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolism', 'Korendyaseva, Tatyana K|Kuvatov, Denis N|Volkov, Vladimir A|Martinov, Michael V|Vitvitsky, Victor M|Banerjee, Ruma|Ataullakhanov, Fazoil I', 'National Research Center for Hematology, RAMS, Moscow, Russia.|National Research Center for Hematology, RAMS, Moscow, Russia.|National Research Center for Hematology, RAMS, Moscow, Russia.|National Research Center for Hematology, RAMS, Moscow, Russia.|National Research Center for Hematology, RAMS, Moscow, Russia.|National Research Center for Hematology, RAMS, Moscow, Russia.|National Research Center for Hematology, RAMS, Moscow, Russia.', '-|-|-|-|-|-|-', 14, 'Animals|Cells, Cultured|Computer Simulation|Hepatocytes|Metabolic Clearance Rate|Methionine|Mice|Models, Biological|S-Adenosylmethionine', 'Journal Article', '10.1371/journal.pcbi.1000076', '18451990', 'Methionine (Met) is an essential amino acid that is needed for the synthesis of S-adenosylmethionine (AdoMet), the major biological methylating agent. Methionine used for AdoMet synthesis can be replenished via remethylation of homocysteine. Alternatively, homocysteine can be converted to cysteine via the transsulfuration pathway. Aberrations in methionine metabolism are associated with a number of complex diseases, including cancer, anemia, and neurodegenerative diseases. The concentration of methionine in blood and in organs is tightly regulated. Liver plays a key role in buffering blood methionine levels, and an interesting feature of its metabolism is that parallel tracks exist for the synthesis and utilization of AdoMet. To elucidate the molecular mechanism that controls metabolic fluxes in liver methionine metabolism, we have studied the dependencies of AdoMet concentration and methionine consumption rate on methionine concentration in native murine hepatocytes at physiologically relevant concentrations (40-400 microM). We find that both [AdoMet] and methionine consumption rates do not change gradually with an increase in [Met] but rise sharply (approximately 10-fold) in the narrow Met interval from 50 to 100 microM. Analysis of our experimental data using a mathematical model reveals that the sharp increase in [AdoMet] and the methionine consumption rate observed within the trigger zone are associated with metabolic switching from methionine conservation to disposal, regulated allosterically by switching between parallel pathways. This regulatory switch is triggered by [Met] and provides a mechanism for stabilization of methionine levels in blood over wide variations in dietary methionine intake.'),
(83892, 2008, 'plos', 'Transient cognitive dynamics, metastability, and decision making', 'Rabinovich, Mikhail I|Huerta, Ramón|Varona, Pablo|Afraimovich, Valentin S', 'Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu', 'United States|United States|United States|United States', 0, 'Animals|Cognition|Computer Simulation|Decision Making|Game Theory|Humans|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000072', '18452000', 'The idea that cognitive activity can be understood using nonlinear dynamics has been intensively discussed at length for the last 15 years. One of the popular points of view is that metastable states play a key role in the execution of cognitive functions. Experimental and modeling studies suggest that most of these functions are the result of transient activity of large-scale brain networks in the presence of noise. Such transients may consist of a sequential switching between different metastable cognitive states. The main problem faced when using dynamical theory to describe transient cognitive processes is the fundamental contradiction between reproducibility and flexibility of transient behavior. In this paper, we propose a theoretical description of transient cognitive dynamics based on the interaction of functionally dependent metastable cognitive states. The mathematical image of such transient activity is a stable heteroclinic channel, i.e., a set of trajectories in the vicinity of a heteroclinic skeleton that consists of saddles and unstable separatrices that connect their surroundings. We suggest a basic mathematical model, a strongly dissipative dynamical system, and formulate the conditions for the robustness and reproducibility of cognitive transients that satisfy the competing requirements for stability and flexibility. Based on this approach, we describe here an effective solution for the problem of sequential decision making, represented as a fixed time game: a player takes sequential actions in a changing noisy environment so as to maximize a cumulative reward. As we predict and verify in computer simulations, noise plays an important role in optimizing the gain.'),
(83893, 2008, 'plos', 'Comparison of immunogen designs that optimize peptide coverage: reply to Fischer et al', 'Nickle, David C|Jojic, Nebojsa|Heckerman, David|Jojic, Vladimir|Kirovski, Darko|Rolland, Morgane|Kosakovsky Pond, Sergei|Mullins, James I', 'Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu|Institute for Nonlinear Science, University of California San Diego, La Jolla, California, United States of America. mrabinovich@ucsd.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'AIDS Vaccines|Antigenic Variation|Epitope Mapping|Humans', 'Comment', '10.1371/journal.pcbi.0040025', '18463692', '-'),
(83894, 2008, 'plos', 'How protein stability and new functions trade off', 'Tokuriki, Nobuhiko|Stricher, Francois|Serrano, Luis|Tawfik, Dan S', 'Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel', 302, 'Amino Acid Sequence|Computer Simulation|Enzyme Stability|Enzymes|Models, Chemical|Models, Molecular|Molecular Sequence Data|Mutagenesis, Site-Directed|Mutation|Protein Folding|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000002', '18463696', 'Numerous studies have noted that the evolution of new enzymatic specificities is accompanied by loss of the proteins thermodynamic stability (DeltaDeltaG), thus suggesting a tradeoff between the acquisition of new enzymatic functions and stability. However, since most mutations are destabilizing (DeltaDeltaG>0), one should ask how destabilizing mutations that confer new or altered enzymatic functions relative to all other mutations are. We applied DeltaDeltaG computations by FoldX to analyze the effects of 548 mutations that arose from the directed evolution of 22 different enzymes. The stability effects, location, and type of function-altering mutations were compared to DeltaDeltaG changes arising from all possible point mutations in the same enzymes. We found that mutations that modulate enzymatic functions are mostly destabilizing (average DeltaDeltaG = +0.9 kcal/mol), and are almost as destabilizing as the average mutation in these enzymes (+1.3 kcal/mol). Although their stability effects are not as dramatic as in key catalytic residues, mutations that modify the substrate binding pockets, and thus mediate new enzymatic specificities, place a larger stability burden than surface mutations that underline neutral, non-adaptive evolutionary changes. How are the destabilizing effects of functional mutations balanced to enable adaptation? Our analysis also indicated that many mutations that appear in directed evolution variants with no obvious role in the new function exert stabilizing effects that may compensate for the destabilizing effects of the crucial function-altering mutations. Thus, the evolution of new enzymatic activities, both in nature and in the laboratory, is dependent on the compensatory, stabilizing effect of apparently silent mutations in regions of the protein that are irrelevant to its function.'),
(83895, 2008, 'plos', 'Sensing and integration of Erk and PI3K signals by Myc', 'Lee, Tae|Yao, Guang|Nevins, Joseph|You, Lingchong', 'Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.|Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.', 'United States|United States|United States|United States', 0, 'Computer Simulation|Gene Expression Regulation|Mitogen-Activated Protein Kinases|Models, Biological|Phosphatidylinositol 3-Kinases|Phosphorylation|Protein Processing, Post-Translational|Proto-Oncogene Proteins c-myc|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000013', '18463697', 'The transcription factor Myc plays a central role in regulating cell-fate decisions, including proliferation, growth, and apoptosis. To maintain a normal cell physiology, it is critical that the control of Myc dynamics is precisely orchestrated. Recent studies suggest that such control of Myc can be achieved at the post-translational level via protein stability modulation. Myc is regulated by two Ras effector pathways: the extracellular signal-regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K) pathways. To gain quantitative insight into Myc dynamics, we have developed a mathematical model to analyze post-translational regulation of Myc via sequential phosphorylation by Erk and PI3K. Our results suggest that Myc integrates Erk and PI3K signals to result in various cellular responses by differential stability control of Myc protein isoforms. Such signal integration confers a flexible dynamic range for the system output, governed by stability change. In addition, signal integration may require saturation of the input signals, leading to sensitive signal integration to the temporal features of the input signals, insensitive response to their amplitudes, and resistance to input fluctuations. We further propose that these characteristics of the protein stability control module in Myc may be commonly utilized in various cell types and classes of proteins.'),
(83896, 2008, 'plos', 'Systematic analysis of pleiotropy in C elegans early embryogenesis', 'Zou, Lihua|Sriswasdi, Sira|Ross, Brian|Missiuro, Patrycja V|Liu, Jun|Ge, Hui', 'Department of Statistics, Harvard University, Cambridge, Massachusetts, USA.|Department of Statistics, Harvard University, Cambridge, Massachusetts, USA.|Department of Statistics, Harvard University, Cambridge, Massachusetts, USA.|Department of Statistics, Harvard University, Cambridge, Massachusetts, USA.|Department of Statistics, Harvard University, Cambridge, Massachusetts, USA.|Department of Statistics, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States', 19, 'Animals|Caenorhabditis elegans|Caenorhabditis elegans Proteins|Cell Cycle|Cell Cycle Proteins|Computer Simulation|Embryonic Development|Evolution, Molecular|Gene Expression Profiling|Models, Biological|Mutation|Phenotype|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000003', '18463698', 'Pleiotropy refers to the phenomenon in which a single gene controls several distinct, and seemingly unrelated, phenotypic effects. We use C. elegans early embryogenesis as a model to conduct systematic studies of pleiotropy. We analyze high-throughput RNA interference (RNAi) data from C. elegans and identify phenotypic signatures, which are sets of cellular defects indicative of certain biological functions. By matching phenotypic profiles to our identified signatures, we assign genes with complex phenotypic profiles to multiple functional classes. Overall, we observe that pleiotropy occurs extensively among genes involved in early embryogenesis, and a small proportion of these genes are highly pleiotropic. We hypothesize that genes involved in early embryogenesis are organized into partially overlapping functional modules, and that pleiotropic genes represent connectors between these modules. In support of this hypothesis, we find that highly pleiotropic genes tend to reside in central positions in protein-protein interaction networks, suggesting that pleiotropic genes act as connecting points between different protein complexes or pathways.'),
(83897, 2008, 'plos', 'Identification of synaptic targets of Drosophila pumilio', 'Chen, Gengxin|Li, Wanhe|Zhang, Qing-Shuo|Regulski, Michael|Sinha, Nishi|Barditch, Jody|Tully, Tim|Krainer, Adrian R|Zhang, Michael Q|Dubnau, Josh', 'Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Amino Acid Sequence|Binding Sites|Drosophila Proteins|Molecular Sequence Data|Neurons|Protein Binding|RNA-Binding Proteins|Sequence Analysis, Protein|Synapses', 'Journal Article', '10.1371/journal.pcbi.1000026', '18463699', 'Drosophila Pumilio (Pum) protein is a translational regulator involved in embryonic patterning and germline development. Recent findings demonstrate that Pum also plays an important role in the nervous system, both at the neuromuscular junction (NMJ) and in long-term memory formation. In neurons, Pum appears to play a role in homeostatic control of excitability via down regulation of para, a voltage gated sodium channel, and may more generally modulate local protein synthesis in neurons via translational repression of eIF-4E. Aside from these, the biologically relevant targets of Pum in the nervous system remain largely unknown. We hypothesized that Pum might play a role in regulating the local translation underlying synapse-specific modifications during memory formation. To identify relevant translational targets, we used an informatics approach to predict Pum targets among mRNAs whose products have synaptic localization. We then used both in vitro binding and two in vivo assays to functionally confirm the fidelity of this informatics screening method. We find that Pum strongly and specifically binds to RNA sequences in the 3UTR of four of the predicted target genes, demonstrating the validity of our method. We then demonstrate that one of these predicted target sequences, in the 3UTR of discs large (dlg1), the Drosophila PSD95 ortholog, can functionally substitute for a canonical NRE (Nanos response element) in vivo in a heterologous functional assay. Finally, we show that the endogenous dlg1 mRNA can be regulated by Pumilio in a neuronal context, the adult mushroom bodies (MB), which is an anatomical site of memory storage.'),
(83898, 2008, 'plos', 'Stochastic differential equation model for cerebellar granule cell excitability', 'Saarinen, Antti|Linne, Marja-Leena|Yli-Harja, Olli', 'Institute of Signal Processing, Tampere University of Technology, Tampere, Finland. antti.saarinen@cs.tut.fi|Institute of Signal Processing, Tampere University of Technology, Tampere, Finland. antti.saarinen@cs.tut.fi|Institute of Signal Processing, Tampere University of Technology, Tampere, Finland. antti.saarinen@cs.tut.fi', 'Finland|Finland|Finland', 38, 'Action Potentials|Animals|Cerebellum|Computer Simulation|Humans|Membrane Potentials|Models, Neurological|Models, Statistical|Neurons|Stochastic Processes|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000004', '18463700', 'Neurons in the brain express intrinsic dynamic behavior which is known to be stochastic in nature. A crucial question in building models of neuronal excitability is how to be able to mimic the dynamic behavior of the biological counterpart accurately and how to perform simulations in the fastest possible way. The well-established Hodgkin-Huxley formalism has formed to a large extent the basis for building biophysically and anatomically detailed models of neurons. However, the deterministic Hodgkin-Huxley formalism does not take into account the stochastic behavior of voltage-dependent ion channels. Ion channel stochasticity is shown to be important in adjusting the transmembrane voltage dynamics at or close to the threshold of action potential firing, at the very least in small neurons. In order to achieve a better understanding of the dynamic behavior of a neuron, a new modeling and simulation approach based on stochastic differential equations and Brownian motion is developed. The basis of the work is a deterministic one-compartmental multi-conductance model of the cerebellar granule cell. This model includes six different types of voltage-dependent conductances described by Hodgkin-Huxley formalism and simple calcium dynamics. A new model for the granule cell is developed by incorporating stochasticity inherently present in the ion channel function into the gating variables of conductances. With the new stochastic model, the irregular electrophysiological activity of an in vitro granule cell is reproduced accurately, with the same parameter values for which the membrane potential of the original deterministic model exhibits regular behavior. The irregular electrophysiological activity includes experimentally observed random subthreshold oscillations, occasional spontaneous spikes, and clusters of action potentials. As a conclusion, the new stochastic differential equation model of the cerebellar granule cell excitability is found to expand the range of dynamics in comparison to the original deterministic model. Inclusion of stochastic elements in the operation of voltage-dependent conductances should thus be emphasized more in modeling the dynamic behavior of small neurons. Furthermore, the presented approach is valuable in providing faster computation times compared to the Markov chain type of modeling approaches and more sophisticated theoretical analysis tools compared to previously presented stochastic modeling approaches.'),
(83899, 2008, 'plos', 'Mouse cognition-related behavior in the open-field: emergence of places of attraction', 'Dvorkin, Anna|Benjamini, Yoav|Golani, Ilan', 'Department of Zoology, Tel Aviv University, Tel Aviv, Israel. annadv@post.tau.ac.il|Department of Zoology, Tel Aviv University, Tel Aviv, Israel. annadv@post.tau.ac.il|Department of Zoology, Tel Aviv University, Tel Aviv, Israel. annadv@post.tau.ac.il', 'Israel|Israel|Israel', 0, 'Animals|Behavior, Animal|Cognition|Computer Simulation|Exploratory Behavior|Locomotion|Mice|Mice, Inbred C57BL|Mice, Inbred DBA|Models, Neurological|Orientation|Recognition (Psychology)|Space Perception|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000027', '18463701', 'Spatial memory is often studied in the Morris Water Maze, where the animals spatial orientation has been shown to be mainly shaped by distal visual cues. Cognition-related behavior has also been described along well-trodden paths--spatial habits established by animals in the wild and in captivity reflecting a form of spatial memory. In the present study we combine the study of Open Field behavior with the study of behavior on well-trodden paths, revealing a form of locational memory that appears to correlate with spatial memory. The tracked path of the mouse is used to examine the dynamics of visiting behavior to locations. A visit is defined as either progressing through a location or stopping there, where progressing and stopping are computationally defined. We then estimate the probability of stopping at a location as a function of the number of previous visits to that location, i.e., we measure the effect of visiting history to a location on stopping in it. This can be regarded as an estimate of the familiarity of the mouse with locations. The recently wild-derived inbred strain CZECHII shows the highest effect of visiting history on stopping, C57 inbred mice show a lower effect, and DBA mice show no effect. We employ a rarely used, bottom-to-top computational approach, starting from simple kinematics of movement and gradually building our way up until we end with (emergent) locational memory. The effect of visiting history to a location on stopping in it can be regarded as an estimate of the familiarity of the mouse with locations, implying memory of these locations. We show that the magnitude of this estimate is strain-specific, implying a genetic influence. The dynamics of this process reveal that locations along the mouses trodden path gradually become places of attraction, where the mouse stops habitually.'),
(83900, 2008, 'plos', 'The signaling petri net-based simulator: a non-parametric strategy for characterizing the dynamics of cell-specific signaling networks', 'Ruths, Derek|Muller, Melissa|Tseng, Jen-Te|Nakhleh, Luay|Ram, Prahlad T', 'Department of Computer Science, Rice University, Houston, Texas, USA druths@rice.edu|Department of Computer Science, Rice University, Houston, Texas, USA druths@rice.edu|Department of Computer Science, Rice University, Houston, Texas, USA druths@rice.edu|Department of Computer Science, Rice University, Houston, Texas, USA druths@rice.edu|Department of Computer Science, Rice University, Houston, Texas, USA druths@rice.edu', '-|-|-|-|-', 70, 'Algorithms|Computer Simulation|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000005', '18463702', 'Reconstructing cellular signaling networks and understanding how they work are major endeavors in cell biology. The scale and complexity of these networks, however, render their analysis using experimental biology approaches alone very challenging. As a result, computational methods have been developed and combined with experimental biology approaches, producing powerful tools for the analysis of these networks. These computational methods mostly fall on either end of a spectrum of model parameterization. On one end is a class of structural network analysis methods, these typically use the network connectivity alone to generate hypotheses about global properties. On the other end is a class of dynamic network analysis methods, these use, in addition to the connectivity, kinetic parameters of the biochemical reactions to predict the networks dynamic behavior. These predictions provide detailed insights into the properties that determine aspects of the networks structure and behavior. However, the difficulty of obtaining numerical values of kinetic parameters is widely recognized to limit the applicability of this latter class of methods. Several researchers have observed that the connectivity of a network alone can provide significant insights into its dynamics. Motivated by this fundamental observation, we present the signaling Petri net, a non-parametric model of cellular signaling networks, and the signaling Petri net-based simulator, a Petri net execution strategy for characterizing the dynamics of signal flow through a signaling network using token distribution and sampling. The result is a very fast method, which can analyze large-scale networks, and provide insights into the trends of molecules activity-levels in response to an external stimulus, based solely on the networks connectivity. We have implemented the signaling Petri net-based simulator in the PathwayOracle toolkit, which is publicly available at http://bioinfo.cs.rice.edu/pathwayoracle. Using this method, we studied a MAPK1,2 and AKT signaling network downstream from EGFR in two breast tumor cell lines. We analyzed, both experimentally and computationally, the activity level of several molecules in response to a targeted manipulation of TSC2 and mTOR-Raptor. The results from our method agreed with experimental results in greater than 90% of the cases considered, and in those where they did not agree, our approach provided valuable insights into discrepancies between known network connectivities and experimental observations.'),
(83901, 2008, 'plos', 'Multi-scale simulations provide supporting evidence for the hypothesis of intramolecular protein translocation in GroEL/GroES complexes', 'Coluzza, Ivan|De Simone, Alfonso|Fraternali, Franca|Frenkel, Daan', 'Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. ic247@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. ic247@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. ic247@cam.ac.uk|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. ic247@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Binding Sites|Chaperonin 10|Chaperonin 60|Computer Simulation|Evidence-Based Medicine|Models, Biological|Models, Chemical|Models, Molecular|Molecular Chaperones|Motion|Multiprotein Complexes|Protein Binding|Protein Folding|Protein Transport|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000006', '18463703', 'The biological function of chaperone complexes is to assist the folding of non-native proteins. The widely studied GroEL chaperonin is a double-barreled complex that can trap non-native proteins in one of its two barrels. The ATP-driven binding of a GroES cap then results in a major structural change of the chamber where the substrate is trapped and initiates a refolding attempt. The two barrels operate anti-synchronously. The central region between the two barrels contains a high concentration of disordered protein chains, the role of which was thus far unclear. In this work we report a combination of atomistic and coarse-grained simulations that probe the structure and dynamics of the equatorial region of the GroEL/GroES chaperonin complex. Surprisingly, our simulations show that the equatorial region provides a translocation channel that will block the passage of folded proteins but allows the passage of secondary units with the diameter of an alpha-helix. We compute the free-energy barrier that has to be overcome during translocation and find that it can easily be crossed under the influence of thermal fluctuations. Hence, strongly non-native proteins can be squeezed like toothpaste from one barrel to the next where they will refold. Proteins that are already fairly close to the native state will not translocate but can refold in the chamber where they were trapped. Several experimental results are compatible with this scenario, and in the case of the experiments of Martin and Hartl, intra chaperonin translocation could explain why under physiological crowding conditions the chaperonin does not release the substrate protein.'),
(83902, 2008, 'plos', 'Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding', 'Serohijos, Adrian W R|Hegedus, Tamás|Riordan, John R|Dokholyan, Nikolay V', 'Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Physics and Astronomy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.', 'United States|United States|United States|United States', 33, 'Amino Acid Substitution|Computer Simulation|Cystic Fibrosis Transmembrane Conductance Regulator|Models, Chemical|Models, Molecular|Molecular Chaperones|Mutation|Protein Conformation|Protein Denaturation|Protein Folding|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000008', '18463704', 'The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes of epithelial cells is responsible for cystic fibrosis (CF). Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1). Biochemical and cell biological studies show that the DeltaF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. The structural basis of the increased misfolding propensity of the DeltaF508 NBD1 mutant is the perturbation of interactions in residue pairs Q493/P574 and F575/F578 found in loop S7-H6. As a proof-of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutations in the identified critical interactions to force the S7-H6 loop into the wild type conformation. Two redesigned NBD1-DeltaF508 variants exhibited significantly higher folding probabilities than the original NBD1-DeltaF508, thereby partially rescuing folding ability of the NBD1-DeltaF508 mutant. We propose that these observed defects in folding kinetics of mutant NBD1 may also be modulated by structures separate from the 508 site. The identified structural determinants of increased misfolding propensity of NBD1-DeltaF508 are essential information in correcting this pathogenic mutant.'),
(83903, 2008, 'plos', 'Computer-based screening of functional conformers of proteins', 'Montiel Molina, Héctor Marlosti|Millán-Pacheco, César|Pastor, Nina|del Rio, Gabriel', 'Departamento de Bioquímica, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.|Departamento de Bioquímica, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.|Departamento de Bioquímica, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.|Departamento de Bioquímica, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.', 'Mexico|Mexico|Mexico|Mexico', 0, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Protein Interaction Mapping|Proteins|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.1000009', '18463705', 'A long-standing goal in biology is to establish the link between function, structure, and dynamics of proteins. Considering that protein function at the molecular level is understood by the ability of proteins to bind to other molecules, the limited structural data of proteins in association with other bio-molecules represents a major hurdle to understanding protein function at the structural level. Recent reports show that protein function can be linked to protein structure and dynamics through network centrality analysis, suggesting that the structures of proteins bound to natural ligands may be inferred computationally. In the present work, a new method is described to discriminate protein conformations relevant to the specific recognition of a ligand. The method relies on a scoring system that matches critical residues with central residues in different structures of a given protein. Central residues are the most traversed residues with the same frequency in networks derived from protein structures. We tested our method in a set of 24 different proteins and more than 260,000 structures of these in the absence of a ligand or bound to it. To illustrate the usefulness of our method in the study of the structure/dynamics/function relationship of proteins, we analyzed mutants of the yeast TATA-binding protein with impaired DNA binding. Our results indicate that critical residues for an interaction are preferentially found as central residues of protein structures in complex with a ligand. Thus, our scoring system effectively distinguishes protein conformations relevant to the function of interest.'),
(83904, 2008, 'plos', 'A novel Bayesian DNA motif comparison method for clustering and retrieval', 'Habib, Naomi|Kaplan, Tommy|Margalit, Hanah|Friedman, Nir', 'School of Computer Science and Engineering, The Hebrew University, Jerusalem, Israel.|School of Computer Science and Engineering, The Hebrew University, Jerusalem, Israel.|School of Computer Science and Engineering, The Hebrew University, Jerusalem, Israel.|School of Computer Science and Engineering, The Hebrew University, Jerusalem, Israel.', 'Israel|Israel|Israel|Israel', 34, 'Algorithms|Artificial Intelligence|Base Sequence|Bayes Theorem|Binding Sites|Cluster Analysis|DNA|Information Storage and Retrieval|Molecular Sequence Data|Pattern Recognition, Automated|Protein Binding|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000010', '18463706', 'Characterizing the DNA-binding specificities of transcription factors is a key problem in computational biology that has been addressed by multiple algorithms. These usually take as input sequences that are putatively bound by the same factor and output one or more DNA motifs. A common practice is to apply several such algorithms simultaneously to improve coverage at the price of redundancy. In interpreting such results, two tasks are crucial: clustering of redundant motifs, and attributing the motifs to transcription factors by retrieval of similar motifs from previously characterized motif libraries. Both tasks inherently involve motif comparison. Here we present a novel method for comparing and merging motifs, based on Bayesian probabilistic principles. This method takes into account both the similarity in positional nucleotide distributions of the two motifs and their dissimilarity to the background distribution. We demonstrate the use of the new comparison method as a basis for motif clustering and retrieval procedures, and compare it to several commonly used alternatives. Our results show that the new method outperforms other available methods in accuracy and sensitivity. We incorporated the resulting motif clustering and retrieval procedures in a large-scale automated pipeline for analyzing DNA motifs. This pipeline integrates the results of various DNA motif discovery algorithms and automatically merges redundant motifs from multiple training sets into a coherent annotated library of motifs. Application of this pipeline to recent genome-wide transcription factor location data in S. cerevisiae successfully identified DNA motifs in a manner that is as good as semi-automated analysis reported in the literature. Moreover, we show how this analysis elucidates the mechanisms of condition-specific preferences of transcription factors.'),
(83905, 2008, 'plos', 'Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation', 'Elango, Navin|Kim, Seong-Ho|Vigoda, Eric|Yi, Soojin V', 'School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.|School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.|School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.|School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA.', 'Georgia|Georgia|Georgia|Georgia', 57, 'Chromosome Mapping|Computer Simulation|CpG Islands|DNA|DNA Mutational Analysis|Evolution, Molecular|Genetic Variation|Models, Genetic|Mutation|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000015', '18463707', 'Transitions at CpG dinucleotides, referred to as CpG substitutions, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates. We show that CpG substitutions occur approximately 15 times more frequently than other single nucleotide substitutions in primate genomes, and that they exhibit substantial regional variation. Patterns of CpG rate variation are consistent with differences in methylation level and susceptibility to subsequent deamination. In particular, we propose a distance-decaying hypothesis, positing that due to the molecular mechanism of a CpG substitution, rates are correlated with the stability of double-stranded DNA surrounding each CpG dinucleotide, and the effect of local DNA stability may decrease with distance from the CpG dinucleotide.Consistent with our distance-decaying hypothesis, rates of CpG substitution are strongly (negatively) correlated with regional G+C content. The influence of G+C content decays as the distance from the target CpG site increases. We estimate that the influence of local G+C content extends up to 1,500 approximately 2,000 bps centered on each CpG site. We also show that the distance-decaying relationship persisted when we controlled for the effect of long-range homogeneity of nucleotide composition. GpC sites, in contrast, do not exhibit such distance-decaying relationship. Our results highlight an example of the distinctive properties of methylation-dependent substitutions versus substitutions mostly arising from errors during DNA replication. Furthermore, the negative relationship between G+C content and CpG rates may provide an explanation for the observation that GC-rich SINEs show lower CpG rates than other repetitive elements.'),
(83906, 2008, 'plos', 'Genome landscapes and bacteriophage codon usage', 'Lucks, Julius B|Nelson, David R|Kudla, Grzegorz R|Plotkin, Joshua B', 'FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.|FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.|FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.|FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States', 0, 'Bacteriophages|Biological Evolution|Chromosome Mapping|Computer Simulation|Evolution, Molecular|Genes, Viral|Genetic Variation|Genome, Viral|Models, Genetic|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.1000001', '18463708', 'Across all kingdoms of biological life, protein-coding genes exhibit unequal usage of synonymous codons. Although alternative theories abound, translational selection has been accepted as an important mechanism that shapes the patterns of codon usage in prokaryotes and simple eukaryotes. Here we analyze patterns of codon usage across 74 diverse bacteriophages that infect E. coli, P. aeruginosa, and L. lactis as their primary host. We use the concept of a genome landscape, which helps reveal non-trivial, long-range patterns in codon usage across a genome. We develop a series of randomization tests that allow us to interrogate the significance of one aspect of codon usage, such as GC content, while controlling for another aspect, such as adaptation to host-preferred codons. We find that 33 phage genomes exhibit highly non-random patterns in their GC3-content, use of host-preferred codons, or both. We show that the head and tail proteins of these phages exhibit significant bias towards host-preferred codons, relative to the non-structural phage proteins. Our results support the hypothesis of translational selection on viral genes for host-preferred codons, over a broad range of bacteriophages.'),
(83907, 2008, 'plos', 'Getting started in biological pathway construction and analysis', 'Viswanathan, Ganesh A|Seto, Jeremy|Patil, Sonali|Nudelman, German|Sealfon, Stuart C', 'Center for Translational Systems Biology and Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.|Center for Translational Systems Biology and Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.|Center for Translational Systems Biology and Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.|Center for Translational Systems Biology and Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.|Center for Translational Systems Biology and Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Computer Simulation|Gene Expression Profiling|Models, Biological|Protein Interaction Mapping|Proteome|Signal Transduction|Software', 'Journal Article', '10.1371/journal.pcbi.0040016', '18463709', '-'),
(83908, 2008, 'plos', 'Computational methods for protein identification from mass spectrometry data', 'McHugh, Leo|Arthur, Jonathan W', 'Discipline of Medicine and Sydney Bioinformatics, University of Sydney, Sydney, New South Wales, Australia.|Discipline of Medicine and Sydney Bioinformatics, University of Sydney, Sydney, New South Wales, Australia.', 'Australia|Australia', 0, 'Algorithms|Amino Acid Sequence|Mass Spectrometry|Molecular Sequence Data|Peptide Mapping|Proteins|Sequence Analysis, Protein|Software', 'Journal Article', '10.1371/journal.pcbi.0040012', '18463710', 'Protein identification using mass spectrometry is an indispensable computational tool in the life sciences. A dramatic increase in the use of proteomic strategies to understand the biology of living systems generates an ongoing need for more effective, efficient, and accurate computational methods for protein identification. A wide range of computational methods, each with various implementations, are available to complement different proteomic approaches. A solid knowledge of the range of algorithms available and, more critically, the accuracy and effectiveness of these techniques is essential to ensure as many of the proteins as possible, within any particular experiment, are correctly identified. Here, we undertake a systematic review of the currently available methods and algorithms for interpreting, managing, and analyzing biological data associated with protein identification. We summarize the advances in computational solutions as they have responded to corresponding advances in mass spectrometry hardware. The evolution of scoring algorithms and metrics for automated protein identification are also discussed with a focus on the relative performance of different techniques. We also consider the relative advantages and limitations of different techniques in particular biological contexts. Finally, we present our perspective on future developments in the area of computational protein identification by considering the most recent literature on new and promising approaches to the problem as well as identifying areas yet to be explored and the potential application of methods from other areas of computational biology.'),
(83909, 2008, 'plos', 'Comprehensive analysis of affymetrix exon arrays using BioConductor', 'Okoniewski, Michaxc5x82 J|Miller, Crispin J', 'Applied Computational Biology and Bioinformatics Group, Cancer Research UK.|Applied Computational Biology and Bioinformatics Group, Cancer Research UK.', 'United Kingdom|United Kingdom', 0, 'Algorithms|Chromosome Mapping|Oligonucleotide Array Sequence Analysis|RNA Splice Sites|Sequence Analysis, DNA|Software', 'Journal Article', '10.1371/journal.pcbi.0040006', '18463711', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83910, 2008, 'plos', 'Short-term memory trace in rapidly adapting synapses of inferior temporal cortex', 'Sugase-Miyamoto, Yasuko|Liu, Zheng|Wiener, Matthew C|Optican, Lance M|Richmond, Barry J', 'Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.|Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.|Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.|Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.|Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.', 'United States|United States|United States|United States|United States', 57, 'Animals|Macaca|Memory, Short-Term|Neurons|Reaction Time|Synapses|Temporal Lobe|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.1000073', '18464917', 'Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity, hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory.'),
(83911, 2008, 'plos', 'Measuring global credibility with application to local sequence alignment', 'Webb-Robertson, Bobbie-Jo M|McCue, Lee Ann|Lawrence, Charles E', 'Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington, United States of America. bj@pnl.gov|Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington, United States of America. bj@pnl.gov|Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington, United States of America. bj@pnl.gov', 'United States|United States|United States', 0, 'Bayes Theorem|Biometry|Genome|Models, Statistical|Molecular Biology|Phylogeny|Probability|Problem Solving|RNA|Reproducibility of Results|Sequence Analysis, RNA', 'Journal Article', '10.1371/journal.pcbi.1000077', '18464927', 'Computational biology is replete with high-dimensional (high-D) discrete prediction and inference problems, including sequence alignment, RNA structure prediction, phylogenetic inference, motif finding, prediction of pathways, and model selection problems in statistical genetics. Even though prediction and inference in these settings are uncertain, little attention has been focused on the development of global measures of uncertainty. Regardless of the procedure employed to produce a prediction, when a procedure delivers a single answer, that answer is a point estimate selected from the solution ensemble, the set of all possible solutions. For high-D discrete space, these ensembles are immense, and thus there is considerable uncertainty. We recommend the use of Bayesian credibility limits to describe this uncertainty, where a (1-alpha)%, 0< or =alpha< or =1, credibility limit is the minimum Hamming distance radius of a hyper-sphere containing (1-alpha)% of the posterior distribution. Because sequence alignment is arguably the most extensively used procedure in computational biology, we employ it here to make these general concepts more concrete. The maximum similarity estimator (i.e., the alignment that maximizes the likelihood) and the centroid estimator (i.e., the alignment that minimizes the mean Hamming distance from the posterior weighted ensemble of alignments) are used to demonstrate the application of Bayesian credibility limits to alignment estimators. Application of Bayesian credibility limits to the alignment of 20 human/rodent orthologous sequence pairs and 125 orthologous sequence pairs from six Shewanella species shows that credibility limits of the alignments of promoter sequences of these species vary widely, and that centroid alignments dependably have tighter credibility limits than traditional maximum similarity alignments.'),
(83912, 2008, 'plos', 'Sequence similarity network reveals common ancestry of multidomain proteins', 'Song, Nan|Joseph, Jacob M|Davis, George B|Durand, Dannie', 'Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 0, 'Amino Acid Sequence|Conserved Sequence|Family|Female|Genomics|Humans|Male|Phylogeny|Proteins|Receptors, Platelet-Derived Growth Factor|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.1000063', '18475320', 'We address the problem of homology identification in complex multidomain families with varied domain architectures. The challenge is to distinguish sequence pairs that share common ancestry from pairs that share an inserted domain but are otherwise unrelated. This distinction is essential for accuracy in gene annotation, function prediction, and comparative genomics. There are two major obstacles to multidomain homology identification: lack of a formal definition and lack of curated benchmarks for evaluating the performance of new methods. We offer preliminary solutions to both problems: 1) an extension of the traditional model of homology to include domain insertions, and 2) a manually curated benchmark of well-studied families in mouse and human. We further present Neighborhood Correlation, a novel method that exploits the local structure of the sequence similarity network to identify homologs with great accuracy based on the observation that gene duplication and domain shuffling leave distinct patterns in the sequence similarity network. In a rigorous, empirical comparison using our curated data, Neighborhood Correlation outperforms sequence similarity, alignment length, and domain architecture comparison. Neighborhood Correlation is well suited for automated, genome-scale analyses. It is easy to compute, does not require explicit knowledge of domain architecture, and classifies both single and multidomain homologs with high accuracy. Homolog predictions obtained with our method, as well as our manually curated benchmark and a web-based visualization tool for exploratory analysis of the network neighborhood structure, are available at http://www.neighborhoodcorrelation.org. Our work represents a departure from the prevailing view that the concept of homology cannot be applied to genes that have undergone domain shuffling. In contrast to current approaches that either focus on the homology of individual domains or consider only families with identical domain architectures, we show that homology can be rationally defined for multidomain families with diverse architectures by considering the genomic context of the genes that encode them. Our study demonstrates the utility of mining network structure for evolutionary information, suggesting this is a fertile approach for investigating evolutionary processes in the post-genomic era.'),
(83913, 2008, 'plos', 'The energy landscapes of repeat-containing proteins: topology, cooperativity, and the folding funnels of one-dimensional architectures', 'Ferreiro, Diego U|Walczak, Aleksandra M|Komives, Elizabeth A|Wolynes, Peter G', '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.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States', 0, 'Computer Simulation|Energy Transfer|Models, Chemical|Models, Molecular|Protein Folding|Proteins|Repetitive Sequences, Amino Acid|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000070', '18483553', 'Repeat-proteins are made up of near repetitions of 20- to 40-amino acid stretches. These polypeptides usually fold up into non-globular, elongated architectures that are stabilized by the interactions within each repeat and those between adjacent repeats, but that lack contacts between residues distant in sequence. The inherent symmetries both in primary sequence and three-dimensional structure are reflected in a folding landscape that may be analyzed as a quasi-one-dimensional problem. We present a general description of repeat-protein energy landscapes based on a formal Ising-like treatment of the elementary interaction energetics in and between foldons, whose collective ensemble are treated as spin variables. The overall folding properties of a complete domain (the stability and cooperativity of the repeating array) can be derived from this microscopic description. The one-dimensional nature of the model implies there are simple relations for the experimental observables: folding free-energy (DeltaG(water)) and the cooperativity of denaturation (m-value), which do not ordinarily apply for globular proteins. We show how the parameters for the coarse-grained description in terms of foldon spin variables can be extracted from more detailed folding simulations on perfectly funneled landscapes. To illustrate the ideas, we present a case-study of a family of tetratricopeptide (TPR) repeat proteins and quantitatively relate the results to the experimentally observed folding transitions. Based on the dramatic effect that single point mutations exert on the experimentally observed folding behavior, we speculate that natural repeat proteins are poised at particular ratios of inter- and intra-element interaction energetics that allow them to readily undergo structural transitions in physiologically relevant conditions, which may be intrinsically related to their biological functions.'),
(83914, 2008, 'plos', 'Context-specific metabolic networks are consistent with experiments', 'Becker, Scott A|Palsson, Bernhard O', 'Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.|Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States', 314, 'Algorithms|Computer Simulation|Gene Expression Profiling|Models, Biological|Proteome|Research Design|Signal Transduction', 'Comparative Study', '10.1371/journal.pcbi.1000082', '18483554', 'Reconstructions of cellular metabolism are publicly available for a variety of different microorganisms and some mammalian genomes. To date, these reconstructions are genome-scale and strive to include all reactions implied by the genome annotation, as well as those with direct experimental evidence. Clearly, many of the reactions in a genome-scale reconstruction will not be active under particular conditions or in a particular cell type. Methods to tailor these comprehensive genome-scale reconstructions into context-specific networks will aid predictive in silico modeling for a particular situation. We present a method called Gene Inactivity Moderated by Metabolism and Expression (GIMME) to achieve this goal. The GIMME algorithm uses quantitative gene expression data and one or more presupposed metabolic objectives to produce the context-specific reconstruction that is most consistent with the available data. Furthermore, the algorithm provides a quantitative inconsistency score indicating how consistent a set of gene expression data is with a particular metabolic objective. We show that this algorithm produces results consistent with biological experiments and intuition for adaptive evolution of bacteria, rational design of metabolic engineering strains, and human skeletal muscle cells. This work represents progress towards producing constraint-based models of metabolism that are specific to the conditions where the expression profiling data is available.'),
(83915, 2008, 'plos', 'Reconstruction of protein backbones from the BriX collection of canonical protein fragments', 'Baeten, Lies|Reumers, Joke|Tur, Vicente|Stricher, François|Lenaerts, Tom|Serrano, Luis|Rousseau, Frederic|Schymkowitz, Joost', 'SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.|SWITCH Laboratory, Vrije Universiteit Brussels, Brussels, Belgium.', 'Belgium|Belgium|Belgium|Belgium|Belgium|Belgium|Belgium|Belgium', 34, 'Amino Acid Sequence|Computer Simulation|Databases, Protein|Models, Chemical|Models, Molecular|Molecular Sequence Data|Peptide Fragments|Protein Conformation|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.1000083', '18483555', 'As modeling of changes in backbone conformation still lacks a computationally efficient solution, we developed a discretisation of the conformational states accessible to the protein backbone similar to the successful rotamer approach in side chains. The BriX fragment database, consisting of fragments from 4 to 14 residues long, was realized through identification of recurrent backbone fragments from a non-redundant set of high-resolution protein structures. BriX contains an alphabet of more than 1,000 frequently observed conformations per peptide length for 6 different variation levels. Analysis of the performance of BriX revealed an average structural coverage of protein structures of more than 99% within a root mean square distance (RMSD) of 1 Angstrom. Globally, we are able to reconstruct protein structures with an average accuracy of 0.48 Angstrom RMSD. As expected, regular structures are well covered, but, interestingly, many loop regions that appear irregular at first glance are also found to form a recurrent structural motif, albeit with lower frequency of occurrence than regular secondary structures. Larger loop regions could be completely reconstructed from smaller recurrent elements, between 4 and 8 residues long. Finally, we observed that a significant amount of short sequences tend to display strong structural ambiguity between alpha helix and extended conformations. When the sequence length increases, this so-called sequence plasticity is no longer observed, illustrating the context dependency of polypeptide structures.'),
(83916, 2008, 'plos', 'Evolution of taxis responses in virtual bacteria: non-adaptive dynamics', 'Goldstein, Richard A|Soyer, Orkun S', 'Mathematical Biology, National Institute for Medical Research, London, United Kingdom. rgoldst@nimr.mrc.ac.uk|Mathematical Biology, National Institute for Medical Research, London, United Kingdom. rgoldst@nimr.mrc.ac.uk', 'United Kingdom|United Kingdom', 28, 'Adaptation, Physiological|Bacterial Physiological Phenomena|Bacterial Proteins|Biological Evolution|Chemotaxis|Computer Simulation|Mechanotransduction, Cellular|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.1000084', '18483577', 'Bacteria are able to sense and respond to a variety of external stimuli, with responses that vary from stimuli to stimuli and from species to species. The best-understood is chemotaxis in the model organism Escherichia coli, where the dynamics and the structure of the underlying pathway are well characterised. It is not clear, however, how well this detailed knowledge applies to mechanisms mediating responses to other stimuli or to pathways in other species. Furthermore, there is increasing experimental evidence that bacteria integrate responses from different stimuli to generate a coherent taxis response. We currently lack a full understanding of the different pathway structures and dynamics and how this integration is achieved. In order to explore different pathway structures and dynamics that can underlie taxis responses in bacteria, we perform a computational simulation of the evolution of taxis. This approach starts with a population of virtual bacteria that move in a virtual environment based on the dynamics of the simple biochemical pathways they harbour. As mutations lead to changes in pathway structure and dynamics, bacteria better able to localise with favourable conditions gain a selective advantage. We find that a certain dynamics evolves consistently under different model assumptions and environments. These dynamics, which we call non-adaptive dynamics, directly couple tumbling probability of the cell to increasing stimuli. Dynamics that are adaptive under a wide range of conditions, as seen in the chemotaxis pathway of E. coli, do not evolve in these evolutionary simulations. However, we find that stimulus scarcity and fluctuations during evolution results in complex pathway dynamics that result both in adaptive and non-adaptive dynamics depending on basal stimuli levels. Further analyses of evolved pathway structures show that effective taxis dynamics can be mediated with as few as two components. The non-adaptive dynamics mediating taxis responses provide an explanation for experimental observations made in mutant strains of E. coli and in wild-type Rhodobacter sphaeroides that could not be explained with standard models. We speculate that such dynamics exist in other bacteria as well and play a role linking the metabolic state of the cell and the taxis response. The simplicity of mechanisms mediating such dynamics makes them a candidate precursor of more complex taxis responses involving adaptation. This study suggests a strong link between stimulus conditions during evolution and evolved pathway dynamics. When evolution was simulated under conditions of scarce and fluctuating stimulus conditions, the evolved pathway contained features of both adaptive and non-adaptive dynamics, suggesting that these two types of dynamics can have different advantages under distinct environmental circumstances.'),
(83917, 2008, 'plos', 'A comparative computer simulation of dendritic morphology', 'Donohue, Duncan E|Ascoli, Giorgio A', 'Neuroscience Program and Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.|Neuroscience Program and Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.', 'United States|United States', 35, 'Brain|Computer Simulation|Dendrites|Models, Anatomic|Models, Neurological|Morphogenesis|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.1000089', '18483611', 'Computational modeling of neuronal morphology is a powerful tool for understanding developmental processes and structure-function relationships. We present a multifaceted approach based on stochastic sampling of morphological measures from digital reconstructions of real cells. We examined how dendritic elongation, branching, and taper are controlled by three morphometric determinants: Branch Order, Radius, and Path Distance from the soma. Virtual dendrites were simulated starting from 3,715 neuronal trees reconstructed in 16 different laboratories, including morphological classes as diverse as spinal motoneurons and dentate granule cells. Several emergent morphometrics were used to compare real and virtual trees. Relating model parameters to Branch Order best constrained the number of terminations for most morphological classes, except pyramidal cell apical trees, which were better described by a dependence on Path Distance. In contrast, bifurcation asymmetry was best constrained by Radius for apical, but Path Distance for basal trees. All determinants showed similar performance in capturing total surface area, while surface area asymmetry was best determined by Path Distance. Grouping by other characteristics, such as size, asymmetry, arborizations, or animal species, showed smaller differences than observed between apical and basal, pointing to the biological importance of this separation. Hybrid models using combinations of the determinants confirmed these trends and allowed a detailed characterization of morphological relations. The differential findings between morphological groups suggest different underlying developmental mechanisms. By comparing the effects of several morphometric determinants on the simulation of different neuronal classes, this approach sheds light on possible growth mechanism variations responsible for the observed neuronal diversity.'),
(83918, 2008, 'plos', 'Dynamic analysis of integrated signaling, metabolic, and regulatory networks', 'Lee, Jong Min|Min Lee, Jong|Gianchandani, Erwin P|Eddy, James A|Papin, Jason A', 'Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, United States of America.|Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, United States of America.', 'United States|United States|United States|United States|United States', 158, 'Computer Simulation|Gene Expression Regulation|Models, Biological|Proteome|Signal Transduction|Systems Integration', 'Journal Article', '10.1371/journal.pcbi.1000086', '18483615', 'Extracellular cues affect signaling, metabolic, and regulatory processes to elicit cellular responses. Although intracellular signaling, metabolic, and regulatory networks are highly integrated, previous analyses have largely focused on independent processes (e.g., metabolism) without considering the interplay that exists among them. However, there is evidence that many diseases arise from multifunctional components with roles throughout signaling, metabolic, and regulatory networks. Therefore, in this study, we propose a flux balance analysis (FBA)-based strategy, referred to as integrated dynamic FBA (idFBA), that dynamically simulates cellular phenotypes arising from integrated networks. The idFBA framework requires an integrated stoichiometric reconstruction of signaling, metabolic, and regulatory processes. It assumes quasi-steady-state conditions for fast reactions and incorporates slow reactions into the stoichiometric formalism in a time-delayed manner. To assess the efficacy of idFBA, we developed a prototypic integrated system comprising signaling, metabolic, and regulatory processes with network features characteristic of actual systems and incorporated kinetic parameters based on typical time scales observed in literature. idFBA was applied to the prototypic system, which was evaluated for different environments and gene regulatory rules. In addition, we applied the idFBA framework in a similar manner to a representative module of the single-cell eukaryotic organism Saccharomyces cerevisiae. Ultimately, idFBA facilitated quantitative, dynamic analysis of systemic effects of extracellular cues on cellular phenotypes and generated comparable time-course predictions when contrasted with an equivalent kinetic model. Since idFBA solves a linear programming problem and does not require an exhaustive list of detailed kinetic parameters, it may be efficiently scaled to integrated intracellular systems that incorporate signaling, metabolic, and regulatory processes at the genome scale, such as the S. cerevisiae system presented here.'),
(83919, 2008, 'plos', 'Computational lipidology: predicting lipoprotein density profiles in human blood plasma', 'Hübner, Katrin|Schwager, Thomas|Winkler, Karl|Reich, Jens-Georg|Holzhütter, Hermann-Georg', 'Computational Systems Biochemistry, Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Germany. katrin.huebner@bioquant.uni-heidelberg.de|Computational Systems Biochemistry, Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Germany. katrin.huebner@bioquant.uni-heidelberg.de|Computational Systems Biochemistry, Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Germany. katrin.huebner@bioquant.uni-heidelberg.de|Computational Systems Biochemistry, Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Germany. katrin.huebner@bioquant.uni-heidelberg.de|Computational Systems Biochemistry, Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Germany. katrin.huebner@bioquant.uni-heidelberg.de', 'Germany|Germany|Germany|Germany|Germany', 17, 'Blood Chemical Analysis|Computer Simulation|Humans|Lipoproteins|Models, Cardiovascular|Models, Statistical|Statistical Distributions', 'Journal Article', '10.1371/journal.pcbi.1000079', '18497853', 'Monitoring cholesterol levels is strongly recommended to identify patients at risk for myocardial infarction. However, clinical markers beyond bad and good cholesterol are needed to precisely predict individual lipid disorders. Our work contributes to this aim by bringing together experiment and theory. We developed a novel computer-based model of the human plasma lipoprotein metabolism in order to simulate the blood lipid levels in high resolution. Instead of focusing on a few conventionally used predefined lipoprotein density classes (LDL, HDL), we consider the entire protein and lipid composition spectrum of individual lipoprotein complexes. Subsequently, their distribution over density (which equals the lipoprotein profile) is calculated. As our main results, we (i) successfully reproduced clinically measured lipoprotein profiles of healthy subjects, (ii) assigned lipoproteins to narrow density classes, named high-resolution density sub-fractions (hrDS), revealing heterogeneous lipoprotein distributions within the major lipoprotein classes, and (iii) present model-based predictions of changes in the lipoprotein distribution elicited by disorders in underlying molecular processes. In its present state, the model offers a platform for many future applications aimed at understanding the reasons for inter-individual variability, identifying new sub-fractions of potential clinical relevance and a patient-oriented diagnosis of the potential molecular causes for individual dyslipidemia.'),
(83920, 2008, 'plos', 'Silent synapses, LTP, and the indirect parallel-fibre pathway: computational consequences of optimal cerebellar noise-processing', 'Porrill, John|Dean, Paul', 'Department of Psychology, Sheffield University, Sheffield, United Kingdom. j.porrill@sheffield.ac.uk|Department of Psychology, Sheffield University, Sheffield, United Kingdom. j.porrill@sheffield.ac.uk', 'United Kingdom|United Kingdom', 22, 'Animals|Cerebellum|Computer Simulation|Humans|Long-Term Potentiation|Models, Neurological|Models, Statistical|Nerve Net|Neural Inhibition|Neural Pathways|Reflex, Vestibulo-Ocular|Stochastic Processes|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000085', '18497864', 'Computational analysis of neural systems is at its most useful when it uncovers principles that provide a unified account of phenomena across multiple scales and levels of description. Here we analyse a widely used model of the cerebellar contribution to sensori-motor learning to demonstrate both that its response to intrinsic and sensor noise is optimal, and that the unexpected synaptic and behavioural consequences of this optimality can explain a wide range of experimental data. The response of the Marr-Albus adaptive-filter model of the cerebellar microcircuit to noise was examined in the context of vestibulo-ocular reflex calibration. We found that, when appropriately connected, an adaptive-filter model using the covariance learning rule to adjust the weights of synapses between parallel fibres and Purkinje cells learns weight values that are optimal given the relative amount of signal and noise carried by each parallel fibre. This optimality principle is consistent with data on the cerebellar role in smooth pursuit eye movements, and predicts that many synaptic weights must be very small, providing an explanation for the experimentally observed preponderance of silent synapses. Such a preponderance has in its turn two further consequences. First, an additional inhibitory pathway from parallel fibre to Purkinje cell is required if Purkinje cell activity is to be altered in either direction from a starting point of silent synapses. Second, cerebellar learning tasks must often proceed via LTP, rather than LTD as is widely assumed. Taken together, these considerations have profound behavioural consequences, including the optimal combination of sensori-motor information, and asymmetry and hysteresis of sensori-motor learning rates.'),
(83921, 2008, 'plos', 'Why are computational neuroscience and systems biology so separate?', 'De Schutter, Erik', 'Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Japan. erik@oist.jp', 'Japan', 61, 'Computer Simulation|Models, Neurological|Neurosciences|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.1000078', '18516226', 'Despite similar computational approaches, there is surprisingly little interaction between the computational neuroscience and the systems biology research communities. In this review I reconstruct the history of the two disciplines and show that this may explain why they grew up apart. The separation is a pity, as both fields can learn quite a bit from each other. Several examples are given, covering sociological, software technical, and methodological aspects. Systems biology is a better organized community which is very effective at sharing resources, while computational neuroscience has more experience in multiscale modeling and the analysis of information processing by biological systems. Finally, I speculate about how the relationship between the two fields may evolve in the near future.'),
(83922, 2008, 'plos', 'A probabilistic model of local sequence alignment that simplifies statistical significance estimation', 'Eddy, Sean R', 'Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, United States of America. eddys@janelia.hhmi.org', 'United States', 180, 'Algorithms|Base Sequence|Chromosome Mapping|Computer Simulation|Data Interpretation, Statistical|Models, Genetic|Models, Statistical|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000069', '18516236', 'Sequence database searches require accurate estimation of the statistical significance of scores. Optimal local sequence alignment scores follow Gumbel distributions, but determining an important parameter of the distribution (lambda) requires time-consuming computational simulation. Moreover, optimal alignment scores are less powerful than probabilistic scores that integrate over alignment uncertainty (Forward scores), but the expected distribution of Forward scores remains unknown. Here, I conjecture that both expected score distributions have simple, predictable forms when full probabilistic modeling methods are used. For a probabilistic model of local sequence alignment, optimal alignment bit scores (Viterbi scores) are Gumbel-distributed with constant lambda = log 2, and the high scoring tail of Forward scores is exponential with the same constant lambda. Simulation studies support these conjectures over a wide range of profile/sequence comparisons, using 9,318 profile-hidden Markov models from the Pfam database. This enables efficient and accurate determination of expectation values (E-values) for both Viterbi and Forward scores for probabilistic local alignments.'),
(83923, 2008, 'plos', 'An introduction to bioinformatics for glycomics research', 'Aoki-Kinoshita, Kiyoko F', 'Department of Bioinformatics, Soka University, Tokyo, Japan. kkiyoko@soka.ac.jp', 'Japan', 53, 'Carbohydrate Metabolism|Carbohydrates|Cell Physiological Phenomena|Computational Biology|Glycomics|Models, Biological|Research', 'Journal Article', '10.1371/journal.pcbi.1000075', '18516240', '-'),
(83924, 2008, 'plos', 'Uncovering interactions in the frequency domain', 'Guo, Shuixia|Wu, Jianhua|Ding, Mingzhou|Feng, Jianfeng', 'Department of Mathematics, Hunan Normal University, Changsha, China.|Department of Mathematics, Hunan Normal University, Changsha, China.|Department of Mathematics, Hunan Normal University, Changsha, China.|Department of Mathematics, Hunan Normal University, Changsha, China.', 'China|China|China|China', 57, 'Animals|Biological Clocks|Brain Mapping|Computer Simulation|Humans|Models, Biological|Nerve Net|Protein Interaction Mapping|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000087', '18516243', 'Oscillatory activity plays a critical role in regulating biological processes at levels ranging from subcellular, cellular, and network to the whole organism, and often involves a large number of interacting elements. We shed light on this issue by introducing a novel approach called partial Granger causality to reliably reveal interaction patterns in multivariate data with exogenous inputs and latent variables in the frequency domain. The method is extensively tested with toy models, and successfully applied to experimental datasets, including (1) gene microarray data of HeLa cell cycle, (2) in vivo multi-electrode array (MEA) local field potentials (LFPs) recorded from the inferotemporal cortex of a sheep, and (3) in vivo LFPs recorded from distributed sites in the right hemisphere of a macaque monkey.'),
(83925, 2008, 'plos', 'Astrocytes optimize the synaptic transmission of information', 'Nadkarni, Suhita|Jung, Peter|Levine, Herbert', 'Center of Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America.|Center of Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America.|Center of Theoretical Biological Physics, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States', 56, 'Animals|Astrocytes|Calcium Signaling|Computer Simulation|Hippocampus|Humans|Models, Neurological|Nerve Net|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.1000088', '18516277', 'Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.'),
(83926, 2008, 'plos', 'CSMET: comparative genomic motif detection via multi-resolution phylogenetic shadowing', 'Ray, Pradipta|Shringarpure, Suyash|Kolar, Mladen|Xing, Eric P', 'School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.|School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 10, 'Algorithms|Amino Acid Motifs|Binding Sites|Chromosome Mapping|Computer Simulation|Evolution, Molecular|Genetic Variation|Models, Genetic|Phylogeny|Protein Binding|Sequence Analysis, DNA|Software|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.1000090', '18535663', 'Functional turnover of transcription factor binding sites (TFBSs), such as whole-motif loss or gain, are common events during genome evolution. Conventional probabilistic phylogenetic shadowing methods model the evolution of genomes only at nucleotide level, and lack the ability to capture the evolutionary dynamics of functional turnover of aligned sequence entities. As a result, comparative genomic search of non-conserved motifs across evolutionarily related taxa remains a difficult challenge, especially in higher eukaryotes, where the cis-regulatory regions containing motifs can be long and divergent, existing methods rely heavily on specialized pattern-driven heuristic search or sampling algorithms, which can be difficult to generalize and hard to interpret based on phylogenetic principles. We propose a new method: Conditional Shadowing via Multi-resolution Evolutionary Trees, or CSMET, which uses a context-dependent probabilistic graphical model that allows aligned sites from different taxa in a multiple alignment to be modeled by either a background or an appropriate motif phylogeny conditioning on the functional specifications of each taxon. The functional specifications themselves are the output of a phylogeny which models the evolution not of individual nucleotides, but of the overall functionality (e.g., functional retention or loss) of the aligned sequence segments over lineages. Combining this method with a hidden Markov model that autocorrelates evolutionary rates on successive sites in the genome, CSMET offers a principled way to take into consideration lineage-specific evolution of TFBSs during motif detection, and a readily computable analytical form of the posterior distribution of motifs under TFBS turnover. On both simulated and real Drosophila cis-regulatory modules, CSMET outperforms other state-of-the-art comparative genomic motif finders.'),
(83927, 2008, 'plos', 'Integrated information in discrete dynamical systems: motivation and theoretical framework', 'Balduzzi, David|Tononi, Giulio', 'Department of Psychiatry, University of Wisconsin, Madison, Wisconsin, USA.|Department of Psychiatry, University of Wisconsin, Madison, Wisconsin, USA.', 'United States|United States', 200, 'Animals|Brain|Cognition|Computer Simulation|Consciousness|Humans|Information Storage and Retrieval|Models, Neurological|Nerve Net|Signal Processing, Computer-Assisted|Systems Integration', 'Journal Article', '10.1371/journal.pcbi.1000091', '18551165', 'This paper introduces a time- and state-dependent measure of integrated information, phi, which captures the repertoire of causal states available to a system as a whole. Specifically, phi quantifies how much information is generated (uncertainty is reduced) when a system enters a particular state through causal interactions among its elements, above and beyond the information generated independently by its parts. Such mathematical characterization is motivated by the observation that integrated information captures two key phenomenological properties of consciousness: (i) there is a large repertoire of conscious experiences so that, when one particular experience occurs, it generates a large amount of information by ruling out all the others, and (ii) this information is integrated, in that each experience appears as a whole that cannot be decomposed into independent parts. This paper extends previous work on stationary systems and applies integrated information to discrete networks as a function of their dynamics and causal architecture. An analysis of basic examples indicates the following: (i) phi varies depending on the state entered by a network, being higher if active and inactive elements are balanced and lower if the network is inactive or hyperactive. (ii) phi varies for systems with identical or similar surface dynamics depending on the underlying causal architecture, being low for systems that merely copy or replay activity states. (iii) phi varies as a function of network architecture. High phi values can be obtained by architectures that conjoin functional specialization with functional integration. Strictly modular and homogeneous systems cannot generate high phi because the former lack integration, whereas the latter lack information. Feedforward and lattice architectures are capable of generating high phi but are inefficient. (iv) In Hopfield networks, phi is low for attractor states and neutral states, but increases if the networks are optimized to achieve tension between local and global interactions. These basic examples appear to match well against neurobiological evidence concerning the neural substrates of consciousness. More generally, phi appears to be a useful metric to characterize the capacity of any physical system to integrate information.'),
(83928, 2008, 'plos', 'Machine-learning approaches for classifying haplogroup from Y chromosome STR data', 'Schlecht, Joseph|Kaplan, Matthew E|Barnard, Kobus|Karafet, Tatiana|Hammer, Michael F|Merchant, Nirav C', 'Computer Science Department, University of Arizona, Tucson, Arizona, USA.|Computer Science Department, University of Arizona, Tucson, Arizona, USA.|Computer Science Department, University of Arizona, Tucson, Arizona, USA.|Computer Science Department, University of Arizona, Tucson, Arizona, USA.|Computer Science Department, University of Arizona, Tucson, Arizona, USA.|Computer Science Department, University of Arizona, Tucson, Arizona, USA.', 'United States|United States|United States|United States|United States|United States', 36, 'Algorithms|Artificial Intelligence|Chromosome Mapping|Chromosomes, Human, Y|DNA Mutational Analysis|Evolution, Molecular|Genetic Variation|Haplotypes|Humans|Microsatellite Repeats|Mutation|Pattern Recognition, Automated|Polymorphism, Single Nucleotide|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.1000093', '18551166', 'Genetic variation on the non-recombining portion of the Y chromosome contains information about the ancestry of male lineages. Because of their low rate of mutation, single nucleotide polymorphisms (SNPs) are the markers of choice for unambiguously classifying Y chromosomes into related sets of lineages known as haplogroups, which tend to show geographic structure in many parts of the world. However, performing the large number of SNP genotyping tests needed to properly infer haplogroup status is expensive and time consuming. A novel alternative for assigning a sampled Y chromosome to a haplogroup is presented here. We show that by applying modern machine-learning algorithms we can infer with high accuracy the proper Y chromosome haplogroup of a sample by scoring a relatively small number of Y-linked short tandem repeats (STRs). Learning is based on a diverse ground-truth data set comprising pairs of SNP test results (haplogroup) and corresponding STR scores. We apply several independent machine-learning methods in tandem to learn formal classification functions. The result is an integrated high-throughput analysis system that automatically classifies large numbers of samples into haplogroups in a cost-effective and accurate manner.'),
(83929, 2008, 'plos', 'Model-based hypothesis testing of key mechanisms in initial phase of insulin signaling', 'Cedersund, Gunnar|Roll, Jacob|Ulfhielm, Erik|Danielsson, Anna|Tidefelt, Henrik|Strålfors, Peter', 'Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 29, 'Adipocytes|Animals|Cell Membrane|Cytosol|Diabetes Mellitus, Type 2|Endocytosis|Energy Metabolism|Feedback, Physiological|Female|Homeostasis|Humans|Insulin|Insulin Resistance|Mice|Models, Biological|Rabbits|Receptor, Insulin|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.1000096', '18551197', 'Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood. We measured time-courses in primary human adipocytes for the short-term phosphorylation dynamics of the insulin receptor (IR) and the IR substrate-1 in response to a step increase in insulin concentration. Both proteins exhibited a rapid transient overshoot in tyrosine phosphorylation, reaching maximum within 1 min, followed by an intermediate steady-state level after approximately 10 min. We used model-based hypothesis testing to evaluate three mechanistic explanations for this behavior: (A) phosphorylation and dephosphorylation of IR at the plasma membrane only, (B) the additional possibility for IR endocytosis, (C) the alternative additional possibility of feedback signals to IR from downstream intermediates. We concluded that (A) is not a satisfactory explanation, that (B) may serve as an explanation only if both internalization, dephosphorylation, and subsequent recycling are permitted, and that (C) is acceptable. These mechanistic insights cannot be obtained by mere inspection of the datasets, and they are rejections and thus stronger and more final conclusions than ordinary model predictions.');
