INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83549, 2006, 'plos', 'Computational inference of neural information flow networks', 'Smith, V Anne|Yu, Jing|Smulders, Tom V|Hartemink, Alexander J|Jarvis, Erich D', 'Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America.', 'United States|United States|United States|United States|United States', 109, 'Action Potentials|Animals|Auditory Cortex|Auditory Perception|Computer Simulation|Electroencephalography|Evoked Potentials, Auditory|Finches|Information Theory|Models, Neurological|Nerve Net|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0020161', '17121460', 'Determining how information flows along anatomical brain pathways is a fundamental requirement for understanding how animals perceive their environments, learn, and behave. Attempts to reveal such neural information flow have been made using linear computational methods, but neural interactions are known to be nonlinear. Here, we demonstrate that a dynamic Bayesian network (DBN) inference algorithm we originally developed to infer nonlinear transcriptional regulatory networks from gene expression data collected with microarrays is also successful at inferring nonlinear neural information flow networks from electrophysiology data collected with microelectrode arrays. The inferred networks we recover from the songbird auditory pathway are correctly restricted to a subset of known anatomical paths, are consistent with timing of the system, and reveal both the importance of reciprocal feedback in auditory processing and greater information flow to higher-order auditory areas when birds hear natural as opposed to synthetic sounds. A linear method applied to the same data incorrectly produces networks with information flow to non-neural tissue and over paths known not to exist. To our knowledge, this study represents the first biologically validated demonstration of an algorithm to successfully infer neural information flow networks.'),
(83550, 2006, 'plos', 'Cooperation is fleeting in the world of transposable elements', 'Wagner, Andreas', 'Department of Biochemistry, University of Zurich, Zurich, Switzerland. aw@bioc.unizh.ch', 'Switzerland', 20, 'Animals|Biological Evolution|DNA Transposable Elements|Evolution, Molecular|Genetic Variation|Genetics, Population|Humans|Interspersed Repetitive Sequences|Models, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020162', '17140282', 'Composite transposons are key vehicles for the worldwide spreading of genes that allow bacteria to survive toxic compounds. Composite transposons consist of two smaller transposable elements called insertion sequences (ISs), which flank the genes that permit such survival. Each IS in a composite transposon can either transpose alone, selfishly, or it can transpose cooperatively, jointly with the other IS. Cooperative transposition can enhance an ISs chance of survival, but it also carries the risk of transposon destruction. I use game theory to show that the conditions under which cooperative transposition is an evolutionarily stable strategy (ESS) are not biologically realistic. I then analyze the distribution of thousands of ISs in more than 200 bacterial genomes to test the following prediction of the game-theoretical model: if cooperative transposition was an ESS, then the closely spaced ISs that characterize composite transposons should be more abundant in genomes than expected by chance. The data show that this is not the case. Cooperativity can only be maintained in a transitional, far-from-equilibrium state shortly after a selection pressure first arises. This is the case in the spreading of antibiotic resistance, where we are witnessing a fleeting moment in evolution, a moment in which cooperation among selfish DNA molecules has provided a means of survival. Because such cooperation does not pay in the long run, the vehicles of such survival will eventually disappear again. My analysis demonstrates that game theory can help explain behavioral strategies even for mobile DNA.'),
(83551, 2006, 'plos', 'Transcriptional regulation by competing transcription factor modules', 'Hermsen, Rutger|Tans, Sander|ten Wolde, Pieter Rein', 'FOM Institute for Atomic and Molecular Physics, Amsterdam, The Netherlands.|FOM Institute for Atomic and Molecular Physics, Amsterdam, The Netherlands.|FOM Institute for Atomic and Molecular Physics, Amsterdam, The Netherlands.', 'Netherlands|Netherlands|Netherlands', 0, 'Algorithms|Binding Sites|Computer Simulation|Gene Expression Regulation|Models, Genetic|Protein Binding|Regulatory Elements, Transcriptional|Sequence Analysis, DNA|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020164', '17140283', 'Gene regulatory networks lie at the heart of cellular computation. In these networks, intracellular and extracellular signals are integrated by transcription factors, which control the expression of transcription units by binding to cis-regulatory regions on the DNA. The designs of both eukaryotic and prokaryotic cis-regulatory regions are usually highly complex. They frequently consist of both repetitive and overlapping transcription factor binding sites. To unravel the design principles of these promoter architectures, we have designed in silico prokaryotic transcriptional logic gates with predefined input-output relations using an evolutionary algorithm. The resulting cis-regulatory designs are often composed of modules that consist of tandem arrays of binding sites to which the transcription factors bind cooperatively. Moreover, these modules often overlap with each other, leading to competition between them. Our analysis thus identifies a new signal integration motif that is based upon the interplay between intramodular cooperativity and intermodular competition. We show that this signal integration mechanism drastically enhances the capacity of cis-regulatory domains to integrate signals. Our results provide a possible explanation for the complexity of promoter architectures and could be used for the rational design of synthetic gene circuits.'),
(83552, 2006, 'plos', 'Computational model explains high activity and rapid cycling of Rho GTPases within protein complexes', 'Goryachev, Andrew B|Pokhilko, Alexandra V', 'Systems Biology Group, Bioinformatics Institute, Singapore, Singapore. Andrew.Goryachev@ed.ac.uk|Systems Biology Group, Bioinformatics Institute, Singapore, Singapore. Andrew.Goryachev@ed.ac.uk', 'Singapore|Singapore', 0, 'Amino Acid Sequence|Computer Simulation|Enzyme Activation|Feedback|GTPase-Activating Proteins|Gene Expression Regulation, Enzymologic|Guanosine Triphosphate|Models, Biological|Models, Chemical|Molecular Sequence Data|Multiprotein Complexes|Signal Transduction|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.0020172', '17140284', 'Formation of multiprotein complexes on cellular membranes is critically dependent on the cyclic activation of small GTPases. FRAP-based analyses demonstrate that within protein complexes, some small GTPases cycle nearly three orders of magnitude faster than they would spontaneously cycle in vitro. At the same time, experiments report concomitant excess of the activated, GTP-bound form of GTPases over their inactive form. Intuitively, high activity and rapid turnover are contradictory requirements. How the cells manage to maximize both remains poorly understood. Here, using GTPases of the Rab and Rho families as a prototype, we introduce a computational model of the GTPase cycle. We quantitatively investigate several plausible layouts of the cycling control module that consist of GEFs, GAPs, and GTPase effectors. We explain the existing experimental data and predict how the cycling of GTPases is controlled by the regulatory proteins in vivo. Our model explains distinct and separable roles that the activating GEFs and deactivating GAPs play in the GTPase cycling control. While the activity of GTPase is mainly defined by GEF, the turnover rate is a sole function of GAP. Maximization of the GTPase activity and turnover rate places conflicting requirements on the concentration of GAP. Therefore, to achieve a high activity and turnover rate at once, cells must carefully maintain concentrations of GEFs and GAPs within the optimal range. The values of these optimal concentrations indicate that efficient cycling can be achieved only within dense protein complexes typically assembled on the membrane surfaces. We show that the concentration requirement for GEF can be dramatically reduced by a GEF-activating GTPase effector that can also significantly boost the cycling efficiency. Interestingly, we find that the cycling regimes are only weakly dependent on the concentration of GTPase itself.'),
(83553, 2006, 'plos', 'Protein homology network families reveal step-wise diversification of Type III and Type IV secretion systems', 'Medini, Duccio|Covacci, Antonello|Donati, Claudio', 'Cellular Microbiology and BioInformatics Unit, Novartis Vaccines and Diagnostics, Siena, Italy.|Cellular Microbiology and BioInformatics Unit, Novartis Vaccines and Diagnostics, Siena, Italy.|Cellular Microbiology and BioInformatics Unit, Novartis Vaccines and Diagnostics, Siena, Italy.', 'Italy|Italy|Italy', 38, 'Amino Acid Sequence|Bacterial Proteins|Databases, Protein|Evolution, Molecular|Genetic Variation|Molecular Sequence Data|Multigene Family|Phylogeny|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0020173', '17140285', 'From the analysis of 251 prokaryotic genomes stored in public databases, the 761,260 deduced proteins were used to reconstruct a complete set of bacterial proteic families. Using the new Overlap algorithm, we have partitioned the Protein Homology Network (PHN), where the proteins are the nodes and the links represent homology relationships. The algorithm identifies the densely connected regions of the PHN that define the families of homologous proteins, here called PHN-Families, recognizing the phylogenetic relationships embedded in the network. By direct comparison with a manually curated dataset, we assessed that this classification algorithm generates data of quality similar to a human expert. Then, we explored the network to identify families involved in the assembly of Type III and Type IV secretion systems (T3SS and T4SS). We noticed that, beside a core of conserved functions (eight proteins for T3SS, seven for T4SS), a variable set of accessory components is always present (one to nine for T3SS, one to five for T4SS). Each member of the core corresponds to a single PHN-Family, while accessory proteins are distributed among different pure families. The PHN-Family classification suggests that T3SS and T4SS have been assembled through a step-wise, discontinuous process, by complementing the conserved core with subgroups of nonconserved proteins. Such genetic modules, independently recruited and probably tuned on specific effectors, contribute to the functional specialization of these organelles to different microenvironments.'),
(83554, 2006, 'plos', 'Detecting statistically significant common insertion sites in retroviral insertional mutagenesis screens', 'de Ridder, Jeroen|Uren, Anthony|Kool, Jaap|Reinders, Marcel|Wessels, Lodewyk', 'Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, The Netherlands.|Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, The Netherlands.|Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, The Netherlands.|Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, The Netherlands.|Information and Communication Theory Group, Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, Delft, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Chromosome Mapping|Computer Simulation|DNA Mutational Analysis|DNA Transposable Elements|Data Interpretation, Statistical|Genetic Testing|Genome, Viral|Models, Genetic|Models, Statistical|Retroviridae|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0020166', '17154714', 'Retroviral insertional mutagenesis screens, which identify genes involved in tumor development in mice, have yielded a substantial number of retroviral integration sites, and this number is expected to grow substantially due to the introduction of high-throughput screening techniques. The data of various retroviral insertional mutagenesis screens are compiled in the publicly available Retroviral Tagged Cancer Gene Database (RTCGD). Integrally analyzing these screens for the presence of common insertion sites (CISs, i.e., regions in the genome that have been hit by viral insertions in multiple independent tumors significantly more than expected by chance) requires an approach that corrects for the increased probability of finding false CISs as the amount of available data increases. Moreover, significance estimates of CISs should be established taking into account both the noise, arising from the random nature of the insertion process, as well as the bias, stemming from preferential insertion sites present in the genome and the data retrieval methodology. We introduce a framework, the kernel convolution (KC) framework, to find CISs in a noisy and biased environment using a predefined significance level while controlling the family-wise error (FWE) (the probability of detecting false CISs). Where previous methods use one, two, or three predetermined fixed scales, our method is capable of operating at any biologically relevant scale. This creates the possibility to analyze the CISs in a scale space by varying the width of the CISs, providing new insights in the behavior of CISs across multiple scales. Our method also features the possibility of including models for background bias. Using simulated data, we evaluate the KC framework using three kernel functions, the Gaussian, triangular, and rectangular kernel function. We applied the Gaussian KC to the data from the combined set of screens in the RTCGD and found that 53% of the CISs do not reach the significance threshold in this combined setting. Still, with the FWE under control, application of our method resulted in the discovery of eight novel CISs, which each have a probability less than 5% of being false detections.'),
(83555, 2006, 'plos', 'Gene expression of Caenorhabditis elegans neurons carries information on their synaptic connectivity', 'Kaufman, Alon|Dror, Gideon|Meilijson, Isaac|Ruppin, Eytan', 'Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. akaufman@alice.nc.huji.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. akaufman@alice.nc.huji.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. akaufman@alice.nc.huji.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. akaufman@alice.nc.huji.ac.il', 'Israel|Israel|Israel|Israel', 0, 'Animals|Caenorhabditis elegans|Caenorhabditis elegans Proteins|Computer Simulation|Gene Expression|Gene Expression Profiling|Models, Neurological|Nerve Tissue Proteins|Neurons|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0020167', '17154715', 'The claim that genetic properties of neurons significantly influence their synaptic network structure is a common notion in neuroscience. The nematode Caenorhabditis elegans provides an exciting opportunity to approach this question in a large-scale quantitative manner. Its synaptic connectivity network has been identified, and, combined with cellular studies, we currently have characteristic connectivity and gene expression signatures for most of its neurons. By using two complementary analysis assays we show that the expression signature of a neuron carries significant information about its synaptic connectivity signature, and identify a list of putative genes predicting neural connectivity. The current study rigorously quantifies the relation between gene expression and synaptic connectivity signatures in the C. elegans nervous system and identifies subsets of neurons where this relation is highly marked. The results presented and the genes identified provide a promising starting point for further, more detailed computational and experimental investigations.'),
(83556, 2006, 'plos', 'On side-chain conformational entropy of proteins', 'Zhang, Jinfeng|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.', 'United States|United States', 35, 'Algorithms|Amino Acid Sequence|Computer Simulation|Crystallography|Entropy|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Conformation|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0020168', '17154716', 'The role of side-chain entropy (SCE) in protein folding has long been speculated about but is still not fully understood. Utilizing a newly developed Monte Carlo method, we conducted a systematic investigation of how the SCE relates to the size of the protein and how it differs among a proteins X-ray, NMR, and decoy structures. We estimated the SCE for a set of 675 nonhomologous proteins, and observed that there is a significant SCE for both exposed and buried residues for all these proteins-the contribution of buried residues approaches approximately 40% of the overall SCE. Furthermore, the SCE can be quite different for structures with similar compactness or even similar conformations. As a striking example, we found that proteins X-ray structures appear to pack more cleverly than their NMR or decoy counterparts in the sense of retaining higher SCE while achieving comparable compactness, which suggests that the SCE plays an important role in favouring native protein structures. By including a SCE term in a simple free energy function, we can significantly improve the discrimination of native protein structures from decoys.'),
(83557, 2006, 'plos', 'Identification of the proliferation/differentiation switch in the cellular network of multicellular organisms', 'Xia, Kai|Xue, Huiling|Dong, Dong|Zhu, Shanshan|Wang, Jiamu|Zhang, Qingpeng|Hou, Lei|Chen, Hua|Tao, Ran|Huang, Zheng|Fu, Zheng|Chen, Ye-Guang|Han, Jing-Dong J', 'The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.|The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, Peoples Republic of China.', 'China|China|China|China|China|China|China|China|China|China|China|China|China', 0, 'Animals|Biology|Cell Differentiation|Cell Proliferation|Cluster Analysis|Computational Biology|Databases, Genetic|Databases, Protein|Drosophila melanogaster|Humans|Phylogeny|Proteins|Proteomics|Systems Biology|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020145', '17166053', 'The protein-protein interaction networks, or interactome networks, have been shown to have dynamic modular structures, yet the functional connections between and among the modules are less well understood. Here, using a new pipeline to integrate the interactome and the transcriptome, we identified a pair of transcriptionally anticorrelated modules, each consisting of hundreds of genes in multicellular interactome networks across different individuals and populations. The two modules are associated with cellular proliferation and differentiation, respectively. The proliferation module is conserved among eukaryotic organisms, whereas the differentiation module is specific to multicellular organisms. Upon differentiation of various tissues and cell lines from different organisms, the expression of the proliferation module is more uniformly suppressed, while the differentiation module is upregulated in a tissue- and species-specific manner. Our results indicate that even at the tissue and organism levels, proliferation and differentiation modules may correspond to two alternative states of the molecular network and may reflect a universal symbiotic relationship in a multicellular organism. Our analyses further predict that the proteins mediating the interactions between these modules may serve as modulators at the proliferation/differentiation switch.'),
(83558, 2006, 'plos', 'Selection of target sites for mobile DNA integration in the human genome', 'Berry, Charles|Hannenhalli, Sridhar|Leipzig, Jeremy|Bushman, Frederic D', 'Department of Family and Preventive Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.|Department of Family and Preventive Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.|Department of Family and Preventive Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.|Department of Family and Preventive Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States', 0, 'Binding Sites|Cluster Analysis|Computational Biology|CpG Islands|DNA|DNA Transposable Elements|Gene Transfer Techniques|Genome, Human|Genomics|Humans|Models, Genetic|Software|Transcription, Genetic|Virus Integration|Viruses', 'Journal Article', '10.1371/journal.pcbi.0020157', '17166054', 'DNA sequences from retroviruses, retrotransposons, DNA transposons, and parvoviruses can all become integrated into the human genome. Accumulation of such sequences accounts for at least 40% of our genome today. These integrating elements are also of interest as gene-delivery vectors for human gene therapy. Here we present a comprehensive bioinformatic analysis of integration targeting by HIV, MLV, ASLV, SFV, L1, SB, and AAV. We used a mathematical method which allowed annotation of each base pair in the human genome for its likelihood of hosting an integration event by each type of element, taking advantage of more than 200 types of genomic annotation. This bioinformatic resource documents a wealth of new associations between genomic features and integration targeting. The study also revealed that the length of genomic intervals analyzed strongly affected the conclusions drawn--thus, answering the question What genomic features affect integration? requires carefully specifying the length scale of interest.'),
(83559, 2006, 'plos', 'Computational reconstruction of iron- and manganese-responsive transcriptional networks in alpha-proteobacteria', 'Rodionov, Dmitry A|Gelfand, Mikhail S|Todd, Jonathan D|Curson, Andrew R J|Johnston, Andrew W B', 'Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia. rodionov@iitp.ru|Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia. rodionov@iitp.ru|Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia. rodionov@iitp.ru|Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia. rodionov@iitp.ru|Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia. rodionov@iitp.ru', '-|-|-|-|-', 0, 'Alphaproteobacteria|Computer Simulation|Gene Expression Regulation, Bacterial|Iron|Manganese|Models, Biological|Signal Transduction|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020163', '17173478', 'We used comparative genomics to investigate the distribution of conserved DNA-binding motifs in the regulatory regions of genes involved in iron and manganese homeostasis in alpha-proteobacteria. Combined with other computational approaches, this allowed us to reconstruct the metal regulatory network in more than three dozen species with available genome sequences. We identified several classes of cis-acting regulatory DNA motifs (Irr-boxes or ICEs, RirA-boxes, Iron-Rhodo-boxes, Fur-alpha-boxes, Mur-box or MRS, MntR-box, and IscR-boxes) in regulatory regions of various genes involved in iron and manganese uptake, Fe-S and heme biosynthesis, iron storage, and usage. Despite the different nature of the iron regulons in selected lineages of alpha-proteobacteria, the overall regulatory network is consistent with, and confirmed by, many experimental observations. This study expands the range of genes involved in iron homeostasis and demonstrates considerable interconnection between iron-responsive regulatory systems. The detailed comparative and phylogenetic analyses of the regulatory systems allowed us to propose a theory about the possible evolution of Fe and Mn regulons in alpha-proteobacteria. The main evolutionary event likely occurred in the common ancestor of the Rhizobiales and Rhodobacterales, where the Fur protein switched to regulating manganese transporters (and hence Fur had become Mur). In these lineages, the role of global iron homeostasis was taken by RirA and Irr, two transcriptional regulators that act by sensing the physiological consequence of the metal availability rather than its concentration per se, and thus provide for more flexible regulation.'),
(83560, 2006, 'plos', 'Insight into the structure of amyloid fibrils from the analysis of globular proteins', 'Trovato, Antonio|Chiti, Fabrizio|Maritan, Amos|Seno, Flavio', 'Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Padova, Padua, Italy. trovato@pd.infn.it|Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Padova, Padua, Italy. trovato@pd.infn.it|Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Padova, Padua, Italy. trovato@pd.infn.it|Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, Unità di Padova, Padua, Italy. trovato@pd.infn.it', 'Italy|Italy|Italy|Italy', 0, 'Amino Acid Sequence|Amyloid|Computer Simulation|Models, Chemical|Models, Molecular|Molecular Sequence Data|Multiprotein Complexes|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0020170', '17173479', 'The conversion from soluble states into cross-beta fibrillar aggregates is a property shared by many different proteins and peptides and was hence conjectured to be a generic feature of polypeptide chains. Increasing evidence is now accumulating that such fibrillar assemblies are generally characterized by a parallel in-register alignment of beta-strands contributed by distinct protein molecules. Here we assume a universal mechanism is responsible for beta-structure formation and deduce sequence-specific interaction energies between pairs of protein fragments from a statistical analysis of the native folds of globular proteins. The derived fragment-fragment interaction was implemented within a novel algorithm, prediction of amyloid structure aggregation (PASTA), to investigate the role of sequence heterogeneity in driving specific aggregation into ordered self-propagating cross-beta structures. The algorithm predicts that the parallel in-register arrangement of sequence portions that participate in the fibril cross-beta core is favoured in most cases. However, the antiparallel arrangement is correctly discriminated when present in fibrils formed by short peptides. The predictions of the most aggregation-prone portions of initially unfolded polypeptide chains are also in excellent agreement with available experimental observations. These results corroborate the recent hypothesis that the amyloid structure is stabilised by the same physicochemical determinants as those operating in folded proteins. They also suggest that side chain-side chain interaction across neighbouring beta-strands is a key determinant of amyloid fibril formation and of their self-propagating ability.'),
(83561, 2006, 'plos', 'Connectivity in the yeast cell cycle transcription network: inferences from neural networks', 'Hart, Christopher E|Mjolsness, Eric|Wold, Barbara J', 'Division of Biology, California Institute of Technology, Pasadena, California, United States of America.|Division of Biology, California Institute of Technology, Pasadena, California, United States of America.|Division of Biology, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States|United States', 11, 'Artificial Intelligence|Cell Cycle Proteins|Computer Simulation|Gene Expression Profiling|Models, Biological|Neural Networks (Computer)|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Saccharomyces cerevisiae Proteins|Signal Transduction|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0020169', '17194216', 'A current challenge is to develop computational approaches to infer gene network regulatory relationships based on multiple types of large-scale functional genomic data. We find that single-layer feed-forward artificial neural network (ANN) models can effectively discover gene network structure by integrating global in vivo protein:DNA interaction data (ChIP/Array) with genome-wide microarray RNA data. We test this on the yeast cell cycle transcription network, which is composed of several hundred genes with phase-specific RNA outputs. These ANNs were robust to noise in data and to a variety of perturbations. They reliably identified and ranked 10 of 12 known major cell cycle factors at the top of a set of 204, based on a sum-of-squared weights metric. Comparative analysis of motif occurrences among multiple yeast species independently confirmed relationships inferred from ANN weights analysis. ANN models can capitalize on properties of biological gene networks that other kinds of models do not. ANNs naturally take advantage of patterns of absence, as well as presence, of factor binding associated with specific expression output, they are easily subjected to in silico mutation to uncover biological redundancies, and they can use the full range of factor binding values. A prominent feature of cell cycle ANNs suggested an analogous property might exist in the biological network. This postulated that network-local discrimination occurs when regulatory connections (here between MBF and target genes) are explicitly disfavored in one network module (G2), relative to others and to the class of genes outside the mitotic network. If correct, this predicts that MBF motifs will be significantly depleted from the discriminated class and that the discrimination will persist through evolution. Analysis of distantly related Schizosaccharomyces pombe confirmed this, suggesting that network-local discrimination is real and complements well-known enrichment of MBF sites in G1 class genes.'),
(83562, 2006, 'plos', 'DARPP-32 is a robust integrator of dopamine and glutamate signals', 'Fernandez, Eric|Schiappa, Renaud|Girault, Jean-Antoine|Le Novère, Nicolas', 'EMBL-EBI, Wellcome-Trust Genome Campus, Hinxton, United Kingdom.|EMBL-EBI, Wellcome-Trust Genome Campus, Hinxton, United Kingdom.|EMBL-EBI, Wellcome-Trust Genome Campus, Hinxton, United Kingdom.|EMBL-EBI, Wellcome-Trust Genome Campus, Hinxton, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 120, 'Basal Ganglia|Computer Simulation|Dopamine|Dopamine and cAMP-Regulated Phosphoprotein 32|Glutamic Acid|Models, Biological|Models, Neurological|Phosphorylation|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0020176', '17194217', 'Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca(2+) signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca(2+) signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca(2+) regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons.'),
(83563, 2006, 'plos', 'The genome: An outsiders view', 'Zimmer, Carl', 'Guilford, Connecticut, United States of America. carl@carlzimmer.com', 'United States', 0, 'Animals|Genome|Humans', 'Journal Article', '10.1371/journal.pcbi.0020156', '17196031', '-'),
(83564, 2006, 'plos', 'Modularity and dynamics of cellular networks', 'Qi, Yuan|Ge, Hui', 'MITs Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts, United States of America.|MITs Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts, United States of America.', 'United States|United States', 63, 'Animals|Biological Evolution|Cells|Humans|Models, Biological|Protein Binding|Signal Transduction|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020174', '17196032', '-'),
(83565, 2006, 'plos', 'Prediction of amyloidogenic and disordered regions in protein chains', 'Galzitskaya, Oxana V|Garbuzynskiy, Sergiy O|Lobanov, Michail Yurievich', 'Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. ogalzit@vega.protres.ru|Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. ogalzit@vega.protres.ru|Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. ogalzit@vega.protres.ru', '-|-|-', 0, 'Amino Acids|Amyloid|Computational Biology|Databases, Protein|Disease|Humans|Peptides|Protein Conformation|Protein Folding', 'Journal Article', '10.1371/journal.pcbi.0020177', '17196033', 'The determination of factors that influence protein conformational changes is very important for the identification of potentially amyloidogenic and disordered regions in polypeptide chains. In our work we introduce a new parameter, mean packing density, to detect both amyloidogenic and disordered regions in a protein sequence. It has been shown that regions with strong expected packing density are responsible for amyloid formation. Our predictions are consistent with known disease-related amyloidogenic regions for eight of 12 amyloid-forming proteins and peptides in which the positions of amyloidogenic regions have been revealed experimentally. Our findings support the concept that the mechanism of amyloid fibril formation is similar for different peptides and proteins. Moreover, we have demonstrated that regions with weak expected packing density are responsible for the appearance of disordered regions. Our method has been tested on datasets of globular proteins and long disordered protein segments, and it shows improved performance over other widely used methods. Thus, we demonstrate that the expected packing density is a useful value with which one can predict both intrinsically disordered and amyloidogenic regions of a protein based on sequence alone. Our results are important for understanding the structural characteristics of protein folding and misfolding.'),
(83566, 2006, 'plos', 'Stern-judging: A simple, successful norm which promotes cooperation under indirect reciprocity', 'Pacheco, Jorge M|Santos, Francisco C|Chalub, Fabio A C C', 'Centro de Física Teórica e Computacional and Departamento de Física da Faculdade de Ciências, Lisbon, Portugal.|Centro de Física Teórica e Computacional and Departamento de Física da Faculdade de Ciências, Lisbon, Portugal.|Centro de Física Teórica e Computacional and Departamento de Física da Faculdade de Ciências, Lisbon, Portugal.', 'Portugal|Portugal|Portugal', 109, 'Animals|Biological Evolution|Cooperative Behavior|Game Theory|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020178', '17196034', 'We study the evolution of cooperation under indirect reciprocity, believed to constitute the biological basis of morality. We employ an evolutionary game theoretical model of multilevel selection, and show that natural selection and mutation lead to the emergence of a robust and simple social norm, which we call stern-judging. Under stern-judging, helping a good individual or refusing help to a bad individual leads to a good reputation, whereas refusing help to a good individual or helping a bad one leads to a bad reputation. Similarly for tit-for-tat and win-stay-lose-shift, the simplest ubiquitous strategies in direct reciprocity, the lack of ambiguity of stern-judging, where implacable punishment is compensated by prompt forgiving, supports the idea that simplicity is often associated with evolutionary success.'),
(83567, 2006, 'plos', 'Targeting neuropilin-1 to inhibit VEGF signaling in cancer: Comparison of therapeutic approaches', 'Mac Gabhann, Feilim|Popel, Aleksander S', 'Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. feilim@jhu.edu|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. feilim@jhu.edu', 'United States|United States', 60, 'Biological Transport|Computational Biology|Computer Simulation|Kinetics|Models, Biological|Neoplasms|Neuropilin-1|Protein Binding|Receptors, Vascular Endothelial Growth Factor|Signal Transduction|Vascular Endothelial Growth Factor A', 'Comparative Study', '10.1371/journal.pcbi.0020180', '17196035', 'Angiogenesis (neovascularization) plays a crucial role in a variety of physiological and pathological conditions including cancer, cardiovascular disease, and wound healing. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Multiple VEGF receptors are expressed on endothelial cells, including signaling receptor tyrosine kinases (VEGFR1 and VEGFR2) and the nonsignaling co-receptor Neuropilin-1. Neuropilin-1 binds only the isoform of VEGF responsible for pathological angiogenesis (VEGF165), and is thus a potential target for inhibiting VEGF signaling. Using the first molecularly detailed computational model of VEGF and its receptors, we have shown previously that the VEGFR-Neuropilin interactions explain the observed differential effects of VEGF isoforms on VEGF signaling in vitro, and demonstrated potent VEGF inhibition by an antibody to Neuropilin-1 that does not block ligand binding but blocks subsequent receptor coupling. In the present study, we extend that computational model to simulation of in vivo VEGF transport and binding, and predict the in vivo efficacy of several Neuropilin-targeted therapies in inhibiting VEGF signaling: (a) blocking Neuropilin-1 expression, (b) blocking VEGF binding to Neuropilin-1, (c) blocking Neuropilin-VEGFR coupling. The model predicts that blockade of Neuropilin-VEGFR coupling is significantly more effective than other approaches in decreasing VEGF-VEGFR2 signaling. In addition, tumor types with different receptor expression levels respond differently to each of these treatments. In designing human therapeutics, the mechanism of attacking the target plays a significant role in the outcome: of the strategies tested here, drugs with similar properties to the Neuropilin-1 antibody are predicted to be most effective. The tumor type and the microenvironment of the target tissue are also significant in determining therapeutic efficacy of each of the treatments studied.'),
(83568, 2007, 'plos', 'A phylogenomic study of human, dog, and mouse', 'Cannarozzi, Gina|Schneider, Adrian|Gonnet, Gaston', 'Institute of Computational Science, ETH Zurich, Zurich, Switzerland.|Institute of Computational Science, ETH Zurich, Zurich, Switzerland.|Institute of Computational Science, ETH Zurich, Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland', 0, 'Animals|Biological Evolution|Chromosome Mapping|Dogs|Humans|Mice|Models, Genetic|Phylogeny|Sequence Homology, Nucleic Acid|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.0030002', '17206860', 'In recent years the phylogenetic relationship of mammalian orders has been addressed in a number of molecular studies. These analyses have frequently yielded inconsistent results with respect to some basal ordinal relationships. For example, the relative placement of primates, rodents, and carnivores has differed in various studies. Here, we attempt to resolve this phylogenetic problem by using data from completely sequenced nuclear genomes to base the analyses on the largest possible amount of data. To minimize the risk of reconstruction artifacts, the trees were reconstructed under different criteria-distance, parsimony, and likelihood. For the distance trees, distance metrics that measure independent phenomena (amino acid replacement, synonymous substitution, and gene reordering) were used, as it is highly improbable that all of the trees would be affected the same way by any reconstruction artifact. In contradiction to the currently favored classification, our results based on full-genome analysis of the phylogenetic relationship between human, dog, and mouse yielded overwhelming support for a primate-carnivore clade with the exclusion of rodents.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83569, 2007, 'plos', 'Modeling HER2 effects on cell behavior from mass spectrometry phosphotyrosine data', 'Kumar, Neil|Wolf-Yadlin, Alejandro|White, Forest M|Lauffenburger, Douglas A', '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.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 85, 'Cell Line|Computer Simulation|Epithelial Cells|Gene Expression Profiling|Humans|Mammary Glands, Human|Mass Spectrometry|Models, Biological|Phosphotyrosine|Receptor, ErbB-2|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030004', '17206861', 'Cellular behavior in response to stimulatory cues is governed by information encoded within a complex intracellular signaling network. An understanding of how phenotype is determined requires the distributed characterization of signaling processes (e.g., phosphorylation states and kinase activities) in parallel with measures of resulting cell function. We previously applied quantitative mass spectrometry methods to characterize the dynamics of tyrosine phosphorylation in human mammary epithelial cells with varying human epidermal growth factor receptor 2 (HER2) expression levels after treatment with epidermal growth factor (EGF) or heregulin (HRG). We sought to identify potential mechanisms by which changes in tyrosine phosphorylation govern changes in cell migration or proliferation, two behaviors that we measured in the same cell system. Here, we describe the use of a computational linear mapping technique, partial least squares regression (PLSR), to detail and characterize signaling mechanisms responsible for HER2-mediated effects on migration and proliferation. PLSR model analysis via principal component inner products identified phosphotyrosine signals most strongly associated with control of migration and proliferation, as HER2 expression or ligand treatment were individually varied. Inspection of these signals revealed both previously identified and novel pathways that correlate with cell behavior. Furthermore, we isolated elements of the signaling network that differentially give rise to migration and proliferation. Finally, model analysis identified nine especially informative phosphorylation sites on six proteins that recapitulated the predictive capability of the full model. A model based on these nine sites and trained solely on data from a low HER2-expressing cell line a priori predicted migration and proliferation in a HER2-overexpressing cell line. We identify the nine signals as a network gauge, meaning that when interrogated together and integrated according to the quantitative rules of the model, these signals capture information content in the network sufficiently to predict cell migration and proliferation under diverse ligand treatments and receptor expression levels. Examination of the network gauge in the context of previous literature indicates that endocytosis and activation of phosphoinositide 3-kinase (PI3K)-mediated pathways together represent particularly strong loci for the integration of the multiple pathways mediating HER2s control of mammary epithelial cell proliferation and migration. Thus, a PLSR modeling approach reveals critical signaling processes regulating HER2-mediated cell behavior.'),
(83570, 2007, 'plos', 'Nitric oxide regulates input specificity of long-term depression and context dependence of cerebellar learning', 'Ogasawara, Hideaki|Doi, Tomokazu|Doya, Kenji|Kawato, Mitsuo', 'ATR Computational Neuroscience Laboratories, Seika, Kyoto, Japan. ogahide@atr.jp|ATR Computational Neuroscience Laboratories, Seika, Kyoto, Japan. ogahide@atr.jp|ATR Computational Neuroscience Laboratories, Seika, Kyoto, Japan. ogahide@atr.jp|ATR Computational Neuroscience Laboratories, Seika, Kyoto, Japan. ogahide@atr.jp', 'Japan|Japan|Japan|Japan', 0, 'Action Potentials|Association Learning|Cerebellum|Computer Simulation|Feedback|Long-Term Synaptic Depression|Models, Neurological|Nerve Net|Nitric Oxide|Purkinje Cells|Sensitivity and Specificity|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0020179', '17222054', 'Recent studies have shown that multiple internal models are acquired in the cerebellum and that these can be switched under a given context of behavior. It has been proposed that long-term depression (LTD) of parallel fiber (PF)-Purkinje cell (PC) synapses forms the cellular basis of cerebellar learning, and that the presynaptically synthesized messenger nitric oxide (NO) is a crucial gatekeeper for LTD. Because NO diffuses freely to neighboring synapses, this volume learning is not input-specific and brings into question the biological significance of LTD as the basic mechanism for efficient supervised learning. To better characterize the role of NO in cerebellar learning, we simulated the sequence of electrophysiological and biochemical events in PF-PC LTD by combining established simulation models of the electrophysiology, calcium dynamics, and signaling pathways of the PC. The results demonstrate that the local NO concentration is critical for induction of LTD and for its input specificity. Pre- and postsynaptic coincident firing is not sufficient for a PF-PC synapse to undergo LTD, and LTD is induced only when a sufficient amount of NO is provided by activation of the surrounding PFs. On the other hand, above-adequate levels of activity in nearby PFs cause accumulation of NO, which also allows LTD in neighboring synapses that were not directly stimulated, ruining input specificity. These findings lead us to propose the hypothesis that NO represents the relevance of a given context and enables context-dependent selection of internal models to be updated. We also predict sparse PF activity in vivo because, otherwise, input specificity would be lost.'),
(83571, 2007, 'plos', 'Protein and DNA sequence determinants of thermophilic adaptation', 'Zeldovich, Konstantin B|Berezovsky, Igor N|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 0, 'Adaptation, Physiological|Amino Acid Sequence|Archaea|Bacterial Proteins|Chromosome Mapping|Conserved Sequence|DNA|Evolution, Molecular|Molecular Sequence Data|Proteome|Sequence Analysis, DNA|Sequence Analysis, Protein|Sequence Homology|Temperature', 'Journal Article', '10.1371/journal.pcbi.0030005', '17222055', 'There have been considerable attempts in the past to relate phenotypic trait--habitat temperature of organisms--to their genotypes, most importantly compositions of their genomes and proteomes. However, despite accumulation of anecdotal evidence, an exact and conclusive relationship between the former and the latter has been elusive. We present an exhaustive study of the relationship between amino acid composition of proteomes, nucleotide composition of DNA, and optimal growth temperature (OGT) of prokaryotes. Based on 204 complete proteomes of archaea and bacteria spanning the temperature range from -10 degrees C to 110 degrees C, we performed an exhaustive enumeration of all possible sets of amino acids and found a set of amino acids whose total fraction in a proteome is correlated, to a remarkable extent, with the OGT. The universal set is Ile, Val, Tyr, Trp, Arg, Glu, Leu (IVYWREL), and the correlation coefficient is as high as 0.93. We also found that the G + C content in 204 complete genomes does not exhibit a significant correlation with OGT (R = -0.10). On the other hand, the fraction of A + G in coding DNA is correlated with temperature, to a considerable extent, due to codon patterns of IVYWREL amino acids. Further, we found strong and independent correlation between OGT and the frequency with which pairs of A and G nucleotides appear as nearest neighbors in genome sequences. This adaptation is achieved via codon bias. These findings present a direct link between principles of proteins structure and stability and evolutionary mechanisms of thermophylic adaptation. On the nucleotide level, the analysis provides an example of how nature utilizes codon bias for evolutionary adaptation to extreme conditions. Together these results provide a complete picture of how compositions of proteomes and genomes in prokaryotes adjust to the extreme conditions of the environment.'),
(83572, 2007, 'plos', 'Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of g protein-coupled receptor signaling', 'Kinzer-Ursem, Tamara L|Linderman, Jennifer J', 'Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States', 57, 'Algorithms|Amino Acid Sequence|Computer Simulation|GTP-Binding Proteins|Kinetics|Ligands|Metabolic Clearance Rate|Models, Biological|Molecular Sequence Data|Protein Binding|Protein Interaction Mapping|Receptors, G-Protein-Coupled', 'Journal Article', '10.1371/journal.pcbi.0030006', '17222056', 'G protein-coupled receptors (GPCRs) exist in multiple dynamic states (e.g., ligand-bound, inactive, G protein-coupled) that influence G protein activation and ultimately response generation. In quantitative models of GPCR signaling that incorporate these varied states, parameter values are often uncharacterized or varied over large ranges, making identification of important parameters and signaling outcomes difficult to intuit. Here we identify the ligand- and cell-specific parameters that are important determinants of cell-response behavior in a dynamic model of GPCR signaling using parameter variation and sensitivity analysis. The character of response (i.e., positive/neutral/inverse agonism) is, not surprisingly, significantly influenced by a ligands ability to bias the receptor into an active conformation. We also find that several cell-specific parameters, including the ratio of active to inactive receptor species, the rate constant for G protein activation, and expression levels of receptors and G proteins also dramatically influence agonism. Expressing either receptor or G protein in numbers several fold above or below endogenous levels may result in system behavior inconsistent with that measured in endogenous systems. Finally, small variations in cell-specific parameters identified by sensitivity analysis as significant determinants of response behavior are found to change ligand-induced responses from positive to negative, a phenomenon termed protean agonism. Our findings offer an explanation for protean agonism reported in beta2--adrenergic and alpha2A-adrenergic receptor systems.'),
(83573, 2007, 'plos', 'Computational aspects of feedback in neural circuits', 'Maass, Wolfgang|Joshi, Prashant|Sontag, Eduardo D', 'Institute for Theoretical Computer Science, Technische Universitaet Graz, Graz, Austria. maass@igi.tugraz.at|Institute for Theoretical Computer Science, Technische Universitaet Graz, Graz, Austria. maass@igi.tugraz.at|Institute for Theoretical Computer Science, Technische Universitaet Graz, Graz, Austria. maass@igi.tugraz.at', 'Austria|Austria|Austria', 0, 'Action Potentials|Adaptation, Physiological|Brain|Computer Simulation|Computers, Molecular|Feedback|Models, Neurological|Nerve Net|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0020165', '17238280', 'It has previously been shown that generic cortical microcircuit models can perform complex real-time computations on continuous input streams, provided that these computations can be carried out with a rapidly fading memory. We investigate the computational capability of such circuits in the more realistic case where not only readout neurons, but in addition a few neurons within the circuit, have been trained for specific tasks. This is essentially equivalent to the case where the output of trained readout neurons is fed back into the circuit. We show that this new model overcomes the limitation of a rapidly fading memory. In fact, we prove that in the idealized case without noise it can carry out any conceivable digital or analog computation on time-varying inputs. But even with noise, the resulting computational model can perform a large class of biologically relevant real-time computations that require a nonfading memory. We demonstrate these computational implications of feedback both theoretically, and through computer simulations of detailed cortical microcircuit models that are subject to noise and have complex inherent dynamics. We show that the application of simple learning procedures (such as linear regression or perceptron learning) to a few neurons enables such circuits to represent time over behaviorally relevant long time spans, to integrate evidence from incoming spike trains over longer periods of time, and to process new information contained in such spike trains in diverse ways according to the current internal state of the circuit. In particular we show that such generic cortical microcircuits with feedback provide a new model for working memory that is consistent with a large set of biological constraints. Although this article examines primarily the computational role of feedback in circuits of neurons, the mathematical principles on which its analysis is based apply to a variety of dynamical systems. Hence they may also throw new light on the computational role of feedback in other complex biological dynamical systems, such as, for example, genetic regulatory networks.'),
(83574, 2007, 'plos', 'Using phylogeny to improve genome-wide distant homology recognition', 'Abeln, Sanne|Teubner, Carlo|Deane, Charlotte M', 'Department of Statistics, University of Oxford, Oxford, United Kingdom.|Department of Statistics, University of Oxford, Oxford, United Kingdom.|Department of Statistics, University of Oxford, Oxford, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 4, 'Algorithms|Base Sequence|Chromosome Mapping|Evolution, Molecular|Genome|Linkage Disequilibrium|Molecular Sequence Data|Phylogeny|Sequence Alignment|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0030003', '17238281', 'The gap between the number of known protein sequences and structures continues to widen, particularly as a result of sequencing projects for entire genomes. Recently there have been many attempts to generate structural assignments to all genes on sets of completed genomes using fold-recognition methods. We developed a method that detects false positives made by these genome-wide structural assignment experiments by identifying isolated occurrences. The method was tested using two sets of assignments, generated by SUPERFAMILY and PSI-BLAST, on 150 completed genomes. A phylogeny of these genomes was built and a parsimony algorithm was used to identify isolated occurrences by detecting occurrences that cause a gain at leaf level. Isolated occurrences tend to have high e-values, and in both sets of assignments, a sudden increase in isolated occurrences is observed for e-values >10(-8) for SUPERFAMILY and >10(-4) for PSI-BLAST. Conditions to predict false positives are based on these results. Independent tests confirm that the predicted false positives are indeed more likely to be incorrectly assigned. Evaluation of the predicted false positives also showed that the accuracy of profile-based fold-recognition methods might depend on secondary structure content and sequence length. We show that false positives generated by fold-recognition methods can be identified by considering structural occurrence patterns on completed genomes, occurrences that are isolated within the phylogeny tend to be less reliable. The method provides a new independent way to examine the quality of fold assignments and may be used to improve the output of any genome-wide fold assignment method.'),
(83575, 2007, 'plos', 'Large-scale discovery of promoter motifs in Drosophila melanogaster', 'Down, Thomas A|Bergman, Casey M|Su, Jing|Hubbard, Tim J P', 'Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. td2@sanger.ac.uk|Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. td2@sanger.ac.uk|Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. td2@sanger.ac.uk|Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. td2@sanger.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 57, 'Amino Acid Motifs|Animals|Base Sequence|Binding Sites|Chromosome Mapping|Drosophila Proteins|Drosophila melanogaster|Molecular Sequence Data|Promoter Regions, Genetic|Protein Binding|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030007', '17238282', 'A key step in understanding gene regulation is to identify the repertoire of transcription factor binding motifs (TFBMs) that form the building blocks of promoters and other regulatory elements. Identifying these experimentally is very laborious, and the number of TFBMs discovered remains relatively small, especially when compared with the hundreds of transcription factor genes predicted in metazoan genomes. We have used a recently developed statistical motif discovery approach, NestedMICA, to detect candidate TFBMs from a large set of Drosophila melanogaster promoter regions. Of the 120 motifs inferred in our initial analysis, 25 were statistically significant matches to previously reported motifs, while 87 appeared to be novel. Analysis of sequence conservation and motif positioning suggested that the great majority of these discovered motifs are predictive of functional elements in the genome. Many motifs showed associations with specific patterns of gene expression in the D. melanogaster embryo, and we were able to obtain confident annotation of expression patterns for 25 of our motifs, including eight of the novel motifs. The motifs are available through Tiffin, a new database of DNA sequence motifs. We have discovered many new motifs that are overrepresented in D. melanogaster promoter regions, and offer several independent lines of evidence that these are novel TFBMs. Our motif dictionary provides a solid foundation for further investigation of regulatory elements in Drosophila, and demonstrates techniques that should be applicable in other species. We suggest that further improvements in computational motif discovery should narrow the gap between the set of known motifs and the total number of transcription factors in metazoan genomes.'),
(83576, 2007, 'plos', 'Evolutionary interactions between N-linked glycosylation sites in 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, 'Amino Acid Sequence|Binding Sites|Conserved Sequence|Evolution, Molecular|Glycosylation|HIV-1|Molecular Sequence Data|Polysaccharides|Protein Binding|Protein Interaction Mapping|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Viral Envelope Proteins', 'Journal Article', '10.1371/journal.pcbi.0030011', '17238283', 'The addition of asparagine (N)-linked polysaccharide chains (i.e., glycans) to the gp120 and gp41 glycoproteins of human immunodeficiency virus type 1 (HIV-1) envelope is not only required for correct protein folding, but also may provide protection against neutralizing antibodies as a glycan shield. As a result, strong host-specific selection is frequently associated with codon positions where nonsynonymous substitutions can create or disrupt potential N-linked glycosylation sites (PNGSs). Moreover, empirical data suggest that the individual contribution of PNGSs to the neutralization sensitivity or infectivity of HIV-1 may be critically dependent on the presence or absence of other PNGSs in the envelope sequence. Here we evaluate how glycan-glycan interactions have shaped the evolution of HIV-1 envelope sequences by analyzing the distribution of PNGSs in a large-sequence alignment. Using a covarion-type phylogenetic model, we find that the rates at which individual PNGSs are gained or lost vary significantly over time, suggesting that the selective advantage of having a PNGS may depend on the presence or absence of other PNGSs in the sequence. Consequently, we identify specific interactions between PNGSs in the alignment using a new paired-character phylogenetic model of evolution, and a Bayesian graphical model. Despite the fundamental differences between these two methods, several interactions are jointly identified by both. Mapping these interactions onto a structural model of HIV-1 gp120 reveals that negative (exclusive) interactions occur significantly more often between colocalized glycans, while positive (inclusive) interactions are restricted to more distant glycans. Our results imply that the adaptive repertoire of alternative configurations in the HIV-1 glycan shield is limited by functional interactions between the N-linked glycans. This represents a potential vulnerability of rapidly evolving HIV-1 populations that may provide useful glycan-based targets for neutralizing antibodies.'),
(83577, 2007, 'plos', 'Automated querying of genome databases', 'Schattner, Peter', 'Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America. schattner@soe.ucsc.edu', 'United States', 0, 'Algorithms|Chromosome Mapping|Database Management Systems|Databases, Genetic|Information Storage and Retrieval|Sequence Analysis, DNA|Software|User-Computer Interface', 'Evaluation Studies', '10.1371/journal.pcbi.0030001', '17257048', '-'),
(83578, 2007, 'plos', 'Identification of functional subclasses in the DJ-1 superfamily proteins', 'Wei, Ying|Ringe, Dagmar|Wilson, Mark A|Ondrechen, Mary Jo', 'Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States', 0, 'Algorithms|Amino Acid Sequence|Binding Sites|Computer Simulation|Intracellular Signaling Peptides and Proteins|Models, Chemical|Models, Molecular|Molecular Sequence Data|Oncogene Proteins|Protein Binding|Protein Conformation|Protein Deglycase DJ-1|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030010', '17257049', 'Genomics has posed the challenge of determination of protein function from sequence and/or 3-D structure. Functional assignment from sequence relationships can be misleading, and structural similarity does not necessarily imply functional similarity. Proteins in the DJ-1 family, many of which are of unknown function, are examples of proteins with both sequence and fold similarity that span multiple functional classes. THEMATICS (theoretical microscopic titration curves), an electrostatics-based computational approach to functional site prediction, is used to sort proteins in the DJ-1 family into different functional classes. Active site residues are predicted for the eight distinct DJ-1 proteins with available 3-D structures. Placement of the predicted residues onto a structural alignment for six of these proteins reveals three distinct types of active sites. Each type overlaps only partially with the others, with only one residue in common across all six sets of predicted residues. Human DJ-1 and YajL from Escherichia coli have very similar predicted active sites and belong to the same probable functional group. Protease I, a known cysteine protease from Pyrococcus horikoshii, and PfpI/YhbO from E. coli, a hypothetical protein of unknown function, belong to a separate class. THEMATICS predicts a set of residues that is typical of a cysteine protease for Protease I, the prediction for PfpI/YhbO bears some similarity. YDR533Cp from Saccharomyces cerevisiae, of unknown function, and the known chaperone Hsp31 from E. coli constitute a third group with nearly identical predicted active sites. While the first four proteins have predicted active sites at dimer interfaces, YDR533Cp and Hsp31 both have predicted sites contained within each subunit. Although YDR533Cp and Hsp31 form different dimers with different orientations between the subunits, the predicted active sites are superimposable within the monomer structures. Thus, the three predicted functional classes form four different types of quaternary structures. The computational prediction of the functional sites for protein structures of unknown function provides valuable clues for functional classification.'),
(83579, 2007, 'plos', 'Emergent dynamics of thymocyte development and lineage determination', 'Efroni, Sol|Harel, David|Cohen, Irun R', 'National Cancer Institute Center for Bioinformatics, National Institutes of Health, Rockville, Maryland, United States of America. sefroni@mail.nih.gov|National Cancer Institute Center for Bioinformatics, National Institutes of Health, Rockville, Maryland, United States of America. sefroni@mail.nih.gov|National Cancer Institute Center for Bioinformatics, National Institutes of Health, Rockville, Maryland, United States of America. sefroni@mail.nih.gov', 'United States|United States|United States', 0, 'Algorithms|Animals|Cell Differentiation|Cell Proliferation|Chemokines|Chemotaxis|Computer Simulation|Gene Expression Regulation, Developmental|Humans|Models, Biological|Receptors, CCR|Receptors, CXCR4|Receptors, Chemokine|Thymus Gland', 'Journal Article', '10.1371/journal.pcbi.0030013', '17257050', 'Experiments have generated a plethora of data about the genes, molecules, and cells involved in thymocyte development. Here, we use a computer-driven simulation that uses data about thymocyte development to generate an integrated dynamic representation-a novel technology we have termed reactive animation (RA). RA reveals emergent properties in complex dynamic biological systems. We apply RA to thymocyte development by reproducing and extending the effects of known gene knockouts: CXCR4 and CCR9. RA simulation revealed a previously unidentified role of thymocyte competition for major histocompatability complex presentation. We now report that such competition is required for normal anatomical compartmentalization, can influence the rate of thymocyte velocities within chemokine gradients, and can account for the disproportion between single-positive CD4 and CD8 lineages developing from double-positive precursors.'),
(83580, 2007, 'plos', 'Detecting key structural features within highly recombined genes', 'Wertz, John E|McGregor, Karen F|Bessen, Debra E', 'Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America. john.wertz@yale.edu|Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America. john.wertz@yale.edu|Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America. john.wertz@yale.edu', 'United States|United States|United States', 7, 'Algorithms|Base Sequence|Chromosome Mapping|DNA Mutational Analysis|Molecular Sequence Data|Penicillin-Binding Proteins|Phylogeny|Recombination, Genetic|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030014', '17257051', 'Many microorganisms exhibit high levels of intragenic recombination following horizontal gene transfer events. Furthermore, many microbial genes are subject to strong diversifying selection as part of the pathogenic process. A multiple sequence alignment is an essential starting point for many of the tools that provide fundamental insights on gene structure and evolution, such as phylogenetics, however, an accurate alignment is not always possible to attain. In this study, a new analytic approach was developed in order to better quantify the genetic organization of highly diversified genes whose alleles do not align. This BLAST-based method, denoted BLAST Miner, employs an iterative process that places short segments of highly similar sequence into discrete datasets that are designated modules. The relative positions of modules along the length of the genes, and their frequency of occurrence, are used to identify sequence duplications, insertions, and rearrangements. Partial alleles of sof from Streptococcus pyogenes, encoding a surface protein under host immune selection, were analyzed for module content. High-frequency Modules 6 and 13 were identified and examined in depth. Nucleotide sequences corresponding to both modules contain numerous duplications and inverted repeats, whereby many codons form palindromic pairs. Combined with evidence for a strong codon usage bias, data suggest that Module 6 and 13 sequences are under selection to preserve their nucleic acid secondary structure. The concentration of overlapping tandem and inverted repeats within a small region of DNA is highly suggestive of a mechanistic role for Module 6 and 13 sequences in promoting aberrant recombination. Analysis of pbp2X alleles from Streptococcus pneumoniae, encoding cell wall enzymes that confer antibiotic resistance, supports the broad applicability of this tool in deciphering the genetic organization of highly recombined genes. BLAST Miner shares with phylogenetics the important predictive quality that leads to the generation of testable hypotheses based on sequence data.'),
(83581, 2007, 'plos', 'Moving education forward', 'Lewitter, Fran', 'Whitehead Institute in Cambridge, Massachusetts, United States of America. lewitter@wi.mit.edu', 'United States', 0, 'Computational Biology|Genomics|Information Dissemination|Periodicals as Topic|Teaching', 'Journal Article', '10.1371/journal.pcbi.0030019', '17257053', '-'),
(83582, 2007, 'plos', 'Robustness can evolve gradually in complex regulatory gene networks with varying topology', 'Ciliberti, Stefano|Martin, Olivier C|Wagner, Andreas', 'Laboratoire de Physique Théoique et Modèles Statistiques, Universite Paris-Sud, Orsay, France.|Laboratoire de Physique Théoique et Modèles Statistiques, Universite Paris-Sud, Orsay, France.|Laboratoire de Physique Théoique et Modèles Statistiques, Universite Paris-Sud, Orsay, France.', 'France|France|France', 257, 'Adaptation, Physiological|Computer Simulation|Evolution, Molecular|Gene Expression Regulation|Models, Genetic|Signal Transduction|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0030015', '17274682', 'The topology of cellular circuits (the who-interacts-with-whom) is key to understand their robustness to both mutations and noise. The reason is that many biochemical parameters driving circuit behavior vary extensively and are thus not fine-tuned. Existing work in this area asks to what extent the function of any one given circuit is robust. But is high robustness truly remarkable, or would it be expected for many circuits of similar topology? And how can high robustness come about through gradual Darwinian evolution that changes circuit topology gradually, one interaction at a time? We here ask these questions for a model of transcriptional regulation networks, in which we explore millions of different network topologies. Robustness to mutations and noise are correlated in these networks. They show a skewed distribution, with a very small number of networks being vastly more robust than the rest. All networks that attain a given gene expression state can be organized into a graph whose nodes are networks that differ in their topology. Remarkably, this graph is connected and can be easily traversed by gradual changes of network topologies. Thus, robustness is an evolvable property. This connectedness and evolvability of robust networks may be a general organizational principle of biological networks. In addition, it exists also for RNA and protein structures, and may thus be a general organizational principle of all biological systems.'),
(83583, 2007, 'plos', 'Automatic extraction of protein point mutations using a graph bigram association', 'Lee, Lawrence C|Horn, Florence|Cohen, Fred E', 'Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.|Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.|Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Artificial Intelligence|Databases, Protein|Information Storage and Retrieval|Mutation|Pattern Recognition, Automated|Proteins|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0030016', '17274683', 'Protein point mutations are an essential component of the evolutionary and experimental analysis of protein structure and function. While many manually curated databases attempt to index point mutations, most experimentally generated point mutations and the biological impacts of the changes are described in the peer-reviewed published literature. We describe an application, Mutation GraB (Graph Bigram), that identifies, extracts, and verifies point mutations from biomedical literature. The principal problem of point mutation extraction is to link the point mutation with its associated protein and organism of origin. Our algorithm uses a graph-based bigram traversal to identify these relevant associations and exploits the Swiss-Prot protein database to verify this information. The graph bigram method is different from other models for point mutation extraction in that it incorporates frequency and positional data of all terms in an article to drive the point mutation-protein association. Our method was tested on 589 articles describing point mutations from the G protein-coupled receptor (GPCR), tyrosine kinase, and ion channel protein families. We evaluated our graph bigram metric against a word-proximity metric for term association on datasets of full-text literature in these three different protein families. Our testing shows that the graph bigram metric achieves a higher F-measure for the GPCRs (0.79 versus 0.76), protein tyrosine kinases (0.72 versus 0.69), and ion channel transporters (0.76 versus 0.74). Importantly, in situations where more than one protein can be assigned to a point mutation and disambiguation is required, the graph bigram metric achieves a precision of 0.84 compared with the word distance metric precision of 0.73. We believe the graph bigram search metric to be a significant improvement over previous search metrics for point mutation extraction and to be applicable to text-mining application requiring the association of words.'),
(83584, 2007, 'plos', 'Efficiency and cost of economical brain functional networks', 'Achard, Sophie|Bullmore, Ed', 'Brain Mapping Unit, Department of Psychiatry, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.|Brain Mapping Unit, Department of Psychiatry, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Adult|Aged|Aging|Brain|Brain Mapping|Computer Simulation|Dopamine Antagonists|Female|Humans|Magnetic Resonance Imaging|Male|Models, Neurological|Nerve Net|Neurons', 'Journal Article', '10.1371/journal.pcbi.0030017', '17274684', 'Brain anatomical networks are sparse, complex, and have economical small-world properties. We investigated the efficiency and cost of human brain functional networks measured using functional magnetic resonance imaging (fMRI) in a factorial design: two groups of healthy old (N = 11, mean age = 66.5 years) and healthy young (N = 15, mean age = 24.7 years) volunteers were each scanned twice in a no-task or resting state following placebo or a single dose of a dopamine receptor antagonist (sulpiride 400 mg). Functional connectivity between 90 cortical and subcortical regions was estimated by wavelet correlation analysis, in the frequency interval 0.06-0.11 Hz, and thresholded to construct undirected graphs. These brain functional networks were small-world and economical in the sense of providing high global and local efficiency of parallel information processing for low connection cost. Efficiency was reduced disproportionately to cost in older people, and the detrimental effects of age on efficiency were localised to frontal and temporal cortical and subcortical regions. Dopamine antagonism also impaired global and local efficiency of the network, but this effect was differentially localised and did not interact with the effect of age. Brain functional networks have economical small-world properties-supporting efficient parallel information transfer at relatively low cost-which are differently impaired by normal aging and pharmacological blockade of dopamine transmission.'),
(83585, 2007, 'plos', 'Mechanochemical coupling in the myosin motor domain I Insights from equilibrium active-site simulations', 'Yu, Haibo|Ma, Liang|Yang, Yang|Cui, Qiang', 'Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.', 'United States|United States|United States|United States', 55, 'Adenosine Triphosphate|Binding Sites|Energy Transfer|Mechanotransduction, Cellular|Models, Biological|Models, Chemical|Models, Molecular|Molecular Motor Proteins|Myosins|Protein Binding', 'Journal Article', '10.1371/journal.pcbi.0030021', '17291159', 'Although the major structural transitions in molecular motors are often argued to couple to the binding of Adenosine triphosphate (ATP), the recovery stroke in the conventional myosin has been shown to be dependent on the hydrolysis of ATP. To obtain a clearer mechanistic picture for such mechanochemical coupling in myosin, equilibrium active-site simulations with explicit solvent have been carried out to probe the behavior of the motor domain as functions of the nucleotide chemical state and conformation of the converter/relay helix. In conjunction with previous studies of ATP hydrolysis with different active-site conformations and normal mode analysis of structural flexibility, the results help establish an energetics-based framework for understanding the mechanochemical coupling. It is proposed that the activation of hydrolysis does not require the rotation of the lever arm per se, but the two processes are tightly coordinated because both strongly couple to the open/close transition of the active site. The underlying picture involves shifts in the dominant population of different structural motifs as a consequence of changes elsewhere in the motor domain. The contribution of this work and the accompanying paper [] is to propose the actual mechanism behind these population shifts and residues that play important roles in the process. It is suggested that structural flexibilities at both the small and large scales inherent to the motor domain make it possible to implement tight couplings between different structural motifs while maintaining small free-energy drops for processes that occur in the detached states, which is likely a feature shared among many molecular motors. The significantly different flexibility of the active site in different X-ray structures with variable level arm orientations supports the notation that external force sensed by the lever arm may transmit into the active site and influence the chemical steps (nucleotide hydrolysis and/or binding).'),
(83586, 2007, 'plos', 'Deprotonation by dehydration: the origin of ammonium sensing in the AmtB channel', 'Bostick, David L|Brooks, Charles L', 'Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.', 'United States|United States', 37, 'Cation Transport Proteins|Computer Simulation|Escherichia coli Proteins|Ion Channel Gating|Lipid Bilayers|Models, Chemical|Models, Molecular|Phosphatidylcholines|Protons|Quaternary Ammonium Compounds|Water', 'Journal Article', '10.1371/journal.pcbi.0030022', '17291160', 'The AmtB channel passively allows the transport of NH4(+) across the membranes of bacteria via a gas NH3 intermediate and is related by homology (sequentially, structurally, and functionally) to many forms of Rh protein (both erythroid and nonerythroid) found in animals and humans. New structural information on this channel has inspired computational studies aimed at clarifying various aspects of NH4(+) recruitment and binding in the periplasm, as well as its deprotonation. However, precise mechanisms for these events are still unknown, and, so far, explanations for subsequent NH3 translocation and reprotonation at the cytoplasmic end of the channel have not been rigorously addressed. We employ molecular dynamics simulations and free energy methods on a full AmtB trimer system in membrane and bathed in electrolyte. Combining the potential of mean force for NH4(+)/NH3 translocation with data from thermodynamic integration calculations allows us to find the apparent pKa of NH4(+) as a function of the transport axis. Our calculations reveal the specific sites at which its deprotonation (at the periplasmic end) and reprotonation (at the cytoplasmic end) occurs. Contrary to most hypotheses, which ascribe a proton-accepting role to various periplasmic or luminal residues of the channel, our results suggest that the most plausible proton donor/acceptor at either of these sites is water. Free-energetic analysis not only verifies crystallographically determined binding sites for NH4(+) and NH3 along the transport axis, but also reveals a previously undetermined binding site for NH4(+) at the cytoplasmic end of the channel. Analysis of dynamics and the free energies of all possible loading states for NH3 inside the channel also reveal that hydrophobic pressure and the free-energetic profile provided by the pore lumen drives this species toward the cytoplasm for protonation just before reaching the newly discovered site.'),
(83587, 2007, 'plos', 'Mechanochemical coupling in the myosin motor domain II Analysis of critical residues', 'Yu, Haibo|Ma, Liang|Yang, Yang|Cui, Qiang', 'Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.', 'United States|United States|United States|United States', 0, 'Amino Acids|Computer Simulation|Mechanotransduction, Cellular|Models, Biological|Models, Chemical|Molecular Motor Proteins|Myosins|Protein Structure, Tertiary|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030023', '17305418', 'An important challenge in the analysis of mechanochemical coupling in molecular motors is to identify residues that dictate the tight coupling between the chemical site and distant structural rearrangements. In this work, a systematic attempt is made to tackle this issue for the conventional myosin. By judiciously combining a range of computational techniques with different approximations and strength, which include targeted molecular dynamics, normal mode analysis, and statistical coupling analysis, we are able to identify a set of important residues and propose their relevant function during the recovery stroke of myosin. These analyses also allowed us to make connections with previous experimental and computational studies in a critical manner. The behavior of the widely used reporter residue, Trp501, in the simulations confirms the concern that its fluorescence does not simply reflect the relay loop conformation or active-site open/close but depends subtly on its microenvironment. The findings in the targeted molecular dynamics and a previous minimum energy path analysis of the recovery stroke have been compared and analyzed, which emphasized the difference and complementarity of the two approaches. In conjunction with our previous studies, the current set of investigations suggest that the modulation of structural flexibility at both the local (e.g., active-site) and domain scales with strategically placed hotspot residues and phosphate chemistry is likely the general feature for mechanochemical coupling in many molecular motors. The fundamental strategies of examining both collective and local changes and combining physically motivated methods and informatics-driven techniques are expected to be valuable to the study of other molecular motors and allosteric systems in general.'),
(83588, 2007, 'plos', 'Specificity and evolvability in eukaryotic protein interaction networks', 'Beltrao, Pedro|Serrano, Luis', 'European Molecular Biology Laboratory, Structures and Computational Biology Program, Heidelberg, Germany. beltrao@embl.de|European Molecular Biology Laboratory, Structures and Computational Biology Program, Heidelberg, Germany. beltrao@embl.de', 'Germany|Germany', 0, 'Animals|Eukaryotic Cells|Evolution, Molecular|Gene Expression|Humans|Models, Biological|Protein Binding|Protein Interaction Mapping|Proteome|Sensitivity and Specificity|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030025', '17305419', 'Progress in uncovering the protein interaction networks of several species has led to questions of what underlying principles might govern their organization. Few studies have tried to determine the impact of protein interaction network evolution on the observed physiological differences between species. Using comparative genomics and structural information, we show here that eukaryotic species have rewired their interactomes at a fast rate of approximately 10(-5) interactions changed per protein pair, per million years of divergence. For Homo sapiens this corresponds to 10(3) interactions changed per million years. Additionally we find that the specificity of binding strongly determines the interaction turnover and that different biological processes show significantly different link dynamics. In particular, human proteins involved in immune response, transport, and establishment of localization show signs of positive selection for change of interactions. Our analysis suggests that a small degree of molecular divergence can give rise to important changes at the network level. We propose that the power law distribution observed in protein interaction networks could be partly explained by the cells requirement for different degrees of protein binding specificity.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83589, 2007, 'plos', 'Functional impact of missense variants in BRCA1 predicted by supervised learning', 'Karchin, Rachel|Monteiro, Alvaro N A|Tavtigian, Sean V|Carvalho, Marcelo A|Sali, Andrej', 'Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. karchin@karchinlab.org|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. karchin@karchinlab.org|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. karchin@karchinlab.org|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. karchin@karchinlab.org|Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America. karchin@karchinlab.org', 'United States|United States|United States|United States|United States', 44, 'Algorithms|Amino Acid Sequence|Artificial Intelligence|BRCA1 Protein|Genetic Variation|Molecular Sequence Data|Mutation, Missense|Pattern Recognition, Automated|Sequence Alignment|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030026', '17305420', 'Many individuals tested for inherited cancer susceptibility at the BRCA1 gene locus are discovered to have variants of unknown clinical significance (UCVs). Most UCVs cause a single amino acid residue (missense) change in the BRCA1 protein. They can be biochemically assayed, but such evaluations are time-consuming and labor-intensive. Computational methods that classify and suggest explanations for UCV impact on protein function can complement functional tests. Here we describe a supervised learning approach to classification of BRCA1 UCVs. Using a novel combination of 16 predictive features, the algorithms were applied to retrospectively classify the impact of 36 BRCA1 C-terminal (BRCT) domain UCVs biochemically assayed to measure transactivation function and to blindly classify 54 documented UCVs. Majority vote of three supervised learning algorithms is in agreement with the assay for more than 94% of the UCVs. Two UCVs found deleterious by both the assay and the classifiers reveal a previously uncharacterized putative binding site. Clinicians may soon be able to use computational classifiers such as those described here to better inform patients. These classifiers can be adapted to other cancer susceptibility genes and systematically applied to prioritize the growing number of potential causative loci and variants found by large-scale disease association studies.'),
(83590, 2007, 'plos', 'Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics', 'Lemey, Philippe|Kosakovsky Pond, Sergei L|Drummond, Alexei J|Pybus, Oliver G|Shapiro, Beth|Barroso, Helena|Taveira, Nuno|Rambaut, Andrew', 'Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk|Department of Zoology, University of Oxford, Oxford, United Kingdom. philippe.lemey@zoo.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Amino Acid Sequence|Amino Acid Substitution|Codon|Computer Simulation|DNA Mutational Analysis|Disease Progression|Evolution, Molecular|Genetic Predisposition to Disease|Genetic Variation|HIV Infections|Humans|Models, Genetic|Molecular Sequence Data|Viral Envelope Proteins|Virus Activation|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.0030029', '17305421', 'Upon HIV transmission, some patients develop AIDS in only a few months, while others remain disease free for 20 or more years. This variation in the rate of disease progression is poorly understood and has been attributed to host genetics, host immune responses, co-infection, viral genetics, and adaptation. Here, we develop a new relaxed-clock phylogenetic method to estimate absolute rates of synonymous and nonsynonymous substitution through time. We identify an unexpected association between the synonymous substitution rate of HIV and disease progression parameters. Since immune activation is the major determinant of HIV disease progression, we propose that this process can also determine viral generation times, by creating favourable conditions for HIV replication. These conclusions may apply more generally to HIV evolution, since we also observed an overall low synonymous substitution rate for HIV-2, which is known to be less pathogenic than HIV-1 and capable of tempering the detrimental effects of immune activation. Humoral immune responses, on the other hand, are the major determinant of nonsynonymous rate changes through time in the envelope gene, and our relaxed-clock estimates support a decrease in selective pressure as a consequence of immune system collapse.'),
(83591, 2007, 'plos', 'Unsupervised learning of visual features through spike timing dependent plasticity', 'Masquelier, Timothée|Thorpe, Simon J', 'Centre de Recherche Cerveau et Cognition, Centre National de la Recherche Scientifique, Université Paul Sabatier, Faculté de Médecine de Rangueil, Toulouse, France. timothee.masquelier@alum.mit.edu|Centre de Recherche Cerveau et Cognition, Centre National de la Recherche Scientifique, Université Paul Sabatier, Faculté de Médecine de Rangueil, Toulouse, France. timothee.masquelier@alum.mit.edu', 'France|France', 267, 'Action Potentials|Artificial Intelligence|Computer Simulation|Feedback|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons, Afferent|Pattern Recognition, Visual|Synaptic Transmission|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.0030031', '17305422', 'Spike timing dependent plasticity (STDP) is a learning rule that modifies synaptic strength as a function of the relative timing of pre- and postsynaptic spikes. When a neuron is repeatedly presented with similar inputs, STDP is known to have the effect of concentrating high synaptic weights on afferents that systematically fire early, while postsynaptic spike latencies decrease. Here we use this learning rule in an asynchronous feedforward spiking neural network that mimics the ventral visual pathway and shows that when the network is presented with natural images, selectivity to intermediate-complexity visual features emerges. Those features, which correspond to prototypical patterns that are both salient and consistently present in the images, are highly informative and enable robust object recognition, as demonstrated on various classification tasks. Taken together, these results show that temporal codes may be a key to understanding the phenomenal processing speed achieved by the visual system and that STDP can lead to fast and selective responses.'),
(83592, 2007, 'plos', 'Repressor dimerization in the zebrafish somitogenesis clock', 'Cinquin, Olivier', 'Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, London, United Kingdom. cinquin@wisc.edu', 'United Kingdom', 0, 'Animals|Biological Clocks|Body Patterning|Computer Simulation|Dimerization|Gene Expression|Models, Biological|Repressor Proteins|Signal Transduction|Zebrafish|Zebrafish Proteins', 'Journal Article', '10.1371/journal.pcbi.0030032', '17305423', 'The oscillations of the somitogenesis clock are linked to the fundamental process of vertebrate embryo segmentation, yet little is known about their generation. In zebrafish, it has been proposed that Her proteins repress the transcription of their own mRNA. However, in its simplest form, this model is incompatible with the fact that morpholino knockdown of Her proteins can impair expression of their mRNA. Simple self-repression models also do not account for the spatiotemporal pattern of gene expression, with waves of gene expression shrinking as they propagate. Here we study computationally the networks generated by the wealth of dimerization possibilities amongst transcriptional repressors in the zebrafish somitogenesis clock. These networks can reproduce knockdown phenotypes, and strongly suggest the existence of a Her1-Her7 heterodimer, so far untested experimentally. The networks are the first reported to reproduce the spatiotemporal pattern of the zebrafish somitogenesis clock, they shed new light on the role of Her13.2, the only known link between the somitogenesis clock and positional information in the paraxial mesoderm. The networks can also account for perturbations of the clock by manipulation of FGF signaling. Achieving an understanding of the interplay between clock oscillations and positional information is a crucial first step in the investigation of the segmentation mechanism.'),
(83593, 2007, 'plos', 'From bytes to bedside: data integration and computational biology for translational cancer research', 'Mathew, Jomol P|Taylor, Barry S|Bader, Gary D|Pyarajan, Saiju|Antoniotti, Marco|Chinnaiyan, Arul M|Sander, Chris|Burakoff, Steven J|Mishra, Bud', 'Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. Jomol_Mathew@dfci.harvard.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 44, 'Biomedical Research|Computational Biology|Databases, Factual|Medical Oncology|Neoplasm Proteins|Neoplasms|Research|Research Design|Systems Integration', 'Journal Article', '10.1371/journal.pcbi.0030012', '17319736', '-'),
(83594, 2007, 'plos', 'Improving the Caenorhabditis elegans genome annotation using machine learning', 'Rätsch, Gunnar|Sonnenburg, Sören|Srinivasan, Jagan|Witte, Hanh|Müller, Klaus-R|Sommer, Ralf-J|Schölkopf, Bernhard', 'Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de|Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de|Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de|Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de|Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de|Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de|Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany. Gunnar.Raetsch@tuebingen.mpg.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 51, 'Algorithms|Animals|Artificial Intelligence|Base Sequence|Caenorhabditis elegans|Chromosome Mapping|Databases, Genetic|Documentation|Exons|Introns|Molecular Sequence Data|Pattern Recognition, Automated|Sequence Alignment|Sequence Analysis, DNA', 'Comparative Study', '10.1371/journal.pcbi.0030020', '17319737', 'For modern biology, precise genome annotations are of prime importance, as they allow the accurate definition of genic regions. We employ state-of-the-art machine learning methods to assay and improve the accuracy of the genome annotation of the nematode Caenorhabditis elegans. The proposed machine learning system is trained to recognize exons and introns on the unspliced mRNA, utilizing recent advances in support vector machines and label sequence learning. In 87% (coding and untranslated regions) and 95% (coding regions only) of all genes tested in several out-of-sample evaluations, our method correctly identified all exons and introns. Notably, only 37% and 50%, respectively, of the presently unconfirmed genes in the C. elegans genome annotation agree with our predictions, thus we hypothesize that a sizable fraction of those genes are not correctly annotated. A retrospective evaluation of the Wormbase WS120 annotation [] of C. elegans reveals that splice form predictions on unconfirmed genes in WS120 are inaccurate in about 18% of the considered cases, while our predictions deviate from the truth only in 10%-13%. We experimentally analyzed 20 controversial genes on which our system and the annotation disagree, confirming the superiority of our predictions. While our method correctly predicted 75% of those cases, the standard annotation was never completely correct. The accuracy of our system is further corroborated by a comparison with two other recently proposed systems that can be used for splice form prediction: SNAP and ExonHunter. We conclude that the genome annotation of C. elegans and other organisms can be greatly enhanced using modern machine learning technology.'),
(83595, 2007, 'plos', 'Assessing the nature of lipid raft membranes', 'Niemelä, Perttu S|Ollila, Samuli|Hyvönen, Marja T|Karttunen, Mikko|Vattulainen, Ilpo', 'Laboratory of Physics, Helsinki University of Technology, Helsinki, Finland. psn@fyslab.hut.fi|Laboratory of Physics, Helsinki University of Technology, Helsinki, Finland. psn@fyslab.hut.fi|Laboratory of Physics, Helsinki University of Technology, Helsinki, Finland. psn@fyslab.hut.fi|Laboratory of Physics, Helsinki University of Technology, Helsinki, Finland. psn@fyslab.hut.fi|Laboratory of Physics, Helsinki University of Technology, Helsinki, Finland. psn@fyslab.hut.fi', 'Finland|Finland|Finland|Finland|Finland', 217, 'Computer Simulation|Lipid Bilayers|Membrane Fluidity|Membrane Microdomains|Models, Chemical|Models, Molecular|Molecular Conformation|Phase Transition|Phospholipids', 'Journal Article', '10.1371/journal.pcbi.0030034', '17319738', 'The paradigm of biological membranes has recently gone through a major update. Instead of being fluid and homogeneous, recent studies suggest that membranes are characterized by transient domains with varying fluidity. In particular, a number of experimental studies have revealed the existence of highly ordered lateral domains rich in sphingomyelin and cholesterol (CHOL). These domains, called functional lipid rafts, have been suggested to take part in a variety of dynamic cellular processes such as membrane trafficking, signal transduction, and regulation of the activity of membrane proteins. However, despite the proposed importance of these domains, their properties, and even the precise nature of the lipid phases, have remained open issues mainly because the associated short time and length scales have posed a major challenge to experiments. In this work, we employ extensive atom-scale simulations to elucidate the properties of ternary raft mixtures with CHOL, palmitoylsphingomyelin (PSM), and palmitoyloleoylphosphatidylcholine. We simulate two bilayers of 1,024 lipids for 100 ns in the liquid-ordered phase and one system of the same size in the liquid-disordered phase. The studies provide evidence that the presence of PSM and CHOL in raft-like membranes leads to strongly packed and rigid bilayers. We also find that the simulated raft bilayers are characterized by nanoscale lateral heterogeneity, though the slow lateral diffusion renders the interpretation of the observed lateral heterogeneity more difficult. The findings reveal aspects of the role of favored (specific) lipid-lipid interactions within rafts and clarify the prominent role of CHOL in altering the properties of the membrane locally in its neighborhood. Also, we show that the presence of PSM and CHOL in rafts leads to intriguing lateral pressure profiles that are distinctly different from corresponding profiles in nonraft-like membranes. The results propose that the functioning of certain classes of membrane proteins is regulated by changes in the lateral pressure profile, which can be altered by a change in lipid content.'),
(83596, 2007, 'plos', 'Persistent activity in neural networks with dynamic synapses', 'Barak, Omri|Tsodyks, Misha', 'Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.|Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel', 0, 'Action Potentials|Animals|Biological Clocks|Computer Simulation|Feedback|Humans|Memory|Models, Neurological|Nerve Net|Neurons|Synapses|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030035', '17319739', 'Persistent activity states (attractors), observed in several neocortical areas after the removal of a sensory stimulus, are believed to be the neuronal basis of working memory. One of the possible mechanisms that can underlie persistent activity is recurrent excitation mediated by intracortical synaptic connections. A recent experimental study revealed that connections between pyramidal cells in prefrontal cortex exhibit various degrees of synaptic depression and facilitation. Here we analyze the effect of synaptic dynamics on the emergence and persistence of attractor states in interconnected neural networks. We show that different combinations of synaptic depression and facilitation result in qualitatively different network dynamics with respect to the emergence of the attractor states. This analysis raises the possibility that the framework of attractor neural networks can be extended to represent time-dependent stimuli.'),
(83597, 2007, 'plos', 'Dose response relationship in anti-stress gene regulatory networks', 'Zhang, Qiang|Andersen, Melvin E', 'Division of Computational Biology, CIIT Centers for Health Research, Research Triangle Park, North Carolina, United States of America. qzhang@ciit.org|Division of Computational Biology, CIIT Centers for Health Research, Research Triangle Park, North Carolina, United States of America. qzhang@ciit.org', 'United States|United States', 70, 'Antioxidants|Computer Simulation|Dose-Response Relationship, Drug|Feedback|Gene Expression Regulation|Heat-Shock Response|Models, Biological|Oxidative Stress|Oxygen|Proteome|Reactive Oxygen Species|Signal Transduction|Transcription Factors|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.0030024', '17335342', 'To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.'),
(83598, 2007, 'plos', 'The stem cell population of the human colon crypt: analysis via methylation patterns', 'Nicolas, Pierre|Kim, Kyoung-Mee|Shibata, Darryl|Tavaré, Simon', 'Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr|Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr|Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr|Unité Mathématique Informatique et Génome UR1077, Institut National de la Recherche Agronomique, Jouy-en-Josas, France. pierre.nicolas@jouy.inra.fr', 'France|France|France|France', 62, 'Base Sequence|Cell Count|Colon|CpG Islands|DNA Methylation|DNA Mutational Analysis|Evolution, Molecular|Humans|Molecular Sequence Data|Polymorphism, Single Nucleotide|Sequence Analysis, DNA|Stem Cells', 'Journal Article', '10.1371/journal.pcbi.0030028', '17335343', 'The analysis of methylation patterns is a promising approach to investigate the genealogy of cell populations in an organism. In a stem cell-niche scenario, sampled methylation patterns are the stochastic outcome of a complex interplay between niche structural features such as the number of stem cells within a niche and the niche succession time, the methylation/demethylation process, and the randomness due to sampling. As a consequence, methylation pattern studies can reveal niche characteristics but also require appropriate statistical methods. The analysis of methylation patterns sampled from colon crypts is a prototype of such a study. Previous analyses were based on forward simulation of the cell content of the whole crypt and subsequent comparisons between simulated and experimental data using a few statistics as a proxy to summarize the data. In this paper we develop a more powerful method to analyze these data based on coalescent modelling and Bayesian inference. Results support a scenario where the colon crypt is maintained by a high number of stem cells, the posterior indicates a number greater than eight and the posterior mode is between 15 and 20. The results also provide further evidence for synergistic effects in the methylation/demethylation process that could for the first time be quantitatively assessed through their long-term consequences such as the coexistence of hypermethylated and hypomethylated patterns in the same colon crypt.'),
(83599, 2007, 'plos', 'PPARalpha siRNA-treated expression profiles uncover the causal sufficiency network for compound-induced liver hypertrophy', 'Dai, Xudong|De Souza, Angus T|Dai, Hongyue|Lewis, David L|Lee, Chang-kyu|Spencer, Andy G|Herweijer, Hans|Hagstrom, Jim E|Linsley, Peter S|Bassett, Douglas E|Ulrich, Roger G|He, Yudong D', 'Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com|Informatics, Rosetta Inpharmatics, Seattle, Washington, United States of America. xudong_dai@merck.com', 'United States|United States|United States|United States|United States|United States|United States|Un', 8, 'Animals|Computer Simulation|Gene Expression Profiling|Gene Silencing|Hypertrophy|Liver|Mice|Models, Biological|PPAR alpha|Proteome|RNA, Small Interfering|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030030', '17335344', 'Uncovering pathways underlying drug-induced toxicity is a fundamental objective in the field of toxicogenomics. Developing mechanism-based toxicity biomarkers requires the identification of such novel pathways and the order of their sufficiency in causing a phenotypic response. Genome-wide RNA interference (RNAi) phenotypic screening has emerged as an effective tool in unveiling the genes essential for specific cellular functions and biological activities. However, eliciting the relative contribution of and sufficiency relationships among the genes identified remains challenging. In the rodent, the most widely used animal model in preclinical studies, it is unrealistic to exhaustively examine all potential interactions by RNAi screening. Application of existing computational approaches to infer regulatory networks with biological outcomes in the rodent is limited by the requirements for a large number of targeted permutations. Therefore, we developed a two-step relay method that requires only one targeted perturbation for genome-wide de novo pathway discovery. Using expression profiles in response to small interfering RNAs (siRNAs) against the gene for peroxisome proliferator-activated receptor alpha (Ppara), our method unveiled the potential causal sufficiency order network for liver hypertrophy in the rodent. The validity of the inferred 16 causal transcripts or 15 known genes for PPARalpha-induced liver hypertrophy is supported by their ability to predict non-PPARalpha-induced liver hypertrophy with 84% sensitivity and 76% specificity. Simulation shows that the probability of achieving such predictive accuracy without the inferred causal relationship is exceedingly small (p < 0.005). Five of the most sufficient causal genes have been previously disrupted in mouse models, the resulting phenotypic changes in the liver support the inferred causal roles in liver hypertrophy. Our results demonstrate the feasibility of defining pathways mediating drug-induced toxicity from siRNA-treated expression profiles. When combined with phenotypic evaluation, our approach should help to unleash the full potential of siRNAs in systematically unveiling the molecular mechanism of biological events.'),
(83600, 2007, 'plos', 'The (in)dependence of alternative splicing and gene duplication', 'Talavera, David|Vogel, Christine|Orozco, Modesto|Teichmann, Sarah A|de la Cruz, Xavier', 'Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.|Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.|Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.|Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.|Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.', 'Spain|Spain|Spain|Spain|Spain', 52, 'Alternative Splicing|Base Sequence|Computer Simulation|DNA Mutational Analysis|Evolution, Molecular|Gene Duplication|Genetic Variation|Models, Genetic|Molecular Sequence Data|Proteome|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030033', '17335345', 'Alternative splicing (AS) and gene duplication (GD) both are processes that diversify the protein repertoire. Recent examples have shown that sequence changes introduced by AS may be comparable to those introduced by GD. In addition, the two processes are inversely correlated at the genomic scale: large gene families are depleted in splice variants and vice versa. All together, these data strongly suggest that both phenomena result in interchangeability between their effects. Here, we tested the extent to which this applies with respect to various protein characteristics. The amounts of AS and GD per gene are anticorrelated even when accounting for different gene functions or degrees of sequence divergence. In contrast, the two processes appear to be independent in their influence on variation in mRNA expression. Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions. We find that, in general, alternative splicing affects protein sequence and structure in a more drastic way than gene duplication and subsequent divergence. Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function. We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment.'),
(83601, 2007, 'plos', 'Spatial acuity and prey detection in weakly electric fish', 'Babineau, David|Lewis, John E|Longtin, André', 'Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.|Department of Physics, University of Ottawa, Ottawa, Ontario, Canada.', 'Canada|Canada|Canada', 50, 'Animals|Computer Simulation|Cues|Electric Fish|Electric Organ|Field Dependence-Independence|Models, Neurological|Motion Perception|Pattern Recognition, Physiological|Predatory Behavior|Sensory Receptor Cells|Space Perception|Swimming', 'Journal Article', '10.1371/journal.pcbi.0030038', '17335346', 'It is well-known that weakly electric fish can exhibit extreme temporal acuity at the behavioral level, discriminating time intervals in the submicrosecond range. However, relatively little is known about the spatial acuity of the electrosense. Here we use a recently developed model of the electric field generated by Apteronotus leptorhynchus to study spatial acuity and small signal extraction. We show that the quality of sensory information available on the lateral body surface is highest for objects close to the fishs midbody, suggesting that spatial acuity should be highest at this location. Overall, however, this information is relatively blurry and the electrosense exhibits relatively poor acuity. Despite this apparent limitation, weakly electric fish are able to extract the minute signals generated by small prey, even in the presence of large background signals. In fact, we show that the fishs poor spatial acuity may actually enhance prey detection under some conditions. This occurs because the electric image produced by a spatially dense background is relatively blurred or spatially uniform. Hence, the small spatially localized prey signal pops out when fish motion is simulated. This shows explicitly how the back-and-forth swimming, characteristic of these fish, can be used to generate motion cues that, as in other animals, assist in the extraction of sensory information when signal-to-noise ratios are low. Our study also reveals the importance of the structure of complex electrosensory backgrounds. Whereas large-object spacing is favorable for discriminating the individual elements of a scene, small spacing can increase the fishs ability to resolve a single target object against this background.'),
(83602, 2007, 'plos', 'Characterization and identification of microRNA core promoters in four model species', 'Zhou, Xuefeng|Ruan, Jianhua|Wang, Guandong|Zhang, Weixiong', 'Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, Missouri, United States of America.|Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, Missouri, United States of America.|Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, Missouri, United States of America.|Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, Missouri, United States of America.', 'United States|United States|United States|United States', 236, 'Animals|Arabidopsis|Base Sequence|Caenorhabditis elegans|Conserved Sequence|Humans|MicroRNAs|Molecular Sequence Data|Oryza|Promoter Regions, Genetic|Sequence Alignment|Sequence Analysis, RNA|Sequence Homology, Nucleic Acid|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.0030037', '17352530', 'MicroRNAs are short, noncoding RNAs that play important roles in post-transcriptional gene regulation. Although many functions of microRNAs in plants and animals have been revealed in recent years, the transcriptional mechanism of microRNA genes is not well-understood. To elucidate the transcriptional regulation of microRNA genes, we study and characterize, in a genome scale, the promoters of intergenic microRNA genes in Caenorhabditis elegans, Homo sapiens, Arabidopsis thaliana, and Oryza sativa. We show that most known microRNA genes in these four species have the same type of promoters as protein-coding genes have. To further characterize the promoters of microRNA genes, we developed a novel promoter prediction method, called common query voting (CoVote), which is more effective than available promoter prediction methods. Using this new method, we identify putative core promoters of most known microRNA genes in the four model species. Moreover, we characterize the promoters of microRNA genes in these four species. We discover many significant, characteristic sequence motifs in these core promoters, several of which match or resemble the known cis-acting elements for transcription initiation. Among these motifs, some are conserved across different species while some are specific to microRNA genes of individual species.'),
(83603, 2007, 'plos', 'A look inside HIV resistance through retroviral protease interaction maps', 'Kontijevskis, Aleksejs|Prusis, Peteris|Petrovska, Ramona|Yahorava, Sviatlana|Mutulis, Felikss|Mutule, Ilze|Komorowski, Jan|Wikberg, Jarl E S', 'Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 22, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Drug Resistance, Viral|HIV-1|Models, Biological|Molecular Sequence Data|Peptide Hydrolases|Protein Binding|Protein Interaction Mapping|Retroviridae|Retroviridae Proteins|Sequence Analysis, Protein|Signal Transduction|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030048', '17352531', 'Retroviruses affect a large number of species, from fish and birds to mammals and humans, with global socioeconomic negative impacts. Here the authors report and experimentally validate a novel approach for the analysis of the molecular networks that are involved in the recognition of substrates by retroviral proteases. Using multivariate analysis of the sequence-based physiochemical descriptions of 61 retroviral proteases comprising wild-type proteases, natural mutants, and drug-resistant forms of proteases from nine different viral species in relation to their ability to cleave 299 substrates, the authors mapped the physicochemical properties and cross-dependencies of the amino acids of the proteases and their substrates, which revealed a complex molecular interaction network of substrate recognition and cleavage. The approach allowed a detailed analysis of the molecular-chemical mechanisms involved in substrate cleavage by retroviral proteases.'),
(83604, 2007, 'plos', 'A mathematical model for neutrophil gradient sensing and polarization', 'Onsum, Matthew|Rao, Christopher V', 'AstraZeneca R&D Boston, Waltham, Massachusetts, United States of America.|AstraZeneca R&D Boston, Waltham, Massachusetts, United States of America.', 'United States|United States', 61, 'Cell Polarity|Chemotactic Factors|Chemotaxis|Computer Simulation|Models, Biological|Neutrophils|Phosphatidylinositol 3-Kinases|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.0030036', '17367201', 'Directed cell migration in response to chemical cues, also known as chemotaxis, is an important physiological process involved in wound healing, foraging, and the immune response. Cell migration requires the simultaneous formation of actin polymers at the leading edge and actomyosin complexes at the sides and back of the cell. An unresolved question in eukaryotic chemotaxis is how the same chemoattractant signal determines both the cells front and back. Recent experimental studies have begun to reveal the biochemical mechanisms necessary for this polarized cellular response. We propose a mathematical model of neutrophil gradient sensing and polarization based on experimentally characterized biochemical mechanisms. The model demonstrates that the known dynamics for Rho GTPase and phosphatidylinositol-3-kinase (PI3K) activation are sufficient for both gradient sensing and polarization. In particular, the model demonstrates that these mechanisms can correctly localize the front and rear pathways in response to both uniform concentrations and gradients of chemical attractants, including in actin-inhibited cells. Furthermore, the model predictions are robust to the values of many parameters. A key result of the model is the proposed coincidence circuit involving PI3K and Ras that obviates the need for the global inhibitors proposed, though never experimentally verified, in many previous mathematical models of eukaryotic chemotaxis. Finally, experiments are proposed to (in)validate this model and further our understanding of neutrophil chemotaxis.'),
(83605, 2007, 'plos', 'UV-induced mutagenesis in Escherichia coli SOS response: a quantitative model', 'Krishna, Sandeep|Maslov, Sergei|Sneppen, Kim', 'Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.|Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.|Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.', 'Denmark|Denmark|Denmark', 34, 'Computer Simulation|DNA Damage|DNA, Bacterial|DNA-Directed DNA Polymerase|Dose-Response Relationship, Radiation|Escherichia coli|Models, Biological|Mutagenesis|Radiation Dosage|SOS Response (Genetics)|Ultraviolet Rays', 'Journal Article', '10.1371/journal.pcbi.0030041', '17367202', 'Escherichia coli bacteria respond to DNA damage by a highly orchestrated series of events known as the SOS response, regulated by transcription factors, protein-protein binding, and active protein degradation. We present a dynamical model of the UV-induced SOS response, incorporating mutagenesis by the error-prone polymerase, Pol V. In our model, mutagenesis depends on a combination of two key processes: damage counting by the replication forks and a long-term memory associated with the accumulation of UmuD. Together, these provide a tight regulation of mutagenesis, resulting, we show, in a digital turn-on and turn-off of Pol V. Our model provides a compact view of the topology and design of the SOS network, pinpointing the specific functional role of each of the regulatory processes. In particular, we suggest that the recently observed second peak in the activity of promoters in the SOS regulon (Friedman et al., 2005, PLoS Biology 3(7): e238) is the result of positive feedback from Pol V to RecA filaments.'),
(83606, 2007, 'plos', 'Modeling networks of coupled enzymatic reactions using the total quasi-steady state approximation', 'Ciliberto, Andrea|Capuani, Fabrizio|Tyson, John J', 'The FIRC Institute for Molecular Oncology, Milan, Italy. andrea.ciliberto@ifom-ieo-campus.it|The FIRC Institute for Molecular Oncology, Milan, Italy. andrea.ciliberto@ifom-ieo-campus.it|The FIRC Institute for Molecular Oncology, Milan, Italy. andrea.ciliberto@ifom-ieo-campus.it', 'Italy|Italy|Italy', 122, 'Algorithms|Computer Simulation|Homeostasis|Kinetics|Models, Biological|Multienzyme Complexes|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030045', '17367203', 'In metabolic networks, metabolites are usually present in great excess over the enzymes that catalyze their interconversion, and describing the rates of these reactions by using the Michaelis-Menten rate law is perfectly valid. This rate law assumes that the concentration of enzyme-substrate complex (C) is much less than the free substrate concentration (S0). However, in protein interaction networks, the enzymes and substrates are all proteins in comparable concentrations, and neglecting C with respect to S0 is not valid. Borghans, DeBoer, and Segel developed an alternative description of enzyme kinetics that is valid when C is comparable to S0. We extend this description, which Borghans et al. call the total quasi-steady state approximation, to networks of coupled enzymatic reactions. First, we analyze an isolated Goldbeter-Koshland switch when enzymes and substrates are present in comparable concentrations. Then, on the basis of a real example of the molecular network governing cell cycle progression, we couple two and three Goldbeter-Koshland switches together to study the effects of feedback in networks of protein kinases and phosphatases. Our analysis shows that the total quasi-steady state approximation provides an excellent kinetic formalism for protein interaction networks, because (1) it unveils the modular structure of the enzymatic reactions, (2) it suggests a simple algorithm to formulate correct kinetic equations, and (3) contrary to classical Michaelis-Menten kinetics, it succeeds in faithfully reproducing the dynamics of the network both qualitatively and quantitatively.'),
(83607, 2007, 'plos', 'Measures of clade confidence do not correlate with accuracy of phylogenetic trees', 'Hall, Barry G|Salipante, Stephen J', 'Bellingham Research Institute, Bellingham, Washington, United States of America. barryhall@zeninternet.com|Bellingham Research Institute, Bellingham, Washington, United States of America. barryhall@zeninternet.com', 'United States|United States', 0, 'Algorithms|Computer Simulation|DNA Mutational Analysis|Data Interpretation, Statistical|Escherichia coli|Evolution, Molecular|Genetic Variation|Models, Genetic|Models, Statistical|Phylogeny|Reproducibility of Results|Sensitivity and Specificity|Statistics as Topic', 'Journal Article', '10.1371/journal.pcbi.0030051', '17367204', 'Metrics of phylogenetic tree reliability, such as parametric bootstrap percentages or Bayesian posterior probabilities, represent internal measures of the topological reproducibility of a phylogenetic tree, while the recently introduced aLRT (approximate likelihood ratio test) assesses the likelihood that a branch exists on a maximum-likelihood tree. Although those values are often equated with phylogenetic tree accuracy, they do not necessarily estimate how well a reconstructed phylogeny represents cladistic relationships that actually exist in nature. The authors have therefore attempted to quantify how well bootstrap percentages, posterior probabilities, and aLRT measures reflect the probability that a deduced phylogenetic clade is present in a known phylogeny. The authors simulated the evolution of bacterial genes of varying lengths under biologically realistic conditions, and reconstructed those known phylogenies using both maximum likelihood and Bayesian methods. Then, they measured how frequently clades in the reconstructed trees exhibiting particular bootstrap percentages, aLRT values, or posterior probabilities were found in the true trees. The authors have observed that none of these values correlate with the probability that a given clade is present in the known phylogeny. The major conclusion is that none of the measures provide any information about the likelihood that an individual clade actually exists. It is also found that the mean of all clade support values on a tree closely reflects the average proportion of all clades that have been assigned correctly, and is thus a good representation of the overall accuracy of a phylogenetic tree.'),
(83608, 2007, 'plos', '(A)symmetric stem cell replication and cancer', 'Dingli, David|Traulsen, Arne|Michor, Franziska|Michor, Fransizka', 'Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. dingli@fas.harvard.edu|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. dingli@fas.harvard.edu|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. dingli@fas.harvard.edu|Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, United States of America. dingli@fas.harvard.edu', 'United States|United States|United States|United States', 88, 'Animals|Biological Evolution|Cell Proliferation|Cell Transformation, Neoplastic|Humans|Models, Biological|Mutation|Neoplasms|Stem Cells', 'Journal Article', '10.1371/journal.pcbi.0030053', '17367205', 'Most tissues in metazoans undergo continuous turnover due to cell death or epithelial shedding. Since cellular replication is associated with an inherent risk of mutagenesis, tissues are maintained by a small group of stem cells (SCs) that replicate slowly to maintain their own population and that give rise to differentiated cells. There is increasing evidence that many tumors are also maintained by a small population of cancer stem cells that may arise by mutations from normal SCs. SC replication can be either symmetric or asymmetric. The former can lead to expansion of the SC pool. We describe a simple model to evaluate the impact of (a)symmetric SC replication on the expansion of mutant SCs and to show that mutations that increase the probability of asymmetric replication can lead to rapid mutant SC expansion in the absence of a selective fitness advantage. Mutations in several genes can lead to this process and may be at the root of the carcinogenic process.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83609, 2007, 'plos', 'Global discriminative learning for higher-accuracy computational gene prediction', 'Bernal, Axel|Crammer, Koby|Hatzigeorgiou, Artemis|Pereira, Fernando', 'Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. abernal@seas.upenn.edu|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. abernal@seas.upenn.edu|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. abernal@seas.upenn.edu|Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. abernal@seas.upenn.edu', 'United States|United States|United States|United States', 0, 'Algorithms|Artificial Intelligence|Discriminant Analysis|Exons|Open Reading Frames|Pattern Recognition, Automated|Proteins|Sensitivity and Specificity|Sequence Alignment|Sequence Analysis, DNA', 'Evaluation Studies', '10.1371/journal.pcbi.0030054', '17367206', 'Most ab initio gene predictors use a probabilistic sequence model, typically a hidden Markov model, to combine separately trained models of genomic signals and content. By combining separate models of relevant genomic features, such gene predictors can exploit small training sets and incomplete annotations, and can be trained fairly efficiently. However, that type of piecewise training does not optimize prediction accuracy and has difficulty in accounting for statistical dependencies among different parts of the gene model. With genomic information being created at an ever-increasing rate, it is worth investigating alternative approaches in which many different types of genomic evidence, with complex statistical dependencies, can be integrated by discriminative learning to maximize annotation accuracy. Among discriminative learning methods, large-margin classifiers have become prominent because of the success of support vector machines (SVM) in many classification tasks. We describe CRAIG, a new program for ab initio gene prediction based on a conditional random field model with semi-Markov structure that is trained with an online large-margin algorithm related to multiclass SVMs. Our experiments on benchmark vertebrate datasets and on regions from the ENCODE project show significant improvements in prediction accuracy over published gene predictors that use intrinsic features only, particularly at the gene level and on genes with long introns.'),
(83610, 2007, 'plos', 'Discovering motifs in ranked lists of DNA sequences', 'Eden, Eran|Lipson, Doron|Yogev, Sivan|Yakhini, Zohar', 'Computer Science Department, Technion, Haifa, Israel. eraneden@cs.technion.ac.il|Computer Science Department, Technion, Haifa, Israel. eraneden@cs.technion.ac.il|Computer Science Department, Technion, Haifa, Israel. eraneden@cs.technion.ac.il|Computer Science Department, Technion, Haifa, Israel. eraneden@cs.technion.ac.il', 'Israel|Israel|Israel|Israel', 372, 'Algorithms|Base Sequence|Chromatin Immunoprecipitation|Conserved Sequence|CpG Islands|DNA Methylation|Molecular Sequence Data|Regulatory Sequences, Nucleic Acid|Sequence Alignment|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid|Software', 'Journal Article', '10.1371/journal.pcbi.0030039', '17381235', 'Computational methods for discovery of sequence elements that are enriched in a target set compared with a background set are fundamental in molecular biology research. One example is the discovery of transcription factor binding motifs that are inferred from ChIP-chip (chromatin immuno-precipitation on a microarray) measurements. Several major challenges in sequence motif discovery still require consideration: (i) the need for a principled approach to partitioning the data into target and background sets, (ii) the lack of rigorous models and of an exact p-value for measuring motif enrichment, (iii) the need for an appropriate framework for accounting for motif multiplicity, (iv) the tendency, in many of the existing methods, to report presumably significant motifs even when applied to randomly generated data. In this paper we present a statistical framework for discovering enriched sequence elements in ranked lists that resolves these four issues. We demonstrate the implementation of this framework in a software application, termed DRIM (discovery of rank imbalanced motifs), which identifies sequence motifs in lists of ranked DNA sequences. We applied DRIM to ChIP-chip and CpG methylation data and obtained the following results. (i) Identification of 50 novel putative transcription factor (TF) binding sites in yeast ChIP-chip data. The biological function of some of them was further investigated to gain new insights on transcription regulation networks in yeast. For example, our discoveries enable the elucidation of the network of the TF ARO80. Another finding concerns a systematic TF binding enhancement to sequences containing CA repeats. (ii) Discovery of novel motifs in human cancer CpG methylation data. Remarkably, most of these motifs are similar to DNA sequence elements bound by the Polycomb complex that promotes histone methylation. Our findings thus support a model in which histone methylation and CpG methylation are mechanistically linked. Overall, we demonstrate that the statistical framework embodied in the DRIM software tool is highly effective for identifying regulatory sequence elements in a variety of applications ranging from expression and ChIP-chip to CpG methylation data. DRIM is publicly available at http://bioinfo.cs.technion.ac.il/drim.'),
(83611, 2007, 'plos', 'Positive and negative design in stability and thermal adaptation of natural proteins', 'Berezovsky, Igor N|Zeldovich, Konstantin B|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States', 85, 'Amino Acid Sequence|Archaeal Proteins|Computer Simulation|Drug Stability|Hydrophobic and Hydrophilic Interactions|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Denaturation|Protein Folding|Sequence Alignment|Sequence Analysis, Protein|Structure-Activity Relationship|Temperature', 'Journal Article', '10.1371/journal.pcbi.0030052', '17381236', 'The aim of this work is to elucidate how physical principles of protein design are reflected in natural sequences that evolved in response to the thermal conditions of the environment. Using an exactly solvable lattice model, we design sequences with selected thermal properties. Compositional analysis of designed model sequences and natural proteomes reveals a specific trend in amino acid compositions in response to the requirement of stability at elevated environmental temperature: the increase of fractions of hydrophobic and charged amino acid residues at the expense of polar ones. We show that this from both ends of the hydrophobicity scale trend is due to positive (to stabilize the native state) and negative (to destabilize misfolded states) components of protein design. Negative design strengthens specific repulsive non-native interactions that appear in misfolded structures. A pressure to preserve specific repulsive interactions in non-native conformations may result in correlated mutations between amino acids that are far apart in the native state but may be in contact in misfolded conformations. Such correlated mutations are indeed found in TIM barrel and other proteins.'),
(83612, 2007, 'plos', 'Dynamic simulations on the arachidonic acid metabolic network', 'Yang, Kun|Ma, Wenzhe|Liang, Huanhuan|Ouyang, Qi|Tang, Chao|Lai, Luhua', 'Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.|Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.|Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.|Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.|Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.|Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.', 'China|China|China|China|China|China', 84, 'Anti-Inflammatory Agents|Arachidonic Acid|Cells, Cultured|Computer Simulation|Dose-Response Relationship, Drug|Humans|Immunologic Factors|Leukocytes|Models, Immunological|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030055', '17381237', 'Drug molecules not only interact with specific targets, but also alter the state and function of the associated biological network. How to design drugs and evaluate their functions at the systems level becomes a key issue in highly efficient and low-side-effect drug design. The arachidonic acid metabolic network is the network that produces inflammatory mediators, in which several enzymes, including cyclooxygenase-2 (COX-2), have been used as targets for anti-inflammatory drugs. However, neither the century-old nonsteriodal anti-inflammatory drugs nor the recently revocatory Vioxx have provided completely successful anti-inflammatory treatment. To gain more insights into the anti-inflammatory drug design, the authors have studied the dynamic properties of arachidonic acid (AA) metabolic network in human polymorphous leukocytes. Metabolic flux, exogenous AA effects, and drug efficacy have been analyzed using ordinary differential equations. The flux balance in the AA network was found to be important for efficient and safe drug design. When only the 5-lipoxygenase (5-LOX) inhibitor was used, the flux of the COX-2 pathway was increased significantly, showing that a single functional inhibitor cannot effectively control the production of inflammatory mediators. When both COX-2 and 5-LOX were blocked, the production of inflammatory mediators could be completely shut off. The authors have also investigated the differences between a dual-functional COX-2 and 5-LOX inhibitor and a mixture of these two types of inhibitors. Their work provides an example for the integration of systems biology and drug discovery.'),
(83613, 2007, 'plos', 'Posttranscriptional expression regulation: what determines translation rates?', 'Brockmann, Regina|Beyer, Andreas|Heinisch, Jürgen J|Wilhelm, Thomas', 'Theoretical Systems Biology, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.|Theoretical Systems Biology, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.|Theoretical Systems Biology, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.|Theoretical Systems Biology, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.', 'Germany|Germany|Germany|Germany', 138, 'Computer Simulation|Gene Expression Regulation|Models, Biological|Protein Processing, Post-Translational|Proteome|RNA Processing, Post-Transcriptional|Saccharomyces cerevisiae Proteins|Transcriptional Activation', 'Journal Article', '10.1371/journal.pcbi.0030057', '17381238', 'Recent analyses indicate that differences in protein concentrations are only 20%-40% attributable to variable mRNA levels, underlining the importance of posttranscriptional regulation. Generally, protein concentrations depend on the translation rate (which is proportional to the translational activity, TA) and the degradation rate. By integrating 12 publicly available large-scale datasets and additional database information of the yeast Saccharomyces cerevisiae, we systematically analyzed five factors contributing to TA: mRNA concentration, ribosome density, ribosome occupancy, the codon adaptation index, and a newly developed tRNA adaptation index. Our analysis of the functional relationship between the TA and measured protein concentrations suggests that the TA follows Michaelis-Menten kinetics. The calculated TA, together with measured protein concentrations, allowed us to estimate degradation rates for 4,125 proteins under standard conditions. A significant correlation to recently published degradation rates supports our approach. Moreover, based on a newly developed scoring system, we identified and analyzed genes subjected to the posttranscriptional regulation mechanism, translation on demand. Next we applied these findings to publicly available data of protein and mRNA concentrations under four stress conditions. The integration of these measurements allowed us to compare the condition-specific responses at the posttranscriptional level. Our analysis of all 62 proteins that have been measured under all four conditions revealed proteins with very specific posttranscriptional stress response, in contrast to more generic responders, which were nonspecifically regulated under several conditions. The concept of specific and generic responders is known for transcriptional regulation. Here we show that it also holds true at the posttranscriptional level.'),
(83614, 2007, 'plos', 'Deciphering protein-protein interactions Part I Experimental techniques and databases', 'Shoemaker, Benjamin A|Panchenko, Anna R', 'Computational Biology Branch of the National Center for Biotechnology Information in Bethesda, Maryland, United States of America.|Computational Biology Branch of the National Center for Biotechnology Information in Bethesda, Maryland, United States of America.', 'United States|United States', 271, 'Algorithms|Binding Sites|Computer Simulation|Database Management Systems|Databases, Protein|Information Storage and Retrieval|Models, Biological|Protein Binding|Protein Interaction Mapping|Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030042', '17397251', '-'),
(83615, 2007, 'plos', 'Ten simple rules for a successful collaboration', 'Vicens, Quentin|Bourne, Philip E', 'Computational Biology Branch of the National Center for Biotechnology Information in Bethesda, Maryland, United States of America.|Computational Biology Branch of the National Center for Biotechnology Information in Bethesda, Maryland, United States of America.', 'United States|United States', 27, 'Communication|Cooperative Behavior|Guidelines as Topic|Interprofessional Relations|Research|Science', 'Editorial', '10.1371/journal.pcbi.0030044', '17397252', '-'),
(83616, 2007, 'plos', 'Query-dependent banding (QDB) for faster RNA similarity searches', 'Nawrocki, Eric P|Eddy, Sean R', 'Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, United States of America.|Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, United States of America.', 'United States|United States', 229, 'Base Sequence|Database Management Systems|Databases, Genetic|Information Storage and Retrieval|Molecular Sequence Data|RNA|Sequence Alignment|Sequence Analysis, RNA|Sequence Homology, Nucleic Acid', 'Evaluation Studies', '10.1371/journal.pcbi.0030056', '17397253', 'When searching sequence databases for RNAs, it is desirable to score both primary sequence and RNA secondary structure similarity. Covariance models (CMs) are probabilistic models well-suited for RNA similarity search applications. However, the computational complexity of CM dynamic programming alignment algorithms has limited their practical application. Here we describe an acceleration method called query-dependent banding (QDB), which uses the probabilistic query CM to precalculate regions of the dynamic programming lattice that have negligible probability, independently of the target database. We have implemented QDB in the freely available Infernal software package. QDB reduces the average case time complexity of CM alignment from LN(2.4) to LN(1.3) for a query RNA of N residues and a target database of L residues, resulting in a 4-fold speedup for typical RNA queries. Combined with other improvements to Infernal, including informative mixture Dirichlet priors on model parameters, benchmarks also show increased sensitivity and specificity resulting from improved parameterization.'),
(83617, 2007, 'plos', 'Structural descriptors of gp120 V3 loop for the prediction of HIV-1 coreceptor usage', 'Sander, Oliver|Sing, Tobias|Sommer, Ingolf|Low, Andrew J|Cheung, Peter K|Harrigan, P Richard|Lengauer, Thomas|Domingues, Francisco S', 'Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de|Max-Planck-Institute for Informatics, Saarbrücken, Germany. osander@mpi-sb.mpg.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 74, 'Amino Acid Sequence|HIV-1|Molecular Sequence Data|Receptors, CCR5|Receptors, CXCR4|Sequence Alignment|Sequence Analysis, Protein|Structure-Activity Relationship|Virus Attachment|Virus Internalization', 'Journal Article', '10.1371/journal.pcbi.0030058', '17397254', 'HIV-1 cell entry commonly uses, in addition to CD4, one of the chemokine receptors CCR5 or CXCR4 as coreceptor. Knowledge of coreceptor usage is critical for monitoring disease progression as well as for supporting therapy with the novel drug class of coreceptor antagonists. Predictive methods for inferring coreceptor usage based on the third hypervariable (V3) loop region of the viral gene coding for the envelope protein gp120 can provide us with these monitoring facilities while avoiding expensive phenotypic tests. All simple heuristics (such as the 11/25 rule) as well as statistical learning methods proposed to date predict coreceptor usage based on sequence features of the V3 loop exclusively. Here, we show, based on a recently resolved structure of gp120 with an untruncated V3 loop, that using structural information on the V3 loop in combination with sequence features of V3 variants improves prediction of coreceptor usage. In particular, we propose a distance-based descriptor of the spatial arrangement of physicochemical properties that increases discriminative performance. For a fixed specificity of 0.95, a sensitivity of 0.77 was achieved, improving further to 0.80 when combined with a sequence-based representation using amino acid indicators. This compares favorably with the sensitivities of 0.62 for the traditional 11/25 rule and 0.73 for a prediction based on sequence information as input to a support vector machine and constitutes a statistically significant improvement. A detailed analysis and interpretation of structural features important for classification shows the relevance of several specific hydrogen-bond donor sites and aliphatic side chains to coreceptor specificity towards CCR5 or CXCR4. Furthermore, an analysis of side chain orientation of the specificity-determining residues suggests a major role of one side of the V3 loop in the selection of the coreceptor. The proposed method constitutes the first approach to an improved prediction of coreceptor usage based on an original integration of structural bioinformatics methods with statistical learning.'),
(83618, 2007, 'plos', 'Potential energy landscape and robustness of a gene regulatory network: toggle switch', 'Kim, Keun-Young|Wang, Jin', 'Department of Physics and Astronomy, State University of New York Stony Brook, Stony Brook, New York, United States of America.|Department of Physics and Astronomy, State University of New York Stony Brook, Stony Brook, New York, United States of America.', 'United States|United States', 81, 'Computer Simulation|Energy Metabolism|Gene Expression Regulation|Logistic Models|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030060', '17397255', 'Finding a multidimensional potential landscape is the key for addressing important global issues, such as the robustness of cellular networks. We have uncovered the underlying potential energy landscape of a simple gene regulatory network: a toggle switch. This was realized by explicitly constructing the steady state probability of the gene switch in the protein concentration space in the presence of the intrinsic statistical fluctuations due to the small number of proteins in the cell. We explored the global phase space for the system. We found that the protein synthesis rate and the unbinding rate of proteins to the gene were small relative to the protein degradation rate, the gene switch is monostable with only one stable basin of attraction. When both the protein synthesis rate and the unbinding rate of proteins to the gene are large compared with the protein degradation rate, two global basins of attraction emerge for a toggle switch. These basins correspond to the biologically stable functional states. The potential energy barrier between the two basins determines the time scale of conversion from one to the other. We found as the protein synthesis rate and protein unbinding rate to the gene relative to the protein degradation rate became larger, the potential energy barrier became larger. This also corresponded to systems with less noise or the fluctuations on the protein numbers. It leads to the robustness of the biological basins of the gene switches. The technique used here is general and can be applied to explore the potential energy landscape of the gene networks.'),
(83619, 2007, 'plos', 'DNA familial binding profiles made easy: comparison of various motif alignment and clustering strategies', 'Mahony, Shaun|Auron, Philip E|Benos, Panayiotis V', 'Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States', 94, 'Amino Acid Motifs|Base Sequence|Binding Sites|Cluster Analysis|DNA|Molecular Sequence Data|Multigene Family|Protein Binding|Sequence Alignment|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030061', '17397256', 'Transcription factor (TF) proteins recognize a small number of DNA sequences with high specificity and control the expression of neighbouring genes. The evolution of TF binding preference has been the subject of a number of recent studies, in which generalized binding profiles have been introduced and used to improve the prediction of new target sites. Generalized profiles are generated by aligning and merging the individual profiles of related TFs. However, the distance metrics and alignment algorithms used to compare the binding profiles have not yet been fully explored or optimized. As a result, binding profiles depend on TF structural information and sometimes may ignore important distinctions between subfamilies. Prediction of the identity or the structural class of a protein that binds to a given DNA pattern will enhance the analysis of microarray and ChIP-chip data where frequently multiple putative targets of usually unknown TFs are predicted. Various comparison metrics and alignment algorithms are evaluated (a total of 105 combinations). We find that local alignments are generally better than global alignments at detecting eukaryotic DNA motif similarities, especially when combined with the sum of squared distances or Pearsons correlation coefficient comparison metrics. In addition, multiple-alignment strategies for binding profiles and tree-building methods are tested for their efficiency in constructing generalized binding models. A new method for automatic determination of the optimal number of clusters is developed and applied in the construction of a new set of familial binding profiles which improves upon TF classification accuracy. A software tool, STAMP, is developed to host all tested methods and make them publicly available. This work provides a high quality reference set of familial binding profiles and the first comprehensive platform for analysis of DNA profiles. Detecting similarities between DNA motifs is a key step in the comparative study of transcriptional regulation, and the work presented here will form the basis for tool and method development for future transcriptional modeling studies.'),
(83620, 2006, 'plos', 'Biocurators: contributors to the world of science', 'Bourne, Philip E|McEntyre, Johanna', 'Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States', 17, 'Abstracting and Indexing as Topic|Computational Biology|Database Management Systems|Databases, Factual|Documentation|Information Storage and Retrieval|Internet|Science', 'Comment', '10.1371/journal.pcbi.0020142', '17411327', '-'),
(83621, 2007, 'plos', 'Psychophysical tests of the hypothesis of a bottom-up saliency map in primary visual cortex', 'Zhaoping, Li|May, Keith A', 'Department of Psychology, University College London, London, United Kingdom. z.li@ucl.ac.uk|Department of Psychology, University College London, London, United Kingdom. z.li@ucl.ac.uk', 'United Kingdom|United Kingdom', 59, 'Attention|Computer Simulation|Cues|Humans|Models, Neurological|Nerve Net|Pattern Recognition, Visual|Psychomotor Performance|Psychophysics|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.0030062', '17411335', 'A unique vertical bar among horizontal bars is salient and pops out perceptually. Physiological data have suggested that mechanisms in the primary visual cortex (V1) contribute to the high saliency of such a unique basic feature, but indicated little regarding whether V1 plays an essential or peripheral role in input-driven or bottom-up saliency. Meanwhile, a biologically based V1 model has suggested that V1 mechanisms can also explain bottom-up saliencies beyond the pop-out of basic features, such as the low saliency of a unique conjunction feature such as a red vertical bar among red horizontal and green vertical bars, under the hypothesis that the bottom-up saliency at any location is signaled by the activity of the most active cell responding to it regardless of the cells preferred features such as color and orientation. The model can account for phenomena such as the difficulties in conjunction feature search, asymmetries in visual search, and how background irregularities affect ease of search. In this paper, we report nontrivial predictions from the V1 saliency hypothesis, and their psychophysical tests and confirmations. The prediction that most clearly distinguishes the V1 saliency hypothesis from other models is that task-irrelevant features could interfere in visual search or segmentation tasks which rely significantly on bottom-up saliency. For instance, irrelevant colors can interfere in an orientation-based task, and the presence of horizontal and vertical bars can impair performance in a task based on oblique bars. Furthermore, properties of the intracortical interactions and neural selectivities in V1 predict specific emergent phenomena associated with visual grouping. Our findings support the idea that a bottom-up saliency map can be at a lower visual area than traditionally expected, with implications for top-down selection mechanisms.'),
(83622, 2007, 'plos', 'Integration of genome and chromatin structure with gene expression profiles to predict c-MYC recognition site binding and function', 'Chen, Yili|Blackwell, Thomas W|Chen, Ji|Gao, Jing|Lee, Angel W|States, David J', 'Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Bioinformatics Program, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.', 'United States|United States|United States|United States|United States|United States', 27, 'Binding Sites|Chromatin|Chromosome Mapping|Computer Simulation|DNA-Binding Proteins|Gene Expression Profiling|Models, Biological|Models, Chemical|Protein Binding|Protein Interaction Mapping|Sequence Analysis, Protein|Structure-Activity Relationship|Systems Integration|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030063', '17411336', 'The MYC genes encode nuclear sequence specific-binding DNA-binding proteins that are pleiotropic regulators of cellular function, and the c-MYC proto-oncogene is deregulated and/or mutated in most human cancers. Experimental studies of MYC binding to the genome are not fully consistent. While many c-MYC recognition sites can be identified in c-MYC responsive genes, other motif matches-even experimentally confirmed sites-are associated with genes showing no c-MYC response. We have developed a computational model that integrates multiple sources of evidence to predict which genes will bind and be regulated by MYC in vivo. First, a Bayesian network classifier is used to predict those c-MYC recognition sites that are most likely to exhibit high-occupancy binding in chromatin immunoprecipitation studies. This classifier incorporates genomic sequence, experimentally determined genomic chromatin acetylation islands, and predicted methylation status from a computational model estimating the likelihood of genomic DNA methylation. We find that the predictions from this classifier are also applicable to other transcription factors, such as cAMP-response element-binding protein, whose binding sites are sensitive to DNA methylation. Second, the MYC binding probability is combined with the gene expression profile data from nine independent microarray datasets in multiple tissues. Finally, we may consider gene function annotations in Gene Ontology to predict the c-MYC targets. We assess the performance of our prediction results by comparing them with the c-myc targets identified in the biomedical literature. In total, we predict 460 likely c-MYC target genes in the human genome, of which 67 have been reported to be both bound and regulated by MYC, 68 are bound by MYC, and another 80 are MYC-regulated. The approach thus successfully identifies many known c-MYC targets and suggests many novel sites. Our findings suggest that to identify c-MYC genomic targets, integration of different data sources helps to improve the accuracy.'),
(83623, 2007, 'plos', 'Towards complete sets of farnesylated and geranylgeranylated proteins', 'Maurer-Stroh, Sebastian|Koranda, Manfred|Benetka, Wolfgang|Schneider, Georg|Sirota, Fernanda L|Eisenhaber, Frank', 'Research Institute of Molecular Pathology, Vienna, Austria. smaurers@vub.ac.be|Research Institute of Molecular Pathology, Vienna, Austria. smaurers@vub.ac.be|Research Institute of Molecular Pathology, Vienna, Austria. smaurers@vub.ac.be|Research Institute of Molecular Pathology, Vienna, Austria. smaurers@vub.ac.be|Research Institute of Molecular Pathology, Vienna, Austria. smaurers@vub.ac.be|Research Institute of Molecular Pathology, Vienna, Austria. smaurers@vub.ac.be', 'Austria|Austria|Austria|Austria|Austria|Austria', 117, 'Conserved Sequence|Evolution, Molecular|Membrane Lipids|Membrane Proteins|Protein Interaction Mapping|Protein Prenylation|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0030066', '17411337', 'Three different prenyltransferases attach isoprenyl anchors to C-terminal motifs in substrate proteins. These lipid anchors serve for membrane attachment or protein-protein interactions in many pathways. Although well-tolerated selective prenyltransferase inhibitors are clinically available, their mode of action remains unclear since the known substrate sets of the various prenyltransferases are incomplete. The Prenylation Prediction Suite (PrePS) has been applied for large-scale predictions of prenylated proteins. To prioritize targets for experimental verification, we rank the predictions by their functional importance estimated by evolutionary conservation of the prenylation motifs within protein families. The ranked lists of predictions are accessible as PRENbase (http://mendel.imp.univie.ac.at/sat/PrePS/PRENbase) and can be queried for verification status, type of modifying enzymes (anchor type), and taxonomic distribution. Our results highlight a large group of plant metal-binding chaperones as well as several newly predicted proteins involved in ubiquitin-mediated protein degradation, enriching the known functional repertoire of prenylated proteins. Furthermore, we identify two possibly prenylated proteins in Mimivirus. The section HumanPRENbase provides complete lists of predicted prenylated human proteins-for example, the list of farnesyltransferase targets that cannot become substrates of geranylgeranyltransferase 1 and, therefore, are especially affected by farnesyltransferase inhibitors (FTIs) used in cancer and anti-parasite therapy. We report direct experimental evidence verifying the prediction of the human proteins Prickle1, Prickle2, the BRO1 domain-containing FLJ32421 (termed BROFTI), and Rab28 (short isoform) as exclusive farnesyltransferase targets. We introduce PRENbase, a database of large-scale predictions of protein prenylation substrates ranked by evolutionary conservation of the motif. Experimental evidence is presented for the selective farnesylation of targets with an evolutionary conserved modification site.'),
(83624, 2007, 'plos', 'Cell size at S phase initiation: an emergent property of the G1/S network', 'Barberis, Matteo|Klipp, Edda|Vanoni, Marco|Alberghina, Lilia', 'Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.|Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.', 'Italy|Italy|Italy|Italy', 75, 'Cell Cycle|Cell Cycle Proteins|Cell Size|Computer Simulation|Models, Biological|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030064', '17432928', 'The eukaryotic cell cycle is the repeated sequence of events that enable the division of a cell into two daughter cells. It is divided into four phases: G1, S, G2, and M. Passage through the cell cycle is strictly regulated by a molecular interaction network, which involves the periodic synthesis and destruction of cyclins that bind and activate cyclin-dependent kinases that are present in nonlimiting amounts. Cyclin-dependent kinase inhibitors contribute to cell cycle control. Budding yeast is an established model organism for cell cycle studies, and several mathematical models have been proposed for its cell cycle. An area of major relevance in cell cycle control is the G1 to S transition. In any given growth condition, it is characterized by the requirement of a specific, critical cell size, PS, to enter S phase. The molecular basis of this control is still under discussion. The authors report a mathematical model of the G1 to S network that newly takes into account nucleo/cytoplasmic localization, the role of the cyclin-dependent kinase Sic1 in facilitating nuclear import of its cognate Cdk1-Clb5, Whi5 control, and carbon source regulation of Sic1 and Sic1-containing complexes. The model was implemented by a set of ordinary differential equations that describe the temporal change of the concentration of the involved proteins and protein complexes. The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data. To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins. Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.'),
(83625, 2007, 'plos', 'Inferring noncoding RNA families and classes by means of genome-scale structure-based clustering', 'Will, Sebastian|Reiche, Kristin|Hofacker, Ivo L|Stadler, Peter F|Backofen, Rolf', 'Bioinformatics Group, Institute of Computer Science, University of Freiburg, Freiburg, Germany.|Bioinformatics Group, Institute of Computer Science, University of Freiburg, Freiburg, Germany.|Bioinformatics Group, Institute of Computer Science, University of Freiburg, Freiburg, Germany.|Bioinformatics Group, Institute of Computer Science, University of Freiburg, Freiburg, Germany.|Bioinformatics Group, Institute of Computer Science, University of Freiburg, Freiburg, Germany.', 'Germany|Germany|Germany|Germany|Germany', 318, 'Algorithms|Animals|Chromosome Mapping|Ciona intestinalis|Multigene Family|RNA, Untranslated|Sequence Alignment|Sequence Analysis, RNA|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0030065', '17432929', 'The RFAM database defines families of ncRNAs by means of sequence similarities that are sufficient to establish homology. In some cases, such as microRNAs and box H/ACA snoRNAs, functional commonalities define classes of RNAs that are characterized by structural similarities, and typically consist of multiple RNA families. Recent advances in high-throughput transcriptomics and comparative genomics have produced very large sets of putative noncoding RNAs and regulatory RNA signals. For many of them, evidence for stabilizing selection acting on their secondary structures has been derived, and at least approximate models of their structures have been computed. The overwhelming majority of these hypothetical RNAs cannot be assigned to established families or classes. We present here a structure-based clustering approach that is capable of extracting putative RNA classes from genome-wide surveys for structured RNAs. The LocARNA (local alignment of RNA) tool implements a novel variant of the Sankoff algorithm that is sufficiently fast to deal with several thousand candidate sequences. The method is also robust against false positive predictions, i.e., a contamination of the input data with unstructured or nonconserved sequences. We have successfully tested the LocARNA-based clustering approach on the sequences of the RFAM-seed alignments. Furthermore, we have applied it to a previously published set of 3,332 predicted structured elements in the Ciona intestinalis genome (Missal K, Rose D, Stadler PF (2005) Noncoding RNAs in Ciona intestinalis. Bioinformatics 21 (Supplement 2): i77-i78). In addition to recovering, e.g., tRNAs as a structure-based class, the method identifies several RNA families, including microRNA and snoRNA candidates, and suggests several novel classes of ncRNAs for which to date no representative has been experimentally characterized.'),
(83626, 2007, 'plos', 'Synchronization-induced rhythmicity of circadian oscillators in the suprachiasmatic nucleus', 'Bernard, Samuel|Gonze, Didier|Cajavec, Branka|Herzel, Hanspeter|Kramer, Achim', 'Institute of Applied and Computational Mathematics, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece. samubernard@gmail.com|Institute of Applied and Computational Mathematics, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece. samubernard@gmail.com|Institute of Applied and Computational Mathematics, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece. samubernard@gmail.com|Institute of Applied and Computational Mathematics, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece. samubernard@gmail.com|Institute of Applied and Computational Mathematics, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece. samubernard@gmail.com', 'Greece|Greece|Greece|Greece|Greece', 151, 'Action Potentials|Biological Clocks|Circadian Rhythm|Computer Simulation|Models, Neurological|Nerve Net|Oscillometry|Suprachiasmatic Nucleus', 'Journal Article', '10.1371/journal.pcbi.0030068', '17432930', 'The suprachiasmatic nuclei (SCN) host a robust, self-sustained circadian pacemaker that coordinates physiological rhythms with the daily changes in the environment. Neuronal clocks within the SCN form a heterogeneous network that must synchronize to maintain timekeeping activity. Coherent circadian output of the SCN tissue is established by intercellular signaling factors, such as vasointestinal polypeptide. It was recently shown that besides coordinating cells, the synchronization factors play a crucial role in the sustenance of intrinsic cellular rhythmicity. Disruption of intercellular signaling abolishes sustained rhythmicity in a majority of neurons and desynchronizes the remaining rhythmic neurons. Based on these observations, the authors propose a model for the synchronization of circadian oscillators that combines intracellular and intercellular dynamics at the single-cell level. The model is a heterogeneous network of circadian neuronal oscillators where individual oscillators are damped rather than self-sustained. The authors simulated different experimental conditions and found that: (1) in normal, constant conditions, coupled circadian oscillators quickly synchronize and produce a coherent output, (2) in large populations, such oscillators either synchronize or gradually lose rhythmicity, but do not run out of phase, demonstrating that rhythmicity and synchrony are codependent, (3) the number of oscillators and connectivity are important for these synchronization properties, (4) slow oscillators have a higher impact on the period in mixed populations, and (5) coupled circadian oscillators can be efficiently entrained by light-dark cycles. Based on these results, it is predicted that: (1) a majority of SCN neurons needs periodic synchronization signal to be rhythmic, (2) a small number of neurons or a low connectivity results in desynchrony, and (3) amplitudes and phases of neurons are negatively correlated. The authors conclude that to understand the orchestration of timekeeping in the SCN, intracellular circadian clocks cannot be isolated from their intercellular communication components.'),
(83627, 2007, 'plos', 'Increasing the power to detect causal associations by combining genotypic and expression data in segregating populations', 'Zhu, Jun|Wiener, Matthew C|Zhang, Chunsheng|Fridman, Arthur|Minch, Eric|Lum, Pek Y|Sachs, Jeffrey R|Schadt, Eric E', 'Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.|Rosetta Inpharmatics, Seattle, Washington, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 140, 'Animals|Computer Simulation|DNA Mutational Analysis|Gene Expression Profiling|Genetic Variation|Genotype|Mice|Models, Biological|Multigene Family|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030069', '17432931', 'To dissect common human diseases such as obesity and diabetes, a systematic approach is needed to study how genes interact with one another, and with genetic and environmental factors, to determine clinical end points or disease phenotypes. Bayesian networks provide a convenient framework for extracting relationships from noisy data and are frequently applied to large-scale data to derive causal relationships among variables of interest. Given the complexity of molecular networks underlying common human disease traits, and the fact that biological networks can change depending on environmental conditions and genetic factors, large datasets, generally involving multiple perturbations (experiments), are required to reconstruct and reliably extract information from these networks. With limited resources, the balance of coverage of multiple perturbations and multiple subjects in a single perturbation needs to be considered in the experimental design. Increasing the number of experiments, or the number of subjects in an experiment, is an expensive and time-consuming way to improve network reconstruction. Integrating multiple types of data from existing subjects might be more efficient. For example, it has recently been demonstrated that combining genotypic and gene expression data in a segregating population leads to improved network reconstruction, which in turn may lead to better predictions of the effects of experimental perturbations on any given gene. Here we simulate data based on networks reconstructed from biological data collected in a segregating mouse population and quantify the improvement in network reconstruction achieved using genotypic and gene expression data, compared with reconstruction using gene expression data alone. We demonstrate that networks reconstructed using the combined genotypic and gene expression data achieve a level of reconstruction accuracy that exceeds networks reconstructed from expression data alone, and that fewer subjects may be required to achieve this superior reconstruction accuracy. We conclude that this integrative genomics approach to reconstructing networks not only leads to more predictive network models, but also may save time and money by decreasing the amount of data that must be generated under any given condition of interest to construct predictive network models.'),
(83628, 2007, 'plos', 'The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics', 'Yu, Haiyuan|Kim, Philip M|Sprecher, Emmett|Trifonov, Valery|Gerstein, Mark', 'Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.', 'United States|United States|United States|United States|United States', 609, 'Algorithms|Computer Simulation|Gene Expression|Gene Expression Regulation|Models, Biological|Proteome|Signal Transduction|Statistics as Topic|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030059', '17447836', 'It has been a long-standing goal in systems biology to find relations between the topological properties and functional features of protein networks. However, most of the focus in network studies has been on highly connected proteins (hubs). As a complementary notion, it is possible to define bottlenecks as proteins with a high betweenness centrality (i.e., network nodes that have many shortest paths going through them, analogous to major bridges and tunnels on a highway map). Bottlenecks are, in fact, key connector proteins with surprising functional and dynamic properties. In particular, they are more likely to be essential proteins. In fact, in regulatory and other directed networks, betweenness (i.e., bottleneck-ness) is a much more significant indicator of essentiality than degree (i.e., hub-ness). Furthermore, bottlenecks correspond to the dynamic components of the interaction network-they are significantly less well coexpressed with their neighbors than non-bottlenecks, implying that expression dynamics is wired into the network topology.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83629, 2007, 'plos', 'Regulatory circuit of human microRNA biogenesis', 'Lee, Ji|Li, Zhihua|Brower-Sinning, Rachel|John, Bino', 'Department of Computational Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Department of Computational Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.', 'United States|United States|United States|United States', 0, 'Base Sequence|Evolution, Molecular|Humans|MicroRNAs|Molecular Sequence Data|Open Reading Frames|Regulatory Sequences, Ribonucleic Acid|Sequence Alignment|Sequence Analysis, RNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030067', '17447837', 'miRNAs (microRNAs) are a class of endogenous small RNAs that are thought to negatively regulate protein production. Aberrant expression of many miRNAs is linked to cancer and other diseases. Little is known about the factors that regulate the expression of miRNAs. We have identified numerous regulatory elements upstream of miRNA genes that are likely to be essential to the transcriptional and posttranscriptional regulation of miRNAs. Newly identified regulatory motifs occur frequently and in multiple copies upstream of miRNAs. The motifs are highly enriched in G and C nucleotides, in comparison with the nucleotide composition of miRNA upstream sequences. Although the motifs were predicted using sequences that are upstream of miRNAs, we find that 99% of the top-predicted motifs preferentially occur within the first 500 nucleotides upstream of the transcription start sites of protein-coding genes, the observed preference in location underscores the validity and importance of the motifs identified in this study. Our study also raises the possibility that a considerable number of well-characterized, disease-associated transcription factors (TFs) of protein-coding genes contribute to the abnormal miRNA expression in diseases such as cancer. Further analysis of predicted miRNA-protein interactions lead us to hypothesize that TFs that include c-Myb, NF-Y, Sp-1, MTF-1, and AP-2alpha are master-regulators of miRNA expression. Our predictions are a solid starting point for the systematic elucidation of the causative basis for aberrant expression patterns of disease-related (e.g., cancer) miRNAs. Thus, we point out that focused studies of the TFs that regulate miRNAs will be paramount in developing cures for miRNA-related diseases. The identification of the miRNA regulatory motifs was facilitated by a new computational method, K-Factor. K-Factor predicts regulatory motifs in a set of functionally related sequences, without relying on evolutionary conservation.'),
(83630, 2007, 'plos', 'Risk maps for the spread of highly pathogenic avian influenza in poultry', 'Boender, Gert Jan|Hagenaars, Thomas J|Bouma, Annemarie|Nodelijk, Gonnie|Elbers, Armin R W|de Jong, Mart C M|van Boven, Michiel', 'Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.|Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.|Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.|Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.|Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.|Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.|Animal Sciences Group, Wageningen University and Research Centre, Lelystad, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 131, 'Agriculture|Animal Husbandry|Animals|Computer Simulation|Disease Outbreaks|Incidence|Influenza A Virus, H7N7 Subtype|Influenza in Birds|Models, Biological|Netherlands|Population Dynamics|Poultry|Risk Assessment|Risk Factors', 'Journal Article', '10.1371/journal.pcbi.0030071', '17447838', 'Devastating epidemics of highly contagious animal diseases such as avian influenza, classical swine fever, and foot-and-mouth disease underline the need for improved understanding of the factors promoting the spread of these pathogens. Here the authors present a spatial analysis of the between-farm transmission of a highly pathogenic H7N7 avian influenza virus that caused a large epidemic in The Netherlands in 2003. The authors developed a method to estimate key parameters determining the spread of highly transmissible animal diseases between farms based on outbreak data. The method allows for the identification of high-risk areas for propagating spread in an epidemiologically underpinned manner. A central concept is the transmission kernel, which determines the probability of pathogen transmission from infected to uninfected farms as a function of interfarm distance. The authors show how an estimate of the transmission kernel naturally provides estimates of the critical farm density and local reproduction numbers, which allows one to evaluate the effectiveness of control strategies. For avian influenza, the analyses show that there are two poultry-dense areas in The Netherlands where epidemic spread is possible, and in which local control measures are unlikely to be able to halt an unfolding epidemic. In these regions an epidemic can only be brought to an end by the depletion of susceptible farms by infection or massive culling. The analyses provide an estimate of the spatial range over which highly pathogenic avian influenza viruses spread between farms, and emphasize that control measures aimed at controlling such outbreaks need to take into account the local density of farms.'),
(83631, 2007, 'plos', 'Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes', 'Yang, Mary Q|Koehly, Laura M|Elnitski, Laura L', 'Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland, United States of America.|Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland, United States of America.|Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland, United States of America.', 'United States|United States|United States', 67, 'Base Sequence|Biomarkers, Tumor|Breast Neoplasms|Databases, Genetic|Expressed Sequence Tags|Female|Gene Expression Regulation, Neoplastic|Genetic Predisposition to Disease|Humans|Information Storage and Retrieval|Molecular Sequence Data|Multigene Family|Neoplasm Proteins|Ovarian Neoplasms|Promoter Regions, Genetic|Sequence Alignment|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030072', '17447839', 'A bidirectional gene pair comprises two adjacent genes whose transcription start sites are neighboring and directed away from each other. The intervening regulatory region is called a bidirectional promoter. These promoters are often associated with genes that function in DNA repair, with the potential to participate in the development of cancer. No connection between these gene pairs and cancer has been previously investigated. Using the database of spliced-expressed sequence tags (ESTs), we identified the most complete collection of human transcripts under the control of bidirectional promoters. A rigorous screen of the spliced EST data identified new bidirectional promoters, many of which functioned as alternative promoters or regulated novel transcripts. Additionally, we show a highly significant enrichment of bidirectional promoters in genes implicated in somatic cancer, including a substantial number of genes implicated in breast and ovarian cancers. The repeated use of this promoter structure in the human genome suggests it could regulate co-expression patterns among groups of genes. Using microarray expression data from 79 human tissues, we verify regulatory networks among genes controlled by bidirectional promoters. Subsets of these promoters contain similar combinations of transcription factor binding sites, including evolutionarily conserved ETS factor binding sites in ERBB2, FANCD2, and BRCA2. Interpreting the regulation of genes involved in co-expression networks, especially those involved in cancer, will be an important step toward defining molecular events that may contribute to disease.'),
(83632, 2007, 'plos', 'Deciphering protein-protein interactions Part II Computational methods to predict protein and domain interaction partners', 'Shoemaker, Benjamin A|Panchenko, Anna R', 'Computational Biology Branch, National Center for Biotechnology Information, Bethesda, Maryland, United States of America.|Computational Biology Branch, National Center for Biotechnology Information, Bethesda, Maryland, United States of America.', 'United States|United States', 0, 'Algorithms|Binding Sites|Computer Simulation|Models, Chemical|Protein Binding|Protein Interaction Mapping|Protein Structure, Tertiary|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030043', '17465672', 'Recent advances in high-throughput experimental methods for the identification of protein interactions have resulted in a large amount of diverse data that are somewhat incomplete and contradictory. As valuable as they are, such experimental approaches studying protein interactomes have certain limitations that can be complemented by the computational methods for predicting protein interactions. In this review we describe different approaches to predict protein interaction partners as well as highlight recent achievements in the prediction of specific domains mediating protein-protein interactions. We discuss the applicability of computational methods to different types of prediction problems and point out limitations common to all of them.'),
(83633, 2007, 'plos', 'Dog as an outgroup to human and mouse', 'Lunter, Gerton', 'Computational Biology Branch, National Center for Biotechnology Information, Bethesda, Maryland, United States of America.', 'United States', 24, 'Animals|Biological Evolution|Chromosome Mapping|Dogs|Humans|Mice|Models, Genetic|Phylogeny|Sequence Homology, Nucleic Acid|Species Specificity', 'Comment', '10.1371/journal.pcbi.0030074', '17465673', '-'),
(83634, 2007, 'plos', 'Coping with viral diversity in HIV vaccine design', 'Nickle, David C|Rolland, Morgane|Jensen, Mark A|Pond, Sergei L Kosakovsky|Deng, Wenjie|Seligman, Mark|Heckerman, David|Mullins, James I|Jojic, Nebojsa', 'Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.|Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 77, 'AIDS Vaccines|Antigenic Variation|Drug Design|Epitope Mapping|Gene Products, nef|Genetic Variation|nef Gene Products, Human Immunodeficiency Virus', 'Journal Article', '10.1371/journal.pcbi.0030075', '17465674', 'The ability of human immunodeficiency virus type 1 (HIV-1) to develop high levels of genetic diversity, and thereby acquire mutations to escape immune pressures, contributes to the difficulties in producing a vaccine. Possibly no single HIV-1 sequence can induce sufficiently broad immunity to protect against a wide variety of infectious strains, or block mutational escape pathways available to the virus after infection. The authors describe the generation of HIV-1 immunogens that minimizes the phylogenetic distance of viral strains throughout the known viral population (the center of tree [COT]) and then extend the COT immunogen by addition of a composite sequence that includes high-frequency variable sites preserved in their native contexts. The resulting COT(+) antigens compress the variation found in many independent HIV-1 isolates into lengths suitable for vaccine immunogens. It is possible to capture 62% of the variation found in the Nef protein and 82% of the variation in the Gag protein into immunogens of three gene lengths. The authors put forward immunogen designs that maximize representation of the diverse antigenic features present in a spectrum of HIV-1 strains. These immunogens should elicit immune responses against high-frequency viral strains as well as against most mutant forms of the virus.'),
(83635, 2007, 'plos', 'Patterns of mesenchymal condensation in a multiscale, discrete stochastic model', 'Christley, Scott|Alber, Mark S|Newman, Stuart A', 'Department of Computer Science, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Computer Science, University of Notre Dame, Notre Dame, Indiana, United States of America.|Department of Computer Science, University of Notre Dame, Notre Dame, Indiana, United States of America.', 'India|India|India', 0, 'Animals|Body Patterning|Cartilage|Cell Differentiation|Chondrocytes|Chondrogenesis|Computer Simulation|Extracellular Matrix|Humans|Mesenchymal Stem Cells|Models, Biological|Models, Statistical|Morphogenesis|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0030076', '17465675', 'Cells of the embryonic vertebrate limb in high-density culture undergo chondrogenic pattern formation, which results in the production of regularly spaced islands of cartilage similar to the cartilage primordia of the developing limb skeleton. The first step in this process, in vitro and in vivo, is the generation of cell condensations, in which the precartilage cells become more tightly packed at the sites at which cartilage will form. In this paper we describe a discrete, stochastic model for the behavior of limb bud precartilage mesenchymal cells in vitro. The model uses a biologically motivated reaction-diffusion process and cell-matrix adhesion (haptotaxis) as the bases of chondrogenic pattern formation, whereby the biochemically distinct condensing cells, as well as the size, number, and arrangement of the multicellular condensations, are generated in a self-organizing fashion. Improving on an earlier lattice-gas representation of the same process, it is multiscale (i.e., cell and molecular dynamics occur on distinct scales), and the cells are represented as spatially extended objects that can change their shape. The authors calibrate the model using experimental data and study sensitivity to changes in key parameters. The simulations have disclosed two distinct dynamic regimes for pattern self-organization involving transient or stationary inductive patterns of morphogens. The authors discuss these modes of pattern formation in relation to available experimental evidence for the in vitro system, as well as their implications for understanding limb skeletal patterning during embryonic development.'),
(83636, 2007, 'plos', 'Fundamental limits to position determination by concentration gradients', 'Tostevin, Filipe|ten Wolde, Pieter Rein|Howard, Martin', 'Department of Mathematics, Imperial College London, London, United Kingdom.|Department of Mathematics, Imperial College London, London, United Kingdom.|Department of Mathematics, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom', 88, 'Cell Physiological Phenomena|Computer Simulation|Models, Biological|Protein Transport|Proteins|Tissue Distribution', 'Journal Article', '10.1371/journal.pcbi.0030078', '17465676', 'Position determination in biological systems is often achieved through protein concentration gradients. Measuring the local concentration of such a protein with a spatially varying distribution allows the measurement of position within the system. For these systems to work effectively, position determination must be robust to noise. Here, we calculate fundamental limits to the precision of position determination by concentration gradients due to unavoidable biochemical noise perturbing the gradients. We focus on gradient proteins with first-order reaction kinetics. Systems of this type have been experimentally characterised in both developmental and cell biology settings. For a single gradient we show that, through time-averaging, great precision potentially can be achieved even with very low protein copy numbers. As a second example, we investigate the ability of a system with oppositely directed gradients to find its centre. With this mechanism, positional precision close to the centre improves more slowly with increasing averaging time, and so longer averaging times or higher copy numbers are required for high precision. For both single and double gradients, we demonstrate the existence of optimal length scales for the gradients for which precision is maximized, as well as analyze how precision depends on the size of the concentration-measuring apparatus. These results provide fundamental constraints on the positional precision supplied by concentration gradients in various contexts, including both in developmental biology and also within a single cell.'),
(83637, 2007, 'plos', 'RNAi development', 'Gerstein, Mark|Douglas, Shawn M', 'Department of Mathematics, Imperial College London, London, United Kingdom.|Department of Mathematics, Imperial College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 4, 'Periodicals as Topic|RNA Interference|Research|Science', 'Letter', '10.1371/journal.pcbi.0030080', '17465677', '-'),
(83638, 2007, 'plos', 'Stochastic simulations on the reliability of action potential propagation in thin axons', 'Faisal, A Aldo|Laughlin, Simon B', 'Department of Zoology, Cambridge University, Cambridge, United Kingdom. a.faisal@zoo.cam.ac.uk|Department of Zoology, Cambridge University, Cambridge, United Kingdom. a.faisal@zoo.cam.ac.uk', 'United Kingdom|United Kingdom', 0, 'Action Potentials|Animals|Axons|Computer Simulation|Data Interpretation, Statistical|Decapodiformes|Ion Channel Gating|Membrane Potentials|Mice|Models, Neurological|Models, Statistical|Neural Conduction|Rats|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0030079', '17480115', 'It is generally assumed that axons use action potentials (APs) to transmit information fast and reliably to synapses. Yet, the reliability of transmission along fibers below 0.5 microm diameter, such as cortical and cerebellar axons, is unknown. Using detailed models of rodent cortical and squid axons and stochastic simulations, we show how conduction along such thin axons is affected by the probabilistic nature of voltage-gated ion channels (channel noise). We identify four distinct effects that corrupt propagating spike trains in thin axons: spikes were added, deleted, jittered, or split into groups depending upon the temporal pattern of spikes. Additional APs may appear spontaneously, however, APs in general seldom fail (<1%). Spike timing is jittered on the order of milliseconds over distances of millimeters, as conduction velocity fluctuates in two ways. First, variability in the number of Na channels opening in the early rising phase of the AP cause propagation speed to fluctuate gradually. Second, a novel mode of AP propagation (stochastic microsaltatory conduction), where the AP leaps ahead toward spontaneously formed clusters of open Na channels, produces random discrete jumps in spike time reliability. The combined effect of these two mechanisms depends on the pattern of spikes. Our results show that axonal variability is a general problem and should be taken into account when considering both neural coding and the reliability of synaptic transmission in densely connected cortical networks, where small synapses are typically innervated by thin axons. In contrast we find that thicker axons above 0.5 microm diameter are reliable.'),
(83639, 2007, 'plos', 'Cooperative gating and spatial organization of membrane proteins through elastic interactions', 'Ursell, Tristan|Huang, Kerwyn Casey|Peterson, Eric|Phillips, Rob', 'Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.|Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.|Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.|Department of Applied Physics, California Institute of Technology, Pasadena, California, United States of America.', 'United States|United States|United States|United States', 84, 'Cell Membrane|Computer Simulation|Dimerization|Elasticity|Escherichia coli Proteins|Ion Channels|Lipid Bilayers|Membrane Proteins|Models, Chemical|Models, Molecular|Protein Conformation', 'Journal Article', '10.1371/journal.pcbi.0030081', '17480116', 'Biological membranes are elastic media in which the presence of a transmembrane protein leads to local bilayer deformation. The energetics of deformation allow two membrane proteins in close proximity to influence each others equilibrium conformation via their local deformations, and spatially organize the proteins based on their geometry. We use the mechanosensitive channel of large conductance (MscL) as a case study to examine the implications of bilayer-mediated elastic interactions on protein conformational statistics and clustering. The deformations around MscL cost energy on the order of 10 kBT and extend approximately 3 nm from the protein edge, as such elastic forces induce cooperative gating, and we propose experiments to measure these effects. Additionally, since elastic interactions are coupled to protein conformation, we find that conformational changes can severely alter the average separation between two proteins. This has important implications for how conformational changes organize membrane proteins into functional groups within membranes.'),
(83640, 2007, 'plos', 'Can influenza epidemics be prevented by voluntary vaccination?', 'Vardavas, Raffaele|Breban, Romulus|Blower, Sally', 'Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, United States of America.|Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, United States of America.|Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, United States of America.', 'United States|United States|United States', 99, 'Computer Simulation|Disease Outbreaks|Humans|Incidence|Influenza Vaccines|Influenza, Human|Models, Biological|Patient Compliance|Population Dynamics|Risk Assessment|Risk Factors|Treatment Outcome|Vaccination', 'Journal Article', '10.1371/journal.pcbi.0030085', '17480117', 'Previous modeling studies have identified the vaccination coverage level necessary for preventing influenza epidemics, but have not shown whether this critical coverage can be reached. Here we use computational modeling to determine, for the first time, whether the critical coverage for influenza can be achieved by voluntary vaccination. We construct a novel individual-level model of human cognition and behavior, individuals are characterized by two biological attributes (memory and adaptability) that they use when making vaccination decisions. We couple this model with a population-level model of influenza that includes vaccination dynamics. The coupled models allow individual-level decisions to influence influenza epidemiology and, conversely, influenza epidemiology to influence individual-level decisions. By including the effects of adaptive decision-making within an epidemic model, we can reproduce two essential characteristics of influenza epidemiology: annual variation in epidemic severity and sporadic occurrence of severe epidemics. We suggest that individual-level adaptive decision-making may be an important (previously overlooked) causal factor in driving influenza epidemiology. We find that severe epidemics cannot be prevented unless vaccination programs offer incentives. Frequency of severe epidemics could be reduced if programs provide, as an incentive to be vaccinated, several years of free vaccines to individuals who pay for one year of vaccination. Magnitude of epidemic amelioration will be determined by the number of years of free vaccination, an individuals adaptability in decision-making, and their memory. This type of incentive program could control epidemics if individuals are very adaptable and have long-term memories. However, incentive-based programs that provide free vaccination for families could increase the frequency of severe epidemics. We conclude that incentive-based vaccination programs are necessary to control influenza, but some may be detrimental. Surprisingly, we find that individuals memories and flexibility in adaptive decision-making can be extremely important factors in determining the success of influenza vaccination programs. Finally, we discuss the implication of our results for controlling pandemics.'),
(83641, 2007, 'plos', 'Integrated mechanisms of anticipation and rate-of-change computations in cortical circuits', 'Puccini, Gabriel D|Sanchez-Vives, Maria V|Compte, Albert', 'Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Sant Joan dAlacant, Spain.|Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Sant Joan dAlacant, Spain.|Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Sant Joan dAlacant, Spain.', 'Spain|Spain|Spain', 28, 'Action Potentials|Attention|Evoked Potentials, Visual|Humans|Models, Neurological|Motion Perception|Nerve Net|Neuronal Plasticity|Neurons, Afferent|Systems Integration|Visual Cortex', 'Journal Article', '10.1371/journal.pcbi.0030082', '17500584', 'Local neocortical circuits are characterized by stereotypical physiological and structural features that subserve generic computational operations. These basic computations of the cortical microcircuit emerge through the interplay of neuronal connectivity, cellular intrinsic properties, and synaptic plasticity dynamics. How these interacting mechanisms generate specific computational operations in the cortical circuit remains largely unknown. Here, we identify the neurophysiological basis of both the rate of change and anticipation computations on synaptic inputs in a cortical circuit. Through biophysically realistic computer simulations and neuronal recordings, we show that the rate-of-change computation is operated robustly in cortical networks through the combination of two ubiquitous brain mechanisms: short-term synaptic depression and spike-frequency adaptation. We then show how this rate-of-change circuit can be embedded in a convergently connected network to anticipate temporally incoming synaptic inputs, in quantitative agreement with experimental findings on anticipatory responses to moving stimuli in the primary visual cortex. Given the robustness of the mechanism and the widespread nature of the physiological machinery involved, we suggest that rate-of-change computation and temporal anticipation are principal, hard-wired functions of neural information processing in the cortical microcircuit.'),
(83642, 2007, 'plos', 'Enhancer responses to similarly distributed antagonistic gradients in development', 'Zinzen, Robert P|Papatsenko, Dmitri', 'Department of Molecular and Cell Biology, Center for Integrative Genomics, University of California, Berkeley, California, United States of America.|Department of Molecular and Cell Biology, Center for Integrative Genomics, University of California, Berkeley, California, United States of America.', 'United States|United States', 28, 'Adaptation, Physiological|Animals|Body Patterning|Computer Simulation|Drosophila|Drosophila Proteins|Gene Expression Regulation, Developmental|Models, Biological|Regulatory Sequences, Nucleic Acid|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030084', '17500585', 'Formation of spatial gene expression patterns in development depends on transcriptional responses mediated by gene control regions, enhancers. Here, we explore possible responses of enhancers to overlapping gradients of antagonistic transcriptional regulators in the Drosophila embryo. Using quantitative models based on enhancer structure, we demonstrate how a pair of antagonistic transcription factor gradients with similar or even identical spatial distributions can lead to the formation of distinct gene expression domains along the embryo axes. The described mechanisms are sufficient to explain the formation of the anterior and the posterior knirps expression, the posterior hunchback expression domain, and the lateral stripes of rhomboid expression and of other ventral neurogenic ectodermal genes. The considered principles of interaction between antagonistic gradients at the enhancer level can also be applied to diverse developmental processes, such as domain specification in imaginal discs, or even eyespot pattern formation in the butterfly wing.'),
(83643, 2007, 'plos', 'HIV-1 subtype B protease and reverse transcriptase amino acid covariation', 'Rhee, Soo-Yon|Liu, Tommy F|Holmes, Susan P|Shafer, Robert W', 'Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, United States of America.|Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, United States of America.|Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, United States of America.|Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, United States of America.', 'United States|United States|United States|United States', 64, 'Amino Acid Substitution|Chromosome Mapping|Genetic Variation|HIV Protease|HIV Reverse Transcriptase|HIV-1|Linkage Disequilibrium', 'Journal Article', '10.1371/journal.pcbi.0030087', '17500586', 'Despite the high degree of HIV-1 protease and reverse transcriptase (RT) mutation in the setting of antiretroviral therapy, the spectrum of possible virus variants appears to be limited by patterns of amino acid covariation. We analyzed patterns of amino acid covariation in protease and RT sequences from more than 7,000 persons infected with HIV-1 subtype B viruses obtained from the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu). In addition, we examined the relationship between conditional probabilities associated with a pair of mutations and the order in which those mutations developed in viruses for which longitudinal sequence data were available. Patterns of RT covariation were dominated by the distinct clustering of Type I and Type II thymidine analog mutations and the Q151M-associated mutations. Patterns of protease covariation were dominated by the clustering of nelfinavir-associated mutations (D30N and N88D), two main groups of protease inhibitor (PI)-resistance mutations associated either with V82A or L90M, and a tight cluster of mutations associated with decreased susceptibility to amprenavir and the most recently approved PI darunavir. Different patterns of covariation were frequently observed for different mutations at the same position including the RT mutations T69D versus T69N, L74V versus L74I, V75I versus V75M, T215F versus T215Y, and K219Q/E versus K219N/R, and the protease mutations M46I versus M46L, I54V versus I54M/L, and N88D versus N88S. Sequence data from persons with correlated mutations in whom earlier sequences were available confirmed that the conditional probabilities associated with correlated mutation pairs could be used to predict the order in which the mutations were likely to have developed. Whereas accessory nucleoside RT inhibitor-resistance mutations nearly always follow primary nucleoside RT inhibitor-resistance mutations, accessory PI-resistance mutations often preceded primary PI-resistance mutations.'),
(83644, 2007, 'plos', 'Binding site graphs: a new graph theoretical framework for prediction of transcription factor binding sites', 'Reddy, Timothy E|DeLisi, Charles|Shakhnovich, Boris E', 'Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.|Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.', 'United States|United States|United States', 13, 'Algorithms|Base Sequence|Binding Sites|Computer Simulation|Models, Chemical|Models, Genetic|Molecular Sequence Data|Promoter Regions, Genetic|Protein Binding|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030090', '17500587', 'Computational prediction of nucleotide binding specificity for transcription factors remains a fundamental and largely unsolved problem. Determination of binding positions is a prerequisite for research in gene regulation, a major mechanism controlling phenotypic diversity. Furthermore, an accurate determination of binding specificities from high-throughput data sources is necessary to realize the full potential of systems biology. Unfortunately, recently performed independent evaluation showed that more than half the predictions from most widely used algorithms are false. We introduce a graph-theoretical framework to describe local sequence similarity as the pair-wise distances between nucleotides in promoter sequences, and hypothesize that densely connected subgraphs are indicative of transcription factor binding sites. Using a well-established sampling algorithm coupled with simple clustering and scoring schemes, we identify sets of closely related nucleotides and test those for known TF binding activity. Using an independent benchmark, we find our algorithm predicts yeast binding motifs considerably better than currently available techniques and without manual curation. Importantly, we reduce the number of false positive predictions in yeast to less than 30%. We also develop a framework to evaluate the statistical significance of our motif predictions. We show that our approach is robust to the choice of input promoters, and thus can be used in the context of predicting binding positions from noisy experimental data. We apply our method to identify binding sites using data from genome scale ChIP-chip experiments. Results from these experiments are publicly available at http://cagt10.bu.edu/BSG. The graphical framework developed here may be useful when combining predictions from numerous computational and experimental measures. Finally, we discuss how our algorithm can be used to improve the sensitivity of computational predictions of transcription factor binding specificities.'),
(83645, 2007, 'plos', 'Ten simple rules for making good oral presentations', 'Bourne, Philip E', 'Program in Bioinformatics and Systems Biology, Boston University, Boston, Massachusetts, United States of America.', 'United States', 26, 'Algorithms|Communication|Guidelines as Topic|Motivation|Teaching', 'Editorial', '10.1371/journal.pcbi.0030077', '17500596', '-'),
(83646, 2007, 'plos', 'A first look at ARFome: dual-coding genes in mammalian genomes', 'Chung, Wen-Yu|Wadhawan, Samir|Szklarczyk, Radek|Pond, Sergei Kosakovsky|Nekrutenko, Anton', 'Center for Comparative Genomics and Bioinformatics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Comparative Genomics and Bioinformatics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Comparative Genomics and Bioinformatics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Comparative Genomics and Bioinformatics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Center for Comparative Genomics and Bioinformatics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 45, 'Animals|Base Sequence|Chromosome Mapping|Computer Simulation|Humans|Mammals|Models, Genetic|Molecular Sequence Data|Multigene Family|Open Reading Frames|RNA Splice Sites|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030091', '17511511', 'Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology.'),
(83647, 2007, 'plos', 'Predictive modeling of signaling crosstalk during C elegans vulval development', 'Fisher, Jasmin|Piterman, Nir|Hajnal, Alex|Henzinger, Thomas A', 'School of Computer and Communication Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. jasmin.fisher@epfl.ch|School of Computer and Communication Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. jasmin.fisher@epfl.ch|School of Computer and Communication Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. jasmin.fisher@epfl.ch|School of Computer and Communication Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. jasmin.fisher@epfl.ch', 'Switzerland|Switzerland|Switzerland|Switzerland', 76, 'Animals|Body Patterning|Caenorhabditis elegans|Caenorhabditis elegans Proteins|Computer Simulation|Female|Gene Expression Regulation, Developmental|Models, Biological|Signal Transduction|Vulva', 'Journal Article', '10.1371/journal.pcbi.0030092', '17511512', 'Caenorhabditis elegans vulval development provides an important paradigm for studying the process of cell fate determination and pattern formation during animal development. Although many genes controlling vulval cell fate specification have been identified, how they orchestrate themselves to generate a robust and invariant pattern of cell fates is not yet completely understood. Here, we have developed a dynamic computational model incorporating the current mechanistic understanding of gene interactions during this patterning process. A key feature of our model is the inclusion of multiple modes of crosstalk between the epidermal growth factor receptor (EGFR) and LIN-12/Notch signaling pathways, which together determine the fates of the six vulval precursor cells (VPCs). Computational analysis, using the model-checking technique, provides new biological insights into the regulatory network governing VPC fate specification and predicts novel negative feedback loops. In addition, our analysis shows that most mutations affecting vulval development lead to stable fate patterns in spite of variations in synchronicity between VPCs. Computational searches for the basis of this robustness show that a sequential activation of the EGFR-mediated inductive signaling and LIN-12 / Notch-mediated lateral signaling pathways is key to achieve a stable cell fate pattern. We demonstrate experimentally a time-delay between the activation of the inductive and lateral signaling pathways in wild-type animals and the loss of sequential signaling in mutants showing unstable fate patterns, thus, validating two key predictions provided by our modeling work. The insights gained by our modeling study further substantiate the usefulness of executing and analyzing mechanistic models to investigate complex biological behaviors.'),
(83648, 2007, 'plos', 'The human genomic melting map', 'Liu, Fang|Tøstesen, Eivind|Sundet, Jostein K|Jenssen, Tor-Kristian|Bock, Christoph|Jerstad, Geir Ivar|Thilly, William G|Hovig, Eivind', 'Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.|Department of Tumor Biology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.', 'Norway|Norway|Norway|Norway|Norway|Norway|Norway|Norway', 35, 'Base Composition|Base Sequence|Computer Simulation|DNA|Models, Chemical|Models, Molecular|Molecular Sequence Data|Nucleic Acid Conformation|Nucleic Acid Denaturation|Sequence Analysis, DNA|Structure-Activity Relationship|Temperature', 'Journal Article', '10.1371/journal.pcbi.0030093', '17511513', 'In a living cell, the antiparallel double-stranded helix of DNA is a dynamically changing structure. The structure relates to interactions between and within the DNA strands, and the array of other macromolecules that constitutes functional chromatin. It is only through its changing conformations that DNA can organize and structure a large number of cellular functions. In particular, DNA must locally uncoil, or melt, and become single-stranded for DNA replication, repair, recombination, and transcription to occur. It has previously been shown that this melting occurs cooperatively, whereby several base pairs act in concert to generate melting bubbles, and in this way constitute a domain that behaves as a unit with respect to local DNA single-strandedness. We have applied a melting map calculation to the complete human genome, which provides information about the propensities of forming local bubbles determined from the whole sequence, and present a first report on its basic features, the extent of cooperativity, and correlations to various physical and biological features of the human genome. Globally, the melting map covaries very strongly with GC content. Most importantly, however, cooperativity of DNA denaturation causes this correlation to be weaker at resolutions fewer than 500 bps. This is also the resolution level at which most structural and biological processes occur, signifying the importance of the informational content inherent in the genomic melting map. The human DNA melting map may be further explored at http://meltmap.uio.no.'),
(83649, 2007, 'plos', 'Comprehensive DNA signature discovery and validation', 'Phillippy, Adam M|Mason, Jacquline A|Ayanbule, Kunmi|Sommer, Daniel D|Taviani, Elisa|Huq, Anwar|Colwell, Rita R|Knight, Ivor T|Salzberg, Steven L', 'Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 48, 'Algorithms|Chromosome Mapping|DNA Fingerprinting|Genome, Bacterial|Genome, Viral|Sequence Alignment|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid|Software|Software Validation|User-Computer Interface', 'Evaluation Studies', '10.1371/journal.pcbi.0030098', '17511514', 'DNA signatures are nucleotide sequences that can be used to detect the presence of an organism and to distinguish that organism from all other species. Here we describe Insignia, a new, comprehensive system for the rapid identification of signatures in the genomes of bacteria and viruses. With the availability of hundreds of complete bacterial and viral genome sequences, it is now possible to use computational methods to identify signature sequences in all of these species, and to use these signatures as the basis for diagnostic assays to detect and genotype microbes in both environmental and clinical samples. The success of such assays critically depends on the methods used to identify signatures that properly differentiate between the target genomes and the sample background. We have used Insignia to compute accurate signatures for most bacterial genomes and made them available through our Web site. A sample of these signatures has been successfully tested on a set of 46 Vibrio cholerae strains, and the results indicate that the signatures are highly sensitive for detection as well as specific for discrimination between these strains and their near relatives. Our approach, whereby the entire genomic complement of organisms are compared to identify probe targets, is a promising method for diagnostic assay development, and it provides assay designers with the flexibility to choose probes from the most relevant genes or genomic regions. The Insignia system is freely accessible via a Web interface and has been released as open source software at: http://insignia.cbcb.umd.edu.'),
(83650, 2006, 'plos', 'One year of PLoS Computational Biology', '-', '-', '-', 48, 'Computational Biology|Periodicals as Topic', 'Editorial', '10.1371/journal.pcbi.0030098', '17523253', '-'),
(83651, 2007, 'plos', 'Simple rules for editors? Here is one rule to tackle neglected problems of publishing', 'Erren, Thomas C|Erren, Michael', 'Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu|Center for Bioinformatics and Computational Biology, University of Maryland, College Park, Maryland, United States of America. amp@umiacs.umd.edu', 'United States|United States', 0, 'Authorship|Editorial Policies|Publishing|United States|Writing', 'Letter', '10.1371/journal.pcbi.0030088', '17530914', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83652, 2007, 'plos', 'Prediction of functional sites based on the fuzzy oil drop model', 'Brylixc5x84ski, Michaxc5x82|Prymula, Katarzyna|Jurkowski, Wiktor|Kochaxc5x84czyk, Marek|Stawowczyk, Ewa|Konieczny, Leszek|Roterman, Irena', 'Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.|Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.|Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.|Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.|Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.|Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.|Department of Bioinformatics and Telemedicine, Jagiellonian University-Collegium Medicum, Krakxc3xb3w, Poland.', 'Poland|Poland|Poland|Poland|Poland|Poland|Poland', 42, 'Algorithms|Amino Acid Sequence|Binding Sites|Computer Simulation|Fuzzy Logic|Hydrophobic and Hydrophilic Interactions|Models, Chemical|Models, Molecular|Molecular Sequence Data|Oils|Protein Binding|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030094', '17530916', 'A description of many biological processes requires knowledge of the 3-D structure of proteins and, in particular, the defined active site responsible for biological function. Many proteins, the genes of which have been identified as the result of human genome sequencing, and which were synthesized experimentally, await identification of their biological activity. Currently used methods do not always yield satisfactory results, and new algorithms need to be developed to recognize the localization of active sites in proteins. This paper describes a computational model that can be used to identify potential areas that are able to interact with other molecules (ligands, substrates, inhibitors, etc.). The model for active site recognition is based on the analysis of hydrophobicity distribution in protein molecules. It is shown, based on the analyses of proteins with known biological activity and of proteins of unknown function, that the region of significantly irregular hydrophobicity distribution in proteins appears to be function related.'),
(83653, 2007, 'plos', 'The emergence of alternative 3 and 5 splice site exons from constitutive exons', 'Koren, Eli|Lev-Maor, Galit|Ast, Gil', 'Department of Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Human Molecular Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel', 48, '3 Flanking Region|5 Flanking Region|Alternative Splicing|Base Sequence|DNA Mutational Analysis|Evolution, Molecular|Exons|Molecular Sequence Data|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030095', '17530917', 'Alternative 3 and 5 splice site (ss) events constitute a significant part of all alternative splicing events. These events were also found to be related to several aberrant splicing diseases. However, only few of the characteristics that distinguish these events from alternative cassette exons are known currently. In this study, we compared the characteristics of constitutive exons, alternative cassette exons, and alternative 3ss and 5ss exons. The results revealed that alternative 3ss and 5ss exons are an intermediate state between constitutive and alternative cassette exons, where the constitutive side resembles constitutive exons, and the alternative side resembles alternative cassette exons. The results also show that alternative 3ss and 5ss exons exhibit low levels of symmetry (frame-preserving), similar to constitutive exons, whereas the sequence between the two alternative splice sites shows high symmetry levels, similar to alternative cassette exons. In addition, flanking intronic conservation analysis revealed that exons whose alternative splice sites are at least nine nucleotides apart show a high conservation level, indicating intronic participation in the regulation of their splicing, whereas exons whose alternative splice sites are fewer than nine nucleotides apart show a low conservation level. Further examination of these exons, spanning seven vertebrate species, suggests an evolutionary model in which the alternative state is a derivative of an ancestral constitutive exon, where a mutation inside the exon or along the flanking intron resulted in the creation of a new splice site that competes with the original one, leading to alternative splice site selection. This model was validated experimentally on four exons, showing that they indeed originated from constitutive exons that acquired a new competing splice site during evolution.'),
(83654, 2007, 'plos', 'Bang-bang control of feeding: role of hypothalamic and satiety signals', 'Zanutto, B Silvano|Staddon, John E R', 'Instituto de Ingeniería Biomédica-Universidad de Buenos Aires, Buenos Aires, Argentina. silvano@fi.uba.ar|Instituto de Ingeniería Biomédica-Universidad de Buenos Aires, Buenos Aires, Argentina. silvano@fi.uba.ar', 'Argentina|Argentina', 10, 'Animals|Appetite|Computer Simulation|Feedback|Feeding Behavior|Hypothalamus|Models, Biological|Neural Inhibition|Rats|Satiety Response', 'Journal Article', '10.1371/journal.pcbi.0030097', '17530919', 'Rats, people, and many other omnivores eat in meals rather than continuously. We show by experimental test that eating in meals is regulated by a simple bang-bang control system, an idea foreshadowed by Le Magnen and many others, shown by us to account for a wide range of behavioral data, but never explicitly tested or tied to neurophysiological facts. The hypothesis is simply that the tendency to eat rises with time at a rate determined by satiety signals. When these signals fall below a set point, eating begins, in on-off fashion. The delayed sequelae of eating increment the satiety signals, which eventually turn eating off. Thus, under free conditions, the organism eats in bouts separated by noneating activities. We report an experiment with rats to test novel predictions about meal patterns that are not explained by existing homeostatic approaches. Access to food was systematically but unpredictably interrupted just as the animal tried to start a new meal. A simple bang-bang model fits the resulting meal-pattern data well, and its elements can be identified with neurophysiological processes. Hypothalamic inputs can provide the set point for longer-term regulation carried out by a comparator in the hindbrain. Delayed gustatory and gastrointestinal aftereffects of eating act via the nucleus of the solitary tract and other hindbrain regions as neural feedback governing short-term regulation. In this way, the model forges real links between a functioning feedback mechanism, neuro-hormonal data, and both short-term (meals) and long-term (eating-rate regulation) behavioral data.'),
(83655, 2007, 'plos', 'Frequent gain and loss of functional transcription factor binding sites', 'Doniger, Scott W|Fay, Justin C', 'Computational Biology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Computational Biology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America.', 'United States|United States', 114, 'Base Sequence|Binding Sites|Evolution, Molecular|Gene Frequency|Genetic Variation|Molecular Sequence Data|Protein Binding|Regulatory Sequences, Nucleic Acid|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Sequence Analysis, DNA|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030099', '17530920', 'Cis-regulatory sequences are not always conserved across species. Divergence within cis-regulatory sequences may result from the evolution of species-specific patterns of gene expression or the flexible nature of the cis-regulatory code. The identification of functional divergence in cis-regulatory sequences is therefore important for both understanding the role of gene regulation in evolution and annotating regulatory elements. We have developed an evolutionary model to detect the loss of constraint on individual transcription factor binding sites (TFBSs). We find that a significant fraction of functionally constrained binding sites have been lost in a lineage-specific manner among three closely related yeast species. Binding site loss has previously been explained by turnover, where the concurrent gain and loss of a binding site maintains gene regulation. We estimate that nearly half of all loss events cannot be explained by binding site turnover. Recreating the mutations that led to binding site loss confirms that these sequence changes affect gene expression in some cases. We also estimate that there is a high rate of binding site gain, as more than half of experimentally identified S. cerevisiae binding sites are not conserved across species. The frequent gain and loss of TFBSs implies that cis-regulatory sequences are labile and, in the absence of turnover, may contribute to species-specific patterns of gene expression.'),
(83656, 2007, 'plos', 'Ten simple rules for a good poster presentation', 'Erren, Thomas C|Bourne, Philip E', 'Computational Biology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Computational Biology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America.', 'United States|United States', 37, 'Algorithms|Audiovisual Aids|Biomedical Research|Communication|Congresses as Topic|Exhibits as Topic|Information Dissemination|Professional Competence', 'Editorial', '10.1371/journal.pcbi.0030102', '17530921', '-'),
(83657, 2007, 'plos', 'Hierarchical processing of auditory objects in humans', 'Kumar, Sukhbinder|Stephan, Klaas E|Warren, Jason D|Friston, Karl J|Griffiths, Timothy D', 'Auditory Group, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.|Auditory Group, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.|Auditory Group, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.|Auditory Group, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.|Auditory Group, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Acoustic Stimulation|Afferent Pathways|Auditory Cortex|Auditory Perception|Computer Simulation|Evoked Potentials, Auditory|Humans|Models, Neurological|Nerve Net', 'Journal Article', '10.1371/journal.pcbi.0030100', '17542641', 'This work examines the computational architecture used by the brain during the analysis of the spectral envelope of sounds, an important acoustic feature for defining auditory objects. Dynamic causal modelling and Bayesian model selection were used to evaluate a family of 16 network models explaining functional magnetic resonance imaging responses in the right temporal lobe during spectral envelope analysis. The models encode different hypotheses about the effective connectivity between Heschls Gyrus (HG), containing the primary auditory cortex, planum temporale (PT), and superior temporal sulcus (STS), and the modulation of that coupling during spectral envelope analysis. In particular, we aimed to determine whether information processing during spectral envelope analysis takes place in a serial or parallel fashion. The analysis provides strong support for a serial architecture with connections from HG to PT and from PT to STS and an increase of the HG to PT connection during spectral envelope analysis. The work supports a computational model of auditory object processing, based on the abstraction of spectro-temporal templates in the PT before further analysis of the abstracted form in anterior temporal lobe areas.'),
(83658, 2007, 'plos', 'Cell surface receptors for signal transduction and ligand transport: a design principles study', 'Shankaran, Harish|Resat, Haluk|Wiley, H Steven', 'Systems Biology Program, Pacific Northwest National Laboratory, Richland, Washington, United States of America.|Systems Biology Program, Pacific Northwest National Laboratory, Richland, Washington, United States of America.|Systems Biology Program, Pacific Northwest National Laboratory, Richland, Washington, United States of America.', 'United States|United States|United States', 65, 'Amino Acid Sequence|Biological Transport, Active|Computer Simulation|Gene Expression Regulation|Ligands|Models, Biological|Molecular Sequence Data|Receptors, Cell Surface|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030101', '17542642', 'Receptors constitute the interface of cells to their external environment. These molecules bind specific ligands involved in multiple processes, such as signal transduction and nutrient transport. Although a variety of cell surface receptors undergo endocytosis, the systems-level design principles that govern the evolution of receptor trafficking dynamics are far from fully understood. We have constructed a generalized mathematical model of receptor-ligand binding and internalization to understand how receptor internalization dynamics encodes receptor function and regulation. A given signaling or transport receptor system represents a particular implementation of this module with a specific set of kinetic parameters. Parametric analysis of the response of receptor systems to ligand inputs reveals that receptor systems can be characterized as being: i) avidity-controlled where the response control depends primarily on the extracellular ligand capture efficiency, ii) consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii) dual-sensitivity where both the avidity and consumption parameters are important. We show that the transferrin and low-density lipoprotein receptors are avidity-controlled, the vitellogenin receptor is consumption-controlled, and the epidermal growth factor receptor is a dual-sensitivity receptor. Significantly, we show that ligand-induced endocytosis is a mechanism to enhance the accuracy of signaling receptors rather than merely serving to attenuate signaling. Our analysis reveals that the location of a receptor system in the avidity-consumption parameter space can be used to understand both its function and its regulation.'),
(83659, 2007, 'plos', 'Bottleneck genes and community structure in the cell cycle network of S pombe', 'Caretta-Cartozo, Cécile|De Los Rios, Paolo|Piazza, Francesco|Liò, Pietro', 'Laboratoire de Biophysique Statistique, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. cecile.carettacartozo@epfl.ch|Laboratoire de Biophysique Statistique, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. cecile.carettacartozo@epfl.ch|Laboratoire de Biophysique Statistique, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. cecile.carettacartozo@epfl.ch|Laboratoire de Biophysique Statistique, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. cecile.carettacartozo@epfl.ch', 'Switzerland|Switzerland|Switzerland|Switzerland', 22, 'Cell Cycle|Cell Cycle Proteins|Computer Simulation|Fungal Proteins|Gene Expression Profiling|Models, Biological|Multigene Family|Schizosaccharomyces|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030103', '17542643', 'The identification of cell cycle-related genes is still a difficult task, even for organisms with relatively few genes such as the fission yeast. Several gene expression studies have been published on S. pombe showing similarities but also discrepancies in their results. We introduce a network in which the weight of each link is a function of the phase difference between the expression peaks of two genes. The analysis of the stability of the clustering through the computation of an entropy parameter reveals a structure made of four clusters, the first one corresponding to a robustly connected M-G1 component, the second to genes in the S phase, and the third and fourth to two G2 components. They are separated by bottleneck structures that appear to correspond to cell cycle checkpoints. We identify a number of genes that are located on these bottlenecks. They represent a novel group of cell cycle regulatory genes. They all show interesting functions, and they are supposed to be involved in the regulation of the transition from one phase to the next. We therefore present a comparison of the available studies on the fission yeast cell cycle and a general statistical bioinformatics methodology to find bottlenecks and gene community structures based on recent developments in network theory.'),
(83660, 2007, 'plos', 'In search of the biological significance of modular structures in protein networks', 'Wang, Zhi|Zhang, Jianzhi', 'Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America.', 'United States|United States', 0, 'Algorithms|Computer Simulation|Models, Biological|Protein Interaction Mapping|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030107', '17542644', 'Many complex networks such as computer and social networks exhibit modular structures, where links between nodes are much denser within modules than between modules. It is widely believed that cellular networks are also modular, reflecting the relative independence and coherence of different functional units in a cell. While many authors have claimed that observations from the yeast protein-protein interaction (PPI) network support the above hypothesis, the observed structural modularity may be an artifact because the current PPI data include interactions inferred from protein complexes through approaches that create modules (e.g., assigning pairwise interactions among all proteins in a complex). Here we analyze the yeast PPI network including protein complexes (PIC network) and excluding complexes (PEC network). We find that both PIC and PEC networks show a significantly greater structural modularity than that of randomly rewired networks. Nonetheless, there is little evidence that the structural modules correspond to functional units, particularly in the PEC network. More disturbingly, there is no evolutionary conservation among yeast, fly, and nematode modules at either the whole-module or protein-pair level. Neither is there a correlation between the evolutionary or phylogenetic conservation of a protein and the extent of its participation in various modules. Using computer simulation, we demonstrate that a higher-than-expected modularity can arise during network growth through a simple model of gene duplication, without natural selection for modularity. Taken together, our results suggest the intriguing possibility that the structural modules in the PPI network originated as an evolutionary byproduct without biological significance.'),
(83661, 2007, 'plos', 'A survey of genomic properties for the detection of regulatory polymorphisms', 'Montgomery, Stephen B|Griffith, Obi L|Schuetz, Johanna M|Brooks-Wilson, Angela|Jones, Steven J M', 'Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sm8@sanger.ac.uk|Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sm8@sanger.ac.uk|Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sm8@sanger.ac.uk|Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sm8@sanger.ac.uk|Canadas Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sm8@sanger.ac.uk', 'Canada|Canada|Canada|Canada|Canada', 0, 'Base Sequence|Chromosome Mapping|DNA Mutational Analysis|Databases, Genetic|Molecular Sequence Data|Polymorphism, Single Nucleotide|Regulatory Sequences, Nucleic Acid|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030106', '17559298', 'Advances in the computational identification of functional noncoding polymorphisms will aid in cataloging novel determinants of health and identifying genetic variants that explain human evolution. To date, however, the development and evaluation of such techniques has been limited by the availability of known regulatory polymorphisms. We have attempted to address this by assembling, from the literature, a computationally tractable set of regulatory polymorphisms within the ORegAnno database (http://www.oreganno.org). We have further used 104 regulatory single-nucleotide polymorphisms from this set and 951 polymorphisms of unknown function, from 2-kb and 152-bp noncoding upstream regions of genes, to investigate the discriminatory potential of 23 properties related to gene regulation and population genetics. Among the most important properties detected in this region are distance to transcription start site, local repetitive content, sequence conservation, minor and derived allele frequencies, and presence of a CpG island. We further used the entire set of properties to evaluate their collective performance in detecting regulatory polymorphisms. Using a 10-fold cross-validation approach, we were able to achieve a sensitivity and specificity of 0.82 and 0.71, respectively, and we show that this performance is strongly influenced by the distance to the transcription start site.'),
(83662, 2007, 'plos', 'A mass conserved reaction-diffusion system captures properties of cell polarity', 'Otsuji, Mikiya|Ishihara, Shuji|Co, Carl|Kaibuchi, Kozo|Mochizuki, Atsushi|Kuroda, Shinya', 'Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. mohtsuji-tky@umin.ac.jp|Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. mohtsuji-tky@umin.ac.jp|Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. mohtsuji-tky@umin.ac.jp|Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. mohtsuji-tky@umin.ac.jp|Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. mohtsuji-tky@umin.ac.jp|Department of Anesthesiology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. mohtsuji-tky@umin.ac.jp', 'Japan|Japan|Japan|Japan|Japan|Japan', 97, 'Cell Movement|Cell Polarity|Computer Simulation|Diffusion|Energy Transfer|Models, Biological|rho GTP-Binding Proteins', 'Journal Article', '10.1371/journal.pcbi.0030108', '17559299', 'Cell polarity is a general cellular process that can be seen in various cell types such as migrating neutrophils and Dictyostelium cells. The Rho small GTP(guanosine 5-tri phosphate)ases have been shown to regulate cell polarity, however, its mechanism of emergence has yet to be clarified. We first developed a reaction-diffusion model of the Rho GTPases, which exhibits switch-like reversible response to a gradient of extracellular signals, exclusive accumulation of Cdc42 and Rac, or RhoA at the maximal or minimal intensity of the signal, respectively, and tracking of changes of a signal gradient by the polarized peak. The previous cell polarity models proposed by Subramanian and Narang show similar behaviors to our Rho GTPase model, despite the difference in molecular networks. This led us to compare these models, and we found that these models commonly share instability and a mass conservation of components. Based on these common properties, we developed conceptual models of a mass conserved reaction-diffusion system with diffusion-driven instability. These conceptual models retained similar behaviors of cell polarity in the Rho GTPase model. Using these models, we numerically and analytically found that multiple polarized peaks are unstable, resulting in a single stable peak (uniqueness of axis), and that sensitivity toward changes of a signal gradient is specifically restricted at the polarized peak (localized sensitivity). Although molecular networks may differ from one cell type to another, the behaviors of cell polarity in migrating cells seem similar, suggesting that there should be a fundamental principle. Thus, we propose that a mass conserved reaction-diffusion system with diffusion-driven instability is one of such principles of cell polarity.'),
(83663, 2007, 'plos', 'Modeling systems-level regulation of host immune responses', 'Thakar, Juilee|Pilione, Mylisa|Kirimanjeswara, Girish|Harvill, Eric T|Albert, Réka', 'Department of Physics, Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Physics, Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Physics, Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Physics, Pennsylvania State University, University Park, Pennsylvania, United States of America.|Department of Physics, Pennsylvania State University, University Park, Pennsylvania, United States of America.', 'United States|United States|United States|United States|United States', 0, 'Animals|Bordetella|Bordetella Infections|Computer Simulation|Gene Expression Regulation|Immunity, Innate|Immunologic Factors|Mice|Models, Immunological', 'Journal Article', '10.1371/journal.pcbi.0030109', '17559300', 'Many pathogens are able to manipulate the signaling pathways responsible for the generation of host immune responses. Here we examine and model a respiratory infection system in which disruption of host immune functions or of bacterial factors changes the dynamics of the infection. We synthesize the network of interactions between host immune components and two closely related bacteria in the genus Bordetellae. We incorporate existing experimental information on the timing of immune regulatory events into a discrete dynamic model, and verify the model by comparing the effects of simulated disruptions to the experimental outcome of knockout mutations. Our model indicates that the infection time course of both Bordetellae can be separated into three distinct phases based on the most active immune processes. We compare and discuss the effect of the species-specific virulence factors on disrupting the immune response during their infection of naive, antibody-treated, diseased, or convalescent hosts. Our model offers predictions regarding cytokine regulation, key immune components, and clearance of secondary infections, we experimentally validate two of these predictions. This type of modeling provides new insights into the virulence, pathogenesis, and host adaptation of disease-causing microorganisms and allows systems-level analysis that is not always possible using traditional methods.'),
(83664, 2007, 'plos', 'CpG island mapping by epigenome prediction', 'Bock, Christoph|Walter, Jörn|Paulsen, Martina|Lengauer, Thomas', 'Max-Planck-Institut für Informatik, Saarbrücken, Germany. cbock@mpi-inf.mpg.de|Max-Planck-Institut für Informatik, Saarbrücken, Germany. cbock@mpi-inf.mpg.de|Max-Planck-Institut für Informatik, Saarbrücken, Germany. cbock@mpi-inf.mpg.de|Max-Planck-Institut für Informatik, Saarbrücken, Germany. cbock@mpi-inf.mpg.de', 'Germany|Germany|Germany|Germany', 0, 'Chromosome Mapping|Computer Simulation|CpG Islands|Epigenesis, Genetic|Models, Genetic|Regulatory Sequences, Nucleic Acid|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030110', '17559301', 'CpG islands were originally identified by epigenetic and functional properties, namely, absence of DNA methylation and frequent promoter association. However, this concept was quickly replaced by simple DNA sequence criteria, which allowed for genome-wide annotation of CpG islands in the absence of large-scale epigenetic datasets. Although widely used, the current CpG island criteria incur significant disadvantages: (1) reliance on arbitrary threshold parameters that bear little biological justification, (2) failure to account for widespread heterogeneity among CpG islands, and (3) apparent lack of specificity when applied to the human genome. This study is driven by the idea that a quantitative score of CpG island strength that incorporates epigenetic and functional aspects can help resolve these issues. We construct an epigenome prediction pipeline that links the DNA sequence of CpG islands to their epigenetic states, including DNA methylation, histone modifications, and chromatin accessibility. By training support vector machines on epigenetic data for CpG islands on human Chromosomes 21 and 22, we identify informative DNA attributes that correlate with open versus compact chromatin structures. These DNA attributes are used to predict the epigenetic states of all CpG islands genome-wide. Combining predictions for multiple epigenetic features, we estimate the inherent CpG island strength for each CpG island in the human genome, i.e., its inherent tendency to exhibit an open and transcriptionally competent chromatin structure. We extensively validate our results on independent datasets, showing that the CpG island strength predictions are applicable and informative across different tissues and cell types, and we derive improved maps of predicted bona fide CpG islands. The mapping of CpG islands by epigenome prediction is conceptually superior to identifying CpG islands by widely used sequence criteria since it links CpG island detection to their characteristic epigenetic and functional states. And it is superior to purely experimental epigenome mapping for CpG island detection since it abstracts from specific properties that are limited to a single cell type or tissue. In addition, using computational epigenetics methods we could identify high correlation between the epigenome and characteristics of the DNA sequence, a finding which emphasizes the need for a better understanding of the mechanistic links between genome and epigenome.'),
(83665, 2007, 'plos', 'From morphology to neural information: the electric sense of the skate', 'Camperi, Marcelo|Tricas, Timothy C|Brown, Brandon R', 'Department of Physics, University of San Francisco, San Francisco, California, United States of America. camperi@usfca.edu|Department of Physics, University of San Francisco, San Francisco, California, United States of America. camperi@usfca.edu|Department of Physics, University of San Francisco, San Francisco, California, United States of America. camperi@usfca.edu', 'United States|United States|United States', 0, 'Action Potentials|Animals|Computer Simulation|Electric Organ|Models, Neurological|Nerve Net|Predatory Behavior|Sense Organs|Skates (Fish)', 'Journal Article', '10.1371/journal.pcbi.0030113', '17571918', 'Morphology typically enhances the fidelity of sensory systems. Sharks, skates, and rays have a well-developed electrosense that presents strikingly unique morphologies. Here, we model the dynamics of the peripheral electrosensory system of the skate, a dorsally flattened batoid, moving near an electric dipole source (e.g., a prey organism). We compute the coincident electric signals that develop across an array of the skates electrosensors, using electrodynamics married to precise morphological measurements of sensor location, infrastructure, and vector projection. Our results demonstrate that skate morphology enhances electrosensory information. Not only could the skate locate prey using a simple population vector algorithm, but its morphology also specifically leads to quick shifts in firing rates that are well-suited to the demonstrated bandwidth of the electrosensory system. Finally, we propose electrophysiology trials to test the modeling scheme.'),
(83666, 2007, 'plos', 'Ligand binding and circular permutation modify residue interaction network in DHFR', 'Hu, Zengjian|Bowen, Donnell|Southerland, William M|del Sol, Antonio|Pan, Yongping|Nussinov, Ruth|Ma, Buyong', 'Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.|Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.|Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.|Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.|Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.|Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.|Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 38, 'Amino Acid Sequence|Amino Acid Substitution|Amino Acids|Ligands|Molecular Sequence Data|Protein Binding|Protein Interaction Mapping|Sequence Analysis, Protein|Structure-Activity Relationship|Tetrahydrofolate Dehydrogenase', 'Journal Article', '10.1371/journal.pcbi.0030117', '17571919', 'Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has network-bridging effects on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness.'),
(83667, 2007, 'plos', 'Digital signal processing reveals circadian baseline oscillation in majority of mammalian genes', 'Ptitsyn, Andrey A|Zvonic, Sanjin|Gimble, Jeffrey M', 'Department of Microbiology, Immunology and Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America. Andrey.Ptitsyn@colostate.edu|Department of Microbiology, Immunology and Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America. Andrey.Ptitsyn@colostate.edu|Department of Microbiology, Immunology and Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America. Andrey.Ptitsyn@colostate.edu', 'United States|United States|United States', 0, 'Animals|Biological Clocks|Circadian Rhythm|Computer Simulation|Gene Expression Regulation|Humans|Mammals|Models, Biological|Pattern Recognition, Automated|Proteome|Signal Processing, Computer-Assisted', 'Journal Article', '10.1371/journal.pcbi.0030120', '17571920', 'In mammals, circadian periodicity has been described for gene expression in the hypothalamus and multiple peripheral tissues. It is accepted that 10%-15% of all genes oscillate in a daily rhythm, regulated by an intrinsic molecular clock. Statistical analyses of periodicity are limited by the small size of datasets and high levels of stochastic noise. Here, we propose a new approach applying digital signal processing algorithms separately to each group of genes oscillating in the same phase. Combined with the statistical tests for periodicity, this method identifies circadian baseline oscillation in almost 100% of all expressed genes. Consequently, circadian oscillation in gene expression should be evaluated in any study related to biological pathways. Changes in gene expression caused by mutations or regulation of environmental factors (such as photic stimuli or feeding) should be considered in the context of changes in the amplitude and phase of genetic oscillations.'),
(83668, 2007, 'plos', 'The effect of stochasticity on the lac operon: an evolutionary perspective', 'van Hoek, Milan|Hogeweg, Paulien', 'Theoretical Biology/Bioinformatics Group, Utrecht University, Utrecht, The Netherlands. M.J.A.vanHoek@bio.uu.nl|Theoretical Biology/Bioinformatics Group, Utrecht University, Utrecht, The Netherlands. M.J.A.vanHoek@bio.uu.nl', 'Netherlands|Netherlands', 0, 'Computer Simulation|Escherichia coli|Evolution, Molecular|Gene Expression Regulation, Bacterial|Gene Expression Regulation, Enzymologic|Lac Operon|Models, Genetic|Models, Statistical|Stochastic Processes|beta-Galactosidase', 'Journal Article', '10.1371/journal.pcbi.0030111', '17590077', 'The role of stochasticity on gene expression is widely discussed. Both potential advantages and disadvantages have been revealed. In some systems, noise in gene expression has been quantified, in among others the lac operon of Escherichia coli. Whether stochastic gene expression in this system is detrimental or beneficial for the cells is, however, still unclear. We are interested in the effects of stochasticity from an evolutionary point of view. We study this question in the lac operon, taking a computational approach: using a detailed, quantitative, spatial model, we evolve through a mutation-selection process the shape of the promoter function and therewith the effective amount of stochasticity. We find that noise values for lactose, the natural inducer, are much lower than for artificial, nonmetabolizable inducers, because these artificial inducers experience a stronger positive feedback. In the evolved promoter functions, noise due to stochasticity in gene expression, when induced by lactose, only plays a very minor role in short-term physiological adaptation, because other sources of population heterogeneity dominate. Finally, promoter functions evolved in the stochastic model evolve to higher repressed transcription rates than those evolved in a deterministic version of the model. This causes these promoter functions to experience less stochasticity in gene expression. We show that a high repression rate and hence high stochasticity increases the delay in lactose uptake in a variable environment. We conclude that the lac operon evolved such that the impact of stochastic gene expression is minor in its natural environment, but happens to respond with much stronger stochasticity when confronted with artificial inducers. In this particular system, we have shown that stochasticity is detrimental. Moreover, we demonstrate that in silico evolution in a quantitative model, by mutating the parameters of interest, is a promising way to unravel the functional properties of biological systems.'),
(83669, 2007, 'plos', 'Flexible and accurate detection of genomic copy-number changes from aCGH', 'Rueda, Oscar M|Díaz-Uriarte, Ramón', 'Structural and Computational Biology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain. omrueda@cnio.es|Structural and Computational Biology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain. omrueda@cnio.es', 'Spain|Spain', 0, 'Algorithms|Artificial Intelligence|Chromosome Mapping|Gene Dosage|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Reproducibility of Results|Sensitivity and Specificity|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030122', '17590078', 'Genomic DNA copy-number alterations (CNAs) are associated with complex diseases, including cancer: CNAs are indeed related to tumoral grade, metastasis, and patient survival. CNAs discovered from array-based comparative genomic hybridization (aCGH) data have been instrumental in identifying disease-related genes and potential therapeutic targets. To be immediately useful in both clinical and basic research scenarios, aCGH data analysis requires accurate methods that do not impose unrealistic biological assumptions and that provide direct answers to the key question, What is the probability that this gene/region has CNAs? Current approaches fail, however, to meet these requirements. Here, we introduce reversible jump aCGH (RJaCGH), a new method for identifying CNAs from aCGH, we use a nonhomogeneous hidden Markov model fitted via reversible jump Markov chain Monte Carlo, and we incorporate model uncertainty through Bayesian model averaging. RJaCGH provides an estimate of the probability that a gene/region has CNAs while incorporating interprobe distance and the capability to analyze data on a chromosome or genome-wide basis. RJaCGH outperforms alternative methods, and the performance difference is even larger with noisy data and highly variable interprobe distance, both commonly found features in aCGH data. Furthermore, our probabilistic method allows us to identify minimal common regions of CNAs among samples and can be extended to incorporate expression data. In summary, we provide a rigorous statistical framework for locating genes and chromosomal regions with CNAs with potential applications to cancer and other complex human diseases.'),
(83670, 2007, 'plos', 'A new principle for information storage in an enzymatic pathway model', 'Delord, Bruno|Berry, Hugues|Guigon, Emmanuel|Genet, Stéphane', 'Institut National de la Santé et de la Recherche Médicale, Unité 742, Université Pierre et Marie Curie-Paris 6, Paris, France. bruno.delord@upmc.fr|Institut National de la Santé et de la Recherche Médicale, Unité 742, Université Pierre et Marie Curie-Paris 6, Paris, France. bruno.delord@upmc.fr|Institut National de la Santé et de la Recherche Médicale, Unité 742, Université Pierre et Marie Curie-Paris 6, Paris, France. bruno.delord@upmc.fr|Institut National de la Santé et de la Recherche Médicale, Unité 742, Université Pierre et Marie Curie-Paris 6, Paris, France. bruno.delord@upmc.fr', 'France|France|France|France', 0, 'Action Potentials|Computer Simulation|Information Storage and Retrieval|Memory|Models, Neurological|Multienzyme Complexes|Neuronal Plasticity|Neurons|Phosphoprotein Phosphatases|Protein Kinases|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030124', '17590079', 'Strong experimental evidence indicates that protein kinase and phosphatase (KP) cycles are critical to both the induction and maintenance of activity-dependent modifications in neurons. However, their contribution to information storage remains controversial, despite impressive modeling efforts. For instance, plasticity models based on KP cycles do not account for the maintenance of plastic modifications. Moreover, bistable KP cycle models that display memory fail to capture essential features of information storage: rapid onset, bidirectional control, graded amplitude, and finite lifetimes. Here, we show in a biophysical model that upstream activation of KP cycles, a ubiquitous mechanism, is sufficient to provide information storage with realistic induction and maintenance properties: plastic modifications are rapid, bidirectional, and graded, with finite lifetimes that are compatible with animal and human memory. The maintenance of plastic modifications relies on negligible reaction rates in basal conditions and thus depends on enzyme nonlinearity and activation properties of the activity-dependent KP cycle. Moreover, we show that information coding and memory maintenance are robust to stochastic fluctuations inherent to the molecular nature of activity-dependent KP cycle operation. This model provides a new principle for information storage where plasticity and memory emerge from a single dynamic process whose rate is controlled by neuronal activity. This principle strongly departs from the long-standing view that memory reflects stable steady states in biological systems, and offers a new perspective on memory in animals and humans.'),
(83671, 2007, 'plos', 'A view from the dark side', 'Searls, David B', 'GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, United States of America. David.B.Searls@GSK.com', 'United States', 3, 'Biotechnology|Computational Biology|Genomics', 'Journal Article', '10.1371/journal.pcbi.0030105', '17604444', '-'),
(83672, 2007, 'plos', 'Slowness: an objective for spike-timing-dependent plasticity?', 'Sprekeler, Henning|Michaelis, Christian|Wiskott, Laurenz', 'Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de', 'Germany|Germany|Germany', 0, 'Action Potentials|Computer Simulation|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Reaction Time|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030112', '17604445', 'Our nervous system can efficiently recognize objects in spite of changes in contextual variables such as perspective or lighting conditions. Several lines of research have proposed that this ability for invariant recognition is learned by exploiting the fact that object identities typically vary more slowly in time than contextual variables or noise. Here, we study the question of how this temporal stability or slowness approach can be implemented within the limits of biologically realistic spike-based learning rules. We first show that slow feature analysis, an algorithm that is based on slowness, can be implemented in linear continuous model neurons by means of a modified Hebbian learning rule. This approach provides a link to the trace rule, which is another implementation of slowness learning. Then, we show analytically that for linear Poisson neurons, slowness learning can be implemented by spike-timing-dependent plasticity (STDP) with a specific learning window. By studying the learning dynamics of STDP, we show that for functional interpretations of STDP, it is not the learning window alone that is relevant but rather the convolution of the learning window with the postsynaptic potential. We then derive STDP learning windows that implement slow feature analysis and the trace rule. The resulting learning windows are compatible with physiological data both in shape and timescale. Moreover, our analysis shows that the learning window can be split into two functionally different components that are sensitive to reversible and irreversible aspects of the input statistics, respectively. The theory indicates that irreversible input statistics are not in favor of stable weight distributions but may generate oscillatory weight dynamics. Our analysis offers a novel interpretation for the functional role of STDP in physiological neurons.'),
(83673, 2007, 'plos', 'Machine learning and its applications to biology', 'Tarca, Adi L|Carey, Vincent J|Chen, Xue-wen|Romero, Roberto|Drxc4x83ghici, Sorin', 'Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. h.sprekeler@biologie.hu-berlin.de', 'Germany|Germany|Germany|Germany|Germany', 250, 'Algorithms|Artificial Intelligence|Biology|Cluster Analysis|Computer Simulation|Models, Biological|Pattern Recognition, Automated', 'Editorial', '10.1371/journal.pcbi.0030116', '17604446', '-'),
(83674, 2007, 'plos', 'ISCB honors Temple F Smith and Eran Segal', 'Maisel, Merry', 'San Diego, California, United States of America. merry.maisel@gmail.com', 'United States', 0, 'Awards and Prizes|Genomics|History, 20th Century|History, 21st Century|Molecular Biology|Portraits as Topic|Societies, Scientific|United States', 'Biography', '10.1371/journal.pcbi.0030128', '17604447', '-');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83675, 2007, 'plos', 'Not all scale-free networks are born equal: the role of the seed graph in PPI network evolution', 'Hormozdiari, Fereydoun|Berenbrink, Petra|Przulj, Natasa|Sahinalp, S Cenk', 'School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.|School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.|School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.|School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.', 'Canada|Canada|Canada|Canada', 59, 'Cluster Analysis|Computer Simulation|Databases, Protein|Evolution, Molecular|Gene Duplication|Gene Regulatory Networks|Neural Networks (Computer)|Protein Interaction Mapping|Proteome|Reference Standards|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction|Systems Biology|Systems Theory', 'Journal Article', '10.1371/journal.pcbi.0030118', '17616981', 'The (asymptotic) degree distributions of the best-known scale-free network models are all similar and are independent of the seed graph used, hence, it has been tempting to assume that networks generated by these models are generally similar. In this paper, we observe that several key topological features of such networks depend heavily on the specific model and the seed graph used. Furthermore, we show that starting with the right seed graph (typically a dense subgraph of the protein-protein interaction network analyzed), the duplication model captures many topological features of publicly available protein-protein interaction networks very well.'),
(83676, 2007, 'plos', 'A computational pipeline for high- throughput discovery of cis-regulatory noncoding RNA in prokaryotes', 'Yao, Zizhen|Barrick, Jeffrey|Weinberg, Zasha|Neph, Shane|Breaker, Ronald|Tompa, Martin|Ruzzo, Walter L', 'Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu|Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu|Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu|Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu|Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu|Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu|Department of Computer Science and Engineering, University of Washington, Seattle, Washington, USA. yzizhen@cs.washington.edu', 'United States|United States|United States|United States|United States|United States|United States', 59, 'Artificial Intelligence|Base Sequence|Computational Biology|Conserved Sequence|Databases, Nucleic Acid|Genes, Regulator|Genome, Bacterial|Molecular Sequence Data|Nucleic Acid Conformation|Pattern Recognition, Automated|RNA, Bacterial|RNA, Untranslated|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0030126', '17616982', 'Noncoding RNAs (ncRNAs) are important functional RNAs that do not code for proteins. We present a highly efficient computational pipeline for discovering cis-regulatory ncRNA motifs de novo. The pipeline differs from previous methods in that it is structure-oriented, does not require a multiple-sequence alignment as input, and is capable of detecting RNA motifs with low sequence conservation. We also integrate RNA motif prediction with RNA homolog search, which improves the quality of the RNA motifs significantly. Here, we report the results of applying this pipeline to Firmicute bacteria. Our top-ranking motifs include most known Firmicute elements found in the RNA family database (Rfam). Comparing our motif models with Rfams hand-curated motif models, we achieve high accuracy in both membership prediction and base-pair-level secondary structure prediction (at least 75% average sensitivity and specificity on both tasks). Of the ncRNA candidates not in Rfam, we find compelling evidence that some of them are functional, and analyze several potential ribosomal protein leaders in depth.'),
(83677, 2007, 'plos', 'Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control', 'Mahdavi, Alborz|Davey, Ryan E|Bhola, Patrick|Yin, Ting|Zandstra, Peter W', 'Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.', 'Canada|Canada|Canada|Canada|Canada', 53, 'Active Transport, Cell Nucleus|Animals|Cell Differentiation|Computer Simulation|Cytokine Receptor gp130|Cytokines|Enzyme Activation|Gene Expression|Gene Expression Regulation|Kinetics|Ligands|Mice|Models, Biological|STAT3 Transcription Factor|Sensitivity and Specificity|Signal Transduction|Stem Cells|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0030130', '17616983', 'Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identified novel pathway responses, for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.'),
(83678, 2007, 'plos', 'Novel algorithms reveal streptococcal transcriptomes and clues about undefined genes', 'Ryan, Patricia A|Kirk, Brian W|Euler, Chad W|Schuch, Raymond|Fischetti, Vincent A', 'Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, USA. ryanp@mail.rockfeller.edu|Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, USA. ryanp@mail.rockfeller.edu|Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, USA. ryanp@mail.rockfeller.edu|Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, USA. ryanp@mail.rockfeller.edu|Department of Bacterial Pathogenesis and Immunology, Rockefeller University, New York, New York, USA. ryanp@mail.rockfeller.edu', 'United States|United States|United States|United States|United States', 0, 'Algorithms|Cell Adhesion|Cell Line|Cluster Analysis|Gene Expression|Gene Expression Profiling|Gene Expression Regulation, Bacterial|Humans|Metabolic Networks and Pathways|Molecular Sequence Data|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Pharynx|Physical Chromosome Mapping|Sequence Analysis, DNA|Streptococcus pyogenes', 'Journal Article', '10.1371/journal.pcbi.0030132', '17616984', 'Bacteria-host interactions are dynamic processes, and understanding transcriptional responses that directly or indirectly regulate the expression of genes involved in initial infection stages would illuminate the molecular events that result in host colonization. We used oligonucleotide microarrays to monitor (in vitro) differential gene expression in group A streptococci during pharyngeal cell adherence, the first overt infection stage. We present neighbor clustering, a new computational method for further analyzing bacterial microarray data that combines two informative characteristics of bacterial genes that share common function or regulation: (1) similar gene expression profiles (i.e., co-expression), and (2) physical proximity of genes on the chromosome. This method identifies statistically significant clusters of co-expressed gene neighbors that potentially share common function or regulation by coupling statistically analyzed gene expression profiles with the chromosomal position of genes. We applied this method to our own data and to those of others, and we show that it identified a greater number of differentially expressed genes, facilitating the reconstruction of more multimeric proteins and complete metabolic pathways than would have been possible without its application. We assessed the biological significance of two identified genes by assaying deletion mutants for adherence in vitro and show that neighbor clustering indeed provides biologically relevant data. Neighbor clustering provides a more comprehensive view of the molecular responses of streptococci during pharyngeal cell adherence.'),
(83679, 2007, 'plos', 'Sarcomere lattice geometry influences cooperative myosin binding in muscle', 'Tanner, Bertrand C W|Daniel, Thomas L|Regnier, Michael', 'Department of Bioengineering, University of Washington, Seattle, Washington, USA.|Department of Bioengineering, University of Washington, Seattle, Washington, USA.|Department of Bioengineering, University of Washington, Seattle, Washington, USA.', 'United States|United States|United States', 63, 'Actins|Adenosine Triphosphate|Calcium Signaling|Computer Simulation|Elasticity|Energy Transfer|Kinetics|Models, Biological|Monte Carlo Method|Movement|Multiprotein Complexes|Muscle Contraction|Muscle Strength|Muscle, Skeletal|Myosins|Protein Binding|Quantitative Structure-Activity Relationship|Sarcomeres|Tropomyosin|Troponin', 'Journal Article', '10.1371/journal.pcbi.0030115', '17630823', 'In muscle, force emerges from myosin binding with actin (forming a cross-bridge). This actomyosin binding depends upon myofilament geometry, kinetics of thin-filament Ca(2+) activation, and kinetics of cross-bridge cycling. Binding occurs within a compliant network of protein filaments where there is mechanical coupling between myosins along the thick-filament backbone and between actin monomers along the thin filament. Such mechanical coupling precludes using ordinary differential equation models when examining the effects of lattice geometry, kinetics, or compliance on force production. This study uses two stochastically driven, spatially explicit models to predict levels of cross-bridge binding, force, thin-filament Ca(2+) activation, and ATP utilization. One model incorporates the 2-to-1 ratio of thin to thick filaments of vertebrate striated muscle (multi-filament model), while the other comprises only one thick and one thin filament (two-filament model). Simulations comparing these models show that the multi-filament predictions of force, fractional cross-bridge binding, and cross-bridge turnover are more consistent with published experimental values. Furthermore, the values predicted by the multi-filament model are greater than those values predicted by the two-filament model. These increases are larger than the relative increase of potential inter-filament interactions in the multi-filament model versus the two-filament model. This amplification of coordinated cross-bridge binding and cycling indicates a mechanism of cooperativity that depends on sarcomere lattice geometry, specifically the ratio and arrangement of myofilaments.'),
(83680, 2007, 'plos', 'Protein-protein interaction hotspots carved into sequences', 'Ofran, Yanay|Rost, Burkhard', 'Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. yo135@columbia.edu|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. yo135@columbia.edu', 'United States|United States', 0, 'Amino Acid Sequence|Amino Acids|Binding Sites|Databases, Protein|Knowledge Bases|Models, Molecular|Multiprotein Complexes|Neural Networks (Computer)|Predictive Value of Tests|Protein Binding|Protein Conformation|Protein Interaction Mapping|Proteins|Proteomics|Sequence Analysis, Protein|User-Computer Interface', 'Journal Article', '10.1371/journal.pcbi.0030119', '17630824', 'Protein-protein interactions, a key to almost any biological process, are mediated by molecular mechanisms that are not entirely clear. The study of these mechanisms often focuses on all residues at protein-protein interfaces. However, only a small subset of all interface residues is actually essential for recognition or binding. Commonly referred to as hotspots, these essential residues are defined as residues that impede protein-protein interactions if mutated. While no in silico tool identifies hotspots in unbound chains, numerous prediction methods were designed to identify all the residues in a protein that are likely to be a part of protein-protein interfaces. These methods typically identify successfully only a small fraction of all interface residues. Here, we analyzed the hypothesis that the two subsets correspond (i.e., that in silico methods may predict few residues because they preferentially predict hotspots). We demonstrate that this is indeed the case and that we can therefore predict directly from the sequence of a single protein which residues are interaction hotspots (without knowledge of the interaction partner). Our results suggested that most protein complexes are stabilized by similar basic principles. The ability to accurately and efficiently identify hotspots from sequence enables the annotation and analysis of protein-protein interaction hotspots in entire organisms and thus may benefit function prediction and drug development. The server for prediction is available at http://www.rostlab.org/services/isis.'),
(83681, 2007, 'plos', 'Efficiency, selectivity, and robustness of nucleocytoplasmic transport', 'Zilman, Anton|Di Talia, Stefano|Chait, Brian T|Rout, Michael P|Magnasco, Marcelo O', 'Laboratory of Mathematical Physics, The Rockefeller University, New York, New York, USA.|Laboratory of Mathematical Physics, The Rockefeller University, New York, New York, USA.|Laboratory of Mathematical Physics, The Rockefeller University, New York, New York, USA.|Laboratory of Mathematical Physics, The Rockefeller University, New York, New York, USA.|Laboratory of Mathematical Physics, The Rockefeller University, New York, New York, USA.', 'United States|United States|United States|United States|United States', 80, 'Active Transport, Cell Nucleus|Allosteric Regulation|Amino Acid Motifs|Binding, Competitive|Cell Nucleus|Diffusion|Energy Transfer|Karyopherins|Models, Biological|Models, Chemical|Nuclear Pore|Nuclear Pore Complex Proteins|Protein Binding|Protein Structure, Tertiary|Thermodynamics', 'Journal Article', '10.1371/journal.pcbi.0030125', '17630825', 'All materials enter or exit the cell nucleus through nuclear pore complexes (NPCs), efficient transport devices that combine high selectivity and throughput. NPC-associated proteins containing phenylalanine-glycine repeats (FG nups) have large, flexible, unstructured proteinaceous regions, and line the NPC. A central feature of NPC-mediated transport is the binding of cargo-carrying soluble transport factors to the unstructured regions of FG nups. Here, we model the dynamics of nucleocytoplasmic transport as diffusion in an effective potential resulting from the interaction of the transport factors with the flexible FG nups, using a minimal number of assumptions consistent with the most well-established structural and functional properties of NPC transport. We discuss how specific binding of transport factors to the FG nups facilitates transport, and how this binding and competition between transport factors and other macromolecules for binding sites and space inside the NPC accounts for the high selectivity of transport. We also account for why transport is relatively insensitive to changes in the number and distribution of FG nups in the NPC, providing an explanation for recent experiments where up to half the total mass of the FG nups has been deleted without abolishing transport. Our results suggest strategies for the creation of artificial nanomolecular sorting devices.'),
(83682, 2007, 'plos', 'Global and local architecture of the mammalian microRNA-transcription factor regulatory network', 'Shalgi, Reut|Lieber, Daniel|Oren, Moshe|Pilpel, Yitzhak', 'Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel', 0, 'Algorithms|Animals|Base Sequence|Binding Sites|Conserved Sequence|Feedback, Physiological|Gene Expression|Gene Expression Profiling|Gene Expression Regulation|Gene Regulatory Networks|Genes, Regulator|Humans|Mammals|MicroRNAs|Promoter Regions, Genetic|Signal Transduction|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030131', '17630826', 'microRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. It is anticipated that, in combination with transcription factors (TFs), they span a regulatory network that controls thousands of mammalian genes. Here we set out to uncover local and global architectural features of the mammalian miR regulatory network. Using evolutionarily conserved potential binding sites of miRs in human targets, and conserved binding sites of TFs in promoters, we uncovered two regulation networks. The first depicts combinatorial interactions between pairs of miRs with many shared targets. The network reveals several levels of hierarchy, whereby a few miRs interact with many other lowly connected miR partners. We revealed hundreds of target hubs genes, each potentially subject to massive regulation by dozens of miRs. Interestingly, many of these target hub genes are transcription regulators and they are often related to various developmental processes. The second network consists of miR-TF pairs that coregulate large sets of common targets. We discovered that the network consists of several recurring motifs. Most notably, in a significant fraction of the miR-TF coregulators the TF appears to regulate the miR, or to be regulated by the miR, forming a diversity of feed-forward loops. Together these findings provide new insights on the architecture of the combined transcriptional-post transcriptional regulatory network.'),
(83683, 2007, 'plos', 'Optimal timing and duration of induction therapy for HIV-1 infection', 'Curlin, Marcel E|Iyer, Shyamala|Mittler, John E', 'Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Medicine, University of Washington, Seattle, Washington, USA.', 'United States|United States|United States', 0, 'Anti-HIV Agents|Antiretroviral Therapy, Highly Active|Computer Simulation|Decision Support Techniques|Disease Progression|Drug Administration Schedule|Drug Resistance, Viral|Drug Therapy, Combination|Drug Therapy, Computer-Assisted|HIV Infections|HIV-1|Half-Life|Humans|Logistic Models|Mutation|Patient Care Planning|Time Factors|Treatment Outcome|Viral Load|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.0030133', '17630827', 'The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction-maintenance therapies might be optimized. Our model suggests that under a variety of biologically plausible conditions, 6-10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen. For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal. The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated. These observations have implications for both the timing and the kinds of drugs selected for induction-maintenance and therapy-intensification strategies.'),
(83684, 2007, 'plos', 'Adaptive, fast walking in a biped robot under neuronal control and learning', 'Manoonpong, Poramate|Geng, Tao|Kulvicius, Tomas|Porr, Bernd|Wörgötter, Florentin', 'Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany.|Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany.', 'Germany|Germany|Germany|Germany|Germany', 0, 'Artificial Intelligence|Biomechanical Phenomena|Bionics|Feedback|Gait|Humans|Models, Neurological|Nerve Net|Neural Networks (Computer)|Neurons|Postural Balance|Reflex|Robotics|Synaptic Transmission|Walking', 'Journal Article', '10.1371/journal.pcbi.0030134', '17630828', 'Human walking is a dynamic, partly self-stabilizing process relying on the interaction of the biomechanical design with its neuronal control. The coordination of this process is a very difficult problem, and it has been suggested that it involves a hierarchy of levels, where the lower ones, e.g., interactions between muscles and the spinal cord, are largely autonomous, and where higher level control (e.g., cortical) arises only pointwise, as needed. This requires an architecture of several nested, sensori-motor loops where the walking process provides feedback signals to the walkers sensory systems, which can be used to coordinate its movements. To complicate the situation, at a maximal walking speed of more than four leg-lengths per second, the cycle period available to coordinate all these loops is rather short. In this study we present a planar biped robot, which uses the design principle of nested loops to combine the self-stabilizing properties of its biomechanical design with several levels of neuronal control. Specifically, we show how to adapt control by including online learning mechanisms based on simulated synaptic plasticity. This robot can walk with a high speed (>3.0 leg length/s), self-adapting to minor disturbances, and reacting in a robust way to abruptly induced gait changes. At the same time, it can learn walking on different terrains, requiring only few learning experiences. This study shows that the tight coupling of physical with neuronal control, guided by sensory feedback from the walking pattern itself, combined with synaptic learning may be a way forward to better understand and solve coordination problems in other complex motor tasks.'),
(83685, 2007, 'plos', 'Evolutionary history of mammalian transposons determined by genome-wide defragmentation', 'Giordano, Joti|Ge, Yongchao|Gelfand, Yevgeniy|Abrusán, György|Benson, Gary|Warburton, Peter E', 'Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.|Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.|Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.|Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.|Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.|Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.', 'United States|United States|United States|United States|United States|United States', 84, 'Animals|Base Pairing|Base Sequence|Cattle|Chronobiology Phenomena|DNA Mutational Analysis|DNA Transposable Elements|Dogs|Evolution, Molecular|Genetic Speciation|Genome, Human|Haplorhini|Humans|Mammals|Mice|Models, Genetic|Molecular Sequence Data|Phylogeny|Rats', 'Journal Article', '10.1371/journal.pcbi.0030137', '17630829', 'The constant bombardment of mammalian genomes by transposable elements (TEs) has resulted in TEs comprising at least 45% of the human genome. Because of their great age and abundance, TEs are important in comparative phylogenomics. However, estimates of TE age were previously based on divergence from derived consensus sequences or phylogenetic analysis, which can be unreliable, especially for older more diverged elements. Therefore, a novel genome-wide analysis of TE organization and fragmentation was performed to estimate TE age independently of sequence composition and divergence or the assumption of a constant molecular clock. Analysis of TEs in the human genome revealed approximately 600,000 examples where TEs have transposed into and fragmented other TEs, covering >40% of all TEs or approximately 542 Mbp of genomic sequence. The relative age of these TEs over evolutionary time is implicit in their organization, because newer TEs have necessarily transposed into older TEs that were already present. A matrix of the number of times that each TE has transposed into every other TE was constructed, and a novel objective function was developed that derived the chronological order and relative ages of human TEs spanning >100 million years. This method has been used to infer the relative ages across all four major TE classes, including the oldest, most diverged elements. Analysis of DNA transposons over the history of the human genome has revealed the early activity of some MER2 transposons, and the relatively recent activity of MER1 transposons during primate lineages. The TEs from six additional mammalian genomes were defragmented and analyzed. Pairwise comparison of the independent chronological orders of TEs in these mammalian genomes revealed species phylogeny, the fact that transposons shared between genomes are older than species-specific transposons, and a subset of TEs that were potentially active during periods of speciation.'),
(83686, 2007, 'plos', 'A first-principles model of early evolution: emergence of gene families, species, and preferred protein folds', 'Zeldovich, Konstantin B|Chen, Peiqiu|Shakhnovich, Boris E|Shakhnovich, Eugene I', 'Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States', 45, 'Animals|Biological Evolution|Chronobiology Phenomena|Computer Simulation|Databases, Protein|Genome|Humans|Life Expectancy|Models, Genetic|Multigene Family|Mutation|Population Growth|Protein Conformation|Protein Folding|Proteins|Selection, Genetic|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Stochastic Processes|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030139', '17630830', 'In this work we develop a microscopic physical model of early evolution where phenotype--organism life expectancy--is directly related to genotype--the stability of its proteins in their native conformations-which can be determined exactly in the model. Simulating the model on a computer, we consistently observe the Big Bang scenario whereby exponential population growth ensues as soon as favorable sequence-structure combinations (precursors of stable proteins) are discovered. Upon that, random diversity of the structural space abruptly collapses into a small set of preferred proteins. We observe that protein folds remain stable and abundant in the population at timescales much greater than mutation or organism lifetime, and the distribution of the lifetimes of dominant folds in a population approximately follows a power law. The separation of evolutionary timescales between discovery of new folds and generation of new sequences gives rise to emergence of protein families and superfamilies whose sizes are power-law distributed, closely matching the same distributions for real proteins. On the population level we observe emergence of species--subpopulations that carry similar genomes. Further, we present a simple theory that relates stability of evolving proteins to the sizes of emerging genomes. Together, these results provide a microscopic first-principles picture of how first-gene families developed in the course of early evolution.'),
(83687, 2007, 'plos', 'Evolution of function in the two dinucleotide binding domains flavoproteins', 'Ojha, Sunil|Meng, Elaine C|Babbitt, Patricia C', 'Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.', 'United States|United States|United States', 0, 'Allosteric Site|Biological Evolution|Catalytic Domain|Coenzymes|Conserved Sequence|Dinucleoside Phosphates|Electron-Transferring Flavoproteins|Flavin-Adenine Dinucleotide|Protein Interaction Domains and Motifs|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030121', '17658942', 'Structural and biochemical constraints force some segments of proteins to evolve more slowly than others, often allowing identification of conserved structural or sequence motifs that can be associated with substrate binding properties, chemical mechanisms, and molecular functions. We have assessed the functional and structural constraints imposed by cofactors on the evolution of new functions in a superfamily of flavoproteins characterized by two-dinucleotide binding domains, the two dinucleotide binding domains flavoproteins (tDBDF) superfamily. Although these enzymes catalyze many different types of oxidation/reduction reactions, each is initiated by a stereospecific hydride transfer reaction between two cofactors, a pyridine nucleotide and flavin adenine dinucleotide (FAD). Sequence and structural analysis of more than 1,600 members of the superfamily reveals new members and identifies details of the evolutionary connections among them. Our analysis shows that in all of the highly divergent families within the superfamily, these cofactors adopt a conserved configuration optimal for stereospecific hydride transfer that is stabilized by specific interactions with amino acids from several motifs distributed among both dinucleotide binding domains. The conservation of cofactor configuration in the active site restricts the pyridine nucleotide to interact with FAD from the re-side, limiting the flow of electrons from the re-side to the si-side. This directionality of electron flow constrains interactions with the different partner proteins of different families to occur on the same face of the cofactor binding domains. As a result, superimposing the structures of tDBDFs aligns not only these interacting proteins, but also their constituent electron acceptors, including heme and iron-sulfur clusters. Thus, not only are specific aspects of the cofactor-directed chemical mechanism conserved across the superfamily, the constraints they impose are manifested in the mode of protein-protein interactions. Overlaid on this foundation of conserved interactions, nature has conscripted different protein partners to serve as electron acceptors, thereby generating diversification of function across the superfamily.'),
(83688, 2007, 'plos', 'Natively unstructured loops differ from other loops', 'Schlessinger, Avner|Liu, Jinfeng|Rost, Burkhard', 'Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. as2067@columbia.edu|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. as2067@columbia.edu|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. as2067@columbia.edu', 'United States|United States|United States', 0, 'Amino Acid Sequence|Animals|Artificial Intelligence|Binding Sites|Caenorhabditis elegans|Computational Biology|Computer Simulation|Databases, Protein|Models, Chemical|Models, Molecular|Neural Networks (Computer)|Predictive Value of Tests|Protein Folding|Protein Interaction Mapping|Protein Structure, Secondary|Proteome|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030140', '17658943', 'Natively unstructured or disordered protein regions may increase the functional complexity of an organism, they are particularly abundant in eukaryotes and often evade structure determination. Many computational methods predict unstructured regions by training on outliers in otherwise well-ordered structures. Here, we introduce an approach that uses a neural network in a very different and novel way. We hypothesize that very long contiguous segments with nonregular secondary structure (NORS regions) differ significantly from regular, well-structured loops, and that a method detecting such features could predict natively unstructured regions. Training our new method, NORSnet, on predicted information rather than on experimental data yielded three major advantages: it removed the overlap between testing and training, it systematically covered entire proteomes, and it explicitly focused on one particular aspect of unstructured regions with a simple structural interpretation, namely that they are loops. Our hypothesis was correct: well-structured and unstructured loops differ so substantially that NORSnet succeeded in their distinction. Benchmarks on previously used and new experimental data of unstructured regions revealed that NORSnet performed very well. Although it was not the best single prediction method, NORSnet was sufficiently accurate to flag unstructured regions in proteins that were previously not annotated. In one application, NORSnet revealed previously undetected unstructured regions in putative targets for structural genomics and may thereby contribute to increasing structural coverage of large eukaryotic families. NORSnet found unstructured regions more often in domain boundaries than expected at random. In another application, we estimated that 50%-70% of all worm proteins observed to have more than seven protein-protein interaction partners have unstructured regions. The comparative analysis between NORSnet and DISOPRED2 suggested that long unstructured loops are a major part of unstructured regions in molecular networks.'),
(83689, 2007, 'plos', 'Computationally derived points of fragility of a human cascade are consistent with current therapeutic strategies', 'Luan, Deyan|Zai, Michael|Varner, Jeffrey D', 'Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.|Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.|Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.', 'United States|United States|United States', 0, 'Anticoagulants|Blood Coagulation|Clinical Protocols|Decision Support Techniques|Enzyme Activation|Enzyme Inhibitors|Factor IXa|Factor VIIIa|Factor Xa|Humans|Models, Biological|Monte Carlo Method|Platelet Activation|Probability|Signal Transduction|Stochastic Processes|Systems Biology|Thrombin', 'Journal Article', '10.1371/journal.pcbi.0030142', '17658944', 'The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein-protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa) activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants, for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of fragility of human relevant cascades could be used as a rational basis for target selection despite model uncertainty.'),
(83690, 2007, 'plos', 'Prediction of gene expression in embryonic structures of Drosophila melanogaster', 'Samsonova, Anastasia A|Niranjan, Mahesan|Russell, Steven|Brazma, Alvis', 'European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. nastja@ebi.ac.uk|European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. nastja@ebi.ac.uk|European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. nastja@ebi.ac.uk|European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. nastja@ebi.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 13, 'Algorithms|Animals|Artificial Intelligence|Cluster Analysis|Computational Biology|Databases, Genetic|Drosophila melanogaster|Embryo, Nonmammalian|Gene Expression|Gene Expression Profiling|Gene Regulatory Networks|Genes, Developmental|Genes, Insect|In Situ Hybridization|Nucleic Acid Hybridization|Oligonucleotide Array Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.0030144', '17658945', 'Understanding how sets of genes are coordinately regulated in space and time to generate the diversity of cell types that characterise complex metazoans is a major challenge in modern biology. The use of high-throughput approaches, such as large-scale in situ hybridisation and genome-wide expression profiling via DNA microarrays, is beginning to provide insights into the complexities of development. However, in many organisms the collection and annotation of comprehensive in situ localisation data is a difficult and time-consuming task. Here, we present a widely applicable computational approach, integrating developmental time-course microarray data with annotated in situ hybridisation studies, that facilitates the de novo prediction of tissue-specific expression for genes that have no in vivo gene expression localisation data available. Using a classification approach, trained with data from microarray and in situ hybridisation studies of gene expression during Drosophila embryonic development, we made a set of predictions on the tissue-specific expression of Drosophila genes that have not been systematically characterised by in situ hybridisation experiments. The reliability of our predictions is confirmed by literature-derived annotations in FlyBase, by overrepresentation of Gene Ontology biological process annotations, and, in a selected set, by detailed gene-specific studies from the literature. Our novel organism-independent method will be of considerable utility in enriching the annotation of gene function and expression in complex multicellular organisms.'),
(83691, 2007, 'plos', 'Retraction: Measures of clade confidence do not correlate with accuracy of phylogenetic trees', 'Hall, Barry G|Salipante, Stephen J', 'European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. nastja@ebi.ac.uk|European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom. nastja@ebi.ac.uk', 'United Kingdom|United Kingdom', 0, '-', 'Retraction of Publication', '10.1371/journal.pcbi.0030158', '17658946', '-'),
(83692, 2007, 'plos', 'Distributed representations accelerate evolution of adaptive behaviours', 'Stone, James V', 'Psychology Department, Sheffield University, Sheffield, United Kingdom. j.v.stone@shef.ac.uk', 'United Kingdom', 0, 'Adaptation, Physiological|Behavior|Biological Evolution|Computer Simulation|Ecosystem|Extinction, Biological|Learning|Models, Genetic|Models, Statistical|Selection, Genetic|Statistical Distributions|Survival Rate', 'Journal Article', '10.1371/journal.pcbi.0030147', '17676948', 'Animals with rudimentary innate abilities require substantial learning to transform those abilities into useful skills, where a skill can be considered as a set of sensory-motor associations. Using linear neural network models, it is proved that if skills are stored as distributed representations, then within-lifetime learning of part of a skill can induce automatic learning of the remaining parts of that skill. More importantly, it is shown that this free-lunch learning (FLL) is responsible for accelerated evolution of skills, when compared with networks which either 1) cannot benefit from FLL or 2) cannot learn. Specifically, it is shown that FLL accelerates the appearance of adaptive behaviour, both in its innate form and as FLL-induced behaviour, and that FLL can accelerate the rate at which learned behaviours become innate.'),
(83693, 2007, 'plos', 'An information-theoretic characterization of the optimal gradient sensing response of cells', 'Andrews, Burton W|Iglesias, Pablo A', 'Department of Electrical and Computer Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States', 68, 'Animals|Cell Communication|Cell Polarity|Chemotactic Factors|Chemotaxis|Computer Simulation|Dictyostelium|Information Theory|Models, Biological|Models, Statistical', 'Journal Article', '10.1371/journal.pcbi.0030153', '17676949', 'Many cellular systems rely on the ability to interpret spatial heterogeneities in chemoattractant concentration to direct cell migration. The accuracy of this process is limited by stochastic fluctuations in the concentration of the external signal and in the internal signaling components. Here we use information theory to determine the optimal scheme to detect the location of an external chemoattractant source in the presence of noise. We compute the minimum amount of mutual information needed between the chemoattractant gradient and the internal signal to achieve a prespecified chemotactic accuracy. We show that more accurate chemotaxis requires greater mutual information. We also demonstrate that a priori information can improve chemotaxis efficiency. We compare the optimal signaling schemes with existing experimental measurements and models of eukaryotic gradient sensing. Remarkably, there is good quantitative agreement between the optimal response when no a priori assumption is made about the location of the existing source, and the observed experimental response of unpolarized Dictyostelium discoideum cells. In contrast, the measured response of polarized D. discoideum cells matches closely the optimal scheme, assuming prior knowledge of the external gradient-for example, through prolonged chemotaxis in a given direction. Our results demonstrate that different observed classes of responses in cells (polarized and unpolarized) are optimal under varying information assumptions.'),
(83694, 2007, 'plos', 'PERIOD-TIMELESS interval timer may require an additional feedback loop', 'Kuczenski, Robert S|Hong, Kevin C|García-Ojalvo, Jordi|Lee, Kelvin H', 'School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.|School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, United States of America.', 'United States|United States|United States|United States', 12, 'Animals|Biological Clocks|Circadian Rhythm|Computer Simulation|Drosophila Proteins|Drosophila melanogaster|Feedback|Models, Biological|Nuclear Proteins|Oscillometry|Period Circadian Proteins|Signal Transduction|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0030154', '17676950', 'In this study we present a detailed, mechanism-based mathematical framework of Drosophila circadian rhythms. This framework facilitates a more systematic approach to understanding circadian rhythms using a comprehensive representation of the network underlying this phenomenon. The possible mechanisms underlying the cytoplasmic interval timer created by PERIOD-TIMELESS association are investigated, suggesting a novel positive feedback regulatory structure. Incorporation of this additional feedback into a full circadian model produced results that are consistent with previous experimental observations of wild-type protein profiles and numerous mutant phenotypes.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83695, 2007, 'plos', 'Image-based modeling reveals dynamic redistribution of DNA damage into nuclear sub-domains', 'Costes, Sylvain V|Ponomarev, Artem|Chen, James L|Nguyen, David|Cucinotta, Francis A|Barcellos-Hoff, Mary Helen', 'Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. svcostes@lbl.gov|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. svcostes@lbl.gov|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. svcostes@lbl.gov|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. svcostes@lbl.gov|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. svcostes@lbl.gov|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America. svcostes@lbl.gov', 'United States|United States|United States|United States|United States|United States', 79, 'Cell Nucleus|Computer Simulation|DNA|DNA Damage|DNA Repair|Epithelial Cells|Humans|Image Interpretation, Computer-Assisted|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.0030155', '17676951', 'Several proteins involved in the response to DNA double strand breaks (DSB) form microscopically visible nuclear domains, or foci, after exposure to ionizing radiation. Radiation-induced foci (RIF) are believed to be located where DNA damage occurs. To test this assumption, we analyzed the spatial distribution of 53BP1, phosphorylated ATM, and gammaH2AX RIF in cells irradiated with high linear energy transfer (LET) radiation and low LET. Since energy is randomly deposited along high-LET particle paths, RIF along these paths should also be randomly distributed. The probability to induce DSB can be derived from DNA fragment data measured experimentally by pulsed-field gel electrophoresis. We used this probability in Monte Carlo simulations to predict DSB locations in synthetic nuclei geometrically described by a complete set of human chromosomes, taking into account microscope optics from real experiments. As expected, simulations produced DNA-weighted random (Poisson) distributions. In contrast, the distributions of RIF obtained as early as 5 min after exposure to high LET (1 GeV/amu Fe) were non-random. This deviation from the expected DNA-weighted random pattern can be further characterized by relative DNA image measurements. This novel imaging approach shows that RIF were located preferentially at the interface between high and low DNA density regions, and were more frequent than predicted in regions with lower DNA density. The same preferential nuclear location was also measured for RIF induced by 1 Gy of low-LET radiation. This deviation from random behavior was evident only 5 min after irradiation for phosphorylated ATM RIF, while gammaH2AX and 53BP1 RIF showed pronounced deviations up to 30 min after exposure. These data suggest that DNA damage-induced foci are restricted to certain regions of the nucleus of human epithelial cells. It is possible that DNA lesions are collected in these nuclear sub-domains for more efficient repair.'),
(83696, 2007, 'plos', 'Introduction to computational proteomics', 'Colinge, Jacques|Bennett, Keiryn L', 'Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. jcolinge@cemm.oeaw.ac.at|Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. jcolinge@cemm.oeaw.ac.at', 'Austria|Austria', 0, 'Computational Biology|Gene Expression Profiling|Peptide Mapping|Proteins|Proteomics|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030114', '17676979', '-'),
(83697, 2007, 'plos', 'Quantitative analysis of cell nucleus organisation', 'Shiels, Carol|Adams, Niall M|Islam, Suhail A|Stephens, David A|Freemont, Paul S', 'Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom|Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom|Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom|Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom|Division of Molecular Biosciences, Faculty of Natural Sciences, Imperial College London, London, United Kingdom', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Cell Nucleus|Models, Biological|Nuclear Proteins', 'Journal Article', '10.1371/journal.pcbi.0030138', '17676980', 'There are almost 1,300 entries for higher eukaryotes in the Nuclear Protein Database. The proteins subcellular distribution patterns within interphase nuclei can be complex, ranging from diffuse to punctate or microspeckled, yet they all work together in a coordinated and controlled manner within the three-dimensional confines of the nuclear volume. In this review we describe recent advances in the use of quantitative methods to understand nuclear spatial organisation and discuss some of the practical applications resulting from this work.'),
(83698, 2007, 'plos', 'Detecting emerging transmissibility of avian influenza virus in human households', 'van Boven, Michiel|Koopmans, Marion|Du Ry van Beest Holle, Mirna|Meijer, Adam|Klinkenberg, Don|Donnelly, Christl A|Heesterbeek, Hans J A P', 'Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Computer Simulation|Disease Outbreaks|Disease Transmission, Infectious|Humans|Incidence|Influenza A Virus, H5N1 Subtype|Influenza A Virus, H7N7 Subtype|Influenza, Human|Models, Biological|Netherlands|Population Surveillance|Risk Assessment|Risk Factors', 'Journal Article', '10.1371/journal.pcbi.0030145', '17676981', 'Accumulating infections of highly pathogenic H5N1 avian influenza in humans underlines the need to track the ability of these viruses to spread among humans. A human-transmissible avian influenza virus is expected to cause clusters of infections in humans living in close contact. Therefore, epidemiological analysis of infection clusters in human households is of key importance. Infection clusters may arise from transmission events from (i) the animal reservoir, (ii) humans who were infected by animals (primary human-to-human transmission), or (iii) humans who were infected by humans (secondary human-to-human transmission). Here we propose a method of analysing household infection data to detect changes in the transmissibility of avian influenza viruses in humans at an early stage. The method is applied to an outbreak of H7N7 avian influenza virus in The Netherlands that was the cause of more than 30 human-to-human transmission events. The analyses indicate that secondary human-to-human transmission is plausible for the Dutch household infection data. Based on the estimates of the within-household transmission parameters, we evaluate the effectiveness of antiviral prophylaxis, and conclude that it is unlikely that all household infections can be prevented with current antiviral drugs. We discuss the applicability of our method for the detection of emerging human-to-human transmission of avian influenza viruses in particular, and for the analysis of within-household infection data in general.'),
(83699, 2007, 'plos', 'Chemotaxis receptor complexes: from signaling to assembly', 'Endres, Robert G|Falke, Joseph J|Wingreen, Ned S', 'Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. rendres@princeton.edu|Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. rendres@princeton.edu|Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. rendres@princeton.edu', 'Jersey|Jersey|Jersey', 17, 'Bacterial Proteins|Chemoreceptor Cells|Chemotactic Factors|Chemotaxis|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Models, Biological|Receptors, Cell Surface|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030150', '17676982', 'Complexes of chemoreceptors in the bacterial cytoplasmic membrane allow for the sensing of ligands with remarkable sensitivity. Despite the excellent characterization of the chemotaxis signaling network, very little is known about what controls receptor complex size. Here we use in vitro signaling data to model the distribution of complex sizes. In particular, we model Tar receptors in membranes as an ensemble of different sized oligomer complexes, i.e., receptor dimers, dimers of dimers, and trimers of dimers, where the relative free energies, including receptor modification, ligand binding, and interaction with the kinase CheA determine the size distribution. Our model compares favorably with a variety of signaling data, including dose-response curves of receptor activity and the dependence of activity on receptor density in the membrane. We propose that the kinetics of complex assembly can be measured in vitro from the temporal response to a perturbation of the complex free energies, e.g., by addition of ligand.'),
(83700, 2007, 'plos', 'Automated discovery of functional generality of human gene expression programs', 'Gerber, Georg K|Dowell, Robin D|Jaakkola, Tommi S|Gifford, David K', 'Department of Computer Science and Electrical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Computer Science and Electrical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Computer Science and Electrical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Computer Science and Electrical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 0, 'Algorithms|Artificial Intelligence|Computer Simulation|Gene Expression|Gene Expression Profiling|Models, Biological|Multigene Family|Oligonucleotide Array Sequence Analysis|Pattern Recognition, Automated|Proteome|Signal Transduction|Software', 'Journal Article', '10.1371/journal.pcbi.0030148', '17696603', 'An important research problem in computational biology is the identification of expression programs, sets of co-expressed genes orchestrating normal or pathological processes, and the characterization of the functional breadth of these programs. The use of human expression data compendia for discovery of such programs presents several challenges including cellular inhomogeneity within samples, genetic and environmental variation across samples, uncertainty in the numbers of programs and sample populations, and temporal behavior. We developed GeneProgram, a new unsupervised computational framework based on Hierarchical Dirichlet Processes that addresses each of the above challenges. GeneProgram uses expression data to simultaneously organize tissues into groups and genes into overlapping programs with consistent temporal behavior, to produce maps of expression programs, which are sorted by generality scores that exploit the automatically learned groupings. Using synthetic and real gene expression data, we showed that GeneProgram outperformed several popular expression analysis methods. We applied GeneProgram to a compendium of 62 short time-series gene expression datasets exploring the responses of human cells to infectious agents and immune-modulating molecules. GeneProgram produced a map of 104 expression programs, a substantial number of which were significantly enriched for genes involved in key signaling pathways and/or bound by NF-kappaB transcription factors in genome-wide experiments. Further, GeneProgram discovered expression programs that appear to implicate surprising signaling pathways or receptor types in the response to infection, including Wnt signaling and neurotransmitter receptors. We believe the discovered map of expression programs involved in the response to infection will be useful for guiding future biological experiments, genes from programs with low generality scores might serve as new drug targets that exhibit minimal cross-talk, and genes from high generality programs may maintain common physiological responses that go awry in disease states. Further, our method is multipurpose, and can be applied readily to novel compendia of biological data.'),
(83701, 2007, 'plos', 'SimulFold: simultaneously inferring RNA structures including pseudoknots, alignments, and trees using a Bayesian MCMC framework', 'Meyer, Irmtraud M|Miklós, István', 'UBC Bioinformatics Centre, University of British Columbia, Vancouver, British Columbia, Canada. irmtraud.meyer@cantab.net|UBC Bioinformatics Centre, University of British Columbia, Vancouver, British Columbia, Canada. irmtraud.meyer@cantab.net', 'Canada|Canada', 0, 'Algorithms|Artificial Intelligence|Base Sequence|Bayes Theorem|Computer Simulation|Conserved Sequence|Evolution, Molecular|Models, Chemical|Models, Genetic|Models, Molecular|Molecular Sequence Data|Monte Carlo Method|Pattern Recognition, Automated|RNA|Sequence Alignment|Sequence Analysis, RNA|Software|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030149', '17696604', 'Computational methods for predicting evolutionarily conserved rather than thermodynamic RNA structures have recently attracted increased interest. These methods are indispensable not only for elucidating the regulatory roles of known RNA transcripts, but also for predicting RNA genes. It has been notoriously difficult to devise them to make the best use of the available data and to predict high-quality RNA structures that may also contain pseudoknots. We introduce a novel theoretical framework for co-estimating an RNA secondary structure including pseudoknots, a multiple sequence alignment, and an evolutionary tree, given several RNA input sequences. We also present an implementation of the framework in a new computer program, called SimulFold, which employs a Bayesian Markov chain Monte Carlo method to sample from the joint posterior distribution of RNA structures, alignments, and trees. We use the new framework to predict RNA structures, and comprehensively evaluate the quality of our predictions by comparing our results to those of several other programs. We also present preliminary data that show SimulFolds potential as an alignment and phylogeny prediction method. SimulFold overcomes many conceptual limitations that current RNA structure prediction methods face, introduces several new theoretical techniques, and generates high-quality predictions of conserved RNA structures that may include pseudoknots. It is thus likely to have a strong impact, both on the field of RNA structure prediction and on a wide range of data analyses.'),
(83702, 2007, 'plos', 'Helicobacter pylori evolution: lineage- specific adaptations in homologs of eukaryotic Sel1-like genes', 'Ogura, Masako|Perez, J Christian|Mittl, Peer R E|Lee, Hae-Kyung|Dailide, Geidrius|Tan, Shumin|Ito, Yoshiyuki|Secka, Ousman|Dailidiene, Daiva|Putty, Kalyani|Berg, Douglas E|Kalia, Awdhesh', 'Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 32, 'Adaptation, Physiological|Amino Acid Sequence|Biological Evolution|Carrier Proteins|Chromosome Mapping|Evolution, Molecular|Genome, Bacterial|Helicobacter pylori|Molecular Sequence Data|Saccharomyces cerevisiae Proteins|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0030151', '17696605', 'Geographic partitioning is postulated to foster divergence of Helicobacter pylori populations as an adaptive response to local differences in predominant host physiology. H. pyloris ability to establish persistent infection despite host inflammatory responses likely involves active management of host defenses using bacterial proteins that may themselves be targets for adaptive evolution. Sequenced H. pylori genomes encode a family of eight or nine secreted proteins containing repeat motifs that are characteristic of the eukaryotic Sel1 regulatory protein, whereas the related Campylobacter and Wolinella genomes each contain only one or two such Sel1-like repeat (SLR) genes (slr genes). Signatures of positive selection (ratio of nonsynonymous to synonymous mutations, dN/dS = omega > 1) were evident in the evolutionary history of H. pylori slr gene family expansion. Sequence analysis of six of these slr genes (hp0160, hp0211, hp0235, hp0519, hp0628, and hp1117) from representative East Asian, European, and African H. pylori strains revealed that all but hp0628 had undergone positive selection, with different amino acids often selected in different regions. Most striking was a divergence of Japanese and Korean alleles of hp0519, with Japanese alleles having undergone particularly strong positive selection (omegaJ > 25), whereas alleles of other genes from these populations were intermingled. Homology-based structural modeling localized most residues under positive selection to SLR protein surfaces. Rapid evolution of certain slr genes in specific H. pylori lineages suggests a model of adaptive change driven by selection for fine-tuning of host responses, and facilitated by geographic isolation. Characterization of such local adaptations should help elucidate how H. pylori manages persistent infection, and potentially lead to interventions tailored to diverse human populations.'),
(83703, 2007, 'plos', 'Mechanisms of firing patterns in fast-spiking cortical interneurons', 'Golomb, David|Donner, Karnit|Shacham, Liron|Shlosberg, Dan|Amitai, Yael|Hansel, David', 'Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel. golomb@bgu.ac.il|Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel. golomb@bgu.ac.il|Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel. golomb@bgu.ac.il|Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel. golomb@bgu.ac.il|Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel. golomb@bgu.ac.il|Department of Physiology, Ben-Gurion University, Beer-Sheva, Israel. golomb@bgu.ac.il', 'Israel|Israel|Israel|Israel|Israel|Israel', 0, 'Action Potentials|Animals|Computer Simulation|Humans|Interneurons|Models, Neurological|Neocortex|Nerve Net|Neural Inhibition|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030156', '17696606', 'Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na(+), delayed-rectifier K(+), and slowly inactivating d-type K(+) conductances. The model is analyzed using nonlinear dynamical system theory. For small Na(+) window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na(+) window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise, subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na(+) window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction.'),
(83704, 2007, 'plos', 'On state-space reduction in multi-strain pathogen models, with an application to antigenic drift in influenza A', 'Kryazhimskiy, Sergey|Dieckmann, Ulf|Levin, Simon A|Dushoff, Jonathan', 'Program in Applied and Computational Mathematics, Princeton University, Princeton, New Jersey, United States of America. skryazhi@princeton.edu|Program in Applied and Computational Mathematics, Princeton University, Princeton, New Jersey, United States of America. skryazhi@princeton.edu|Program in Applied and Computational Mathematics, Princeton University, Princeton, New Jersey, United States of America. skryazhi@princeton.edu|Program in Applied and Computational Mathematics, Princeton University, Princeton, New Jersey, United States of America. skryazhi@princeton.edu', 'Jersey|Jersey|Jersey|Jersey', 43, 'Antigenic Variation|Antigens, Viral|Biological Evolution|Computer Simulation|Genetic Drift|Genetic Variation|Influenza A virus|Models, Genetic|Models, Immunological|Models, Statistical|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.0030159', '17708677', 'Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi-strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state-space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status-based models. The cornerstone of our method is the introduction of immunity variables, which describe multi-strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one-dimensional manifold in a two-dimensional trait space. Our framework broadens the class of multi-strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi-strain pathogens.'),
(83705, 2007, 'plos', 'Automated protein subfamily identification and classification', 'Brown, Duncan P|Krishnamurthy, Nandini|Sjölander, Kimmen', 'Department of Bioengineering, University of California, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, California, United States of America.|Department of Bioengineering, University of California, Berkeley, California, United States of America.', 'United States|United States|United States', 90, 'Algorithms|Amino Acid Sequence|Artificial Intelligence|Markov Chains|Molecular Sequence Data|Pattern Recognition, Automated|Proteins|Reproducibility of Results|Sensitivity and Specificity|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030160', '17708678', 'Function prediction by homology is widely used to provide preliminary functional annotations for genes for which experimental evidence of function is unavailable or limited. This approach has been shown to be prone to systematic error, including percolation of annotation errors through sequence databases. Phylogenomic analysis avoids these errors in function prediction but has been difficult to automate for high-throughput application. To address this limitation, we present a computationally efficient pipeline for phylogenomic classification of proteins. This pipeline uses the SCI-PHY (Subfamily Classification in Phylogenomics) algorithm for automatic subfamily identification, followed by subfamily hidden Markov model (HMM) construction. A simple and computationally efficient scoring scheme using family and subfamily HMMs enables classification of novel sequences to protein families and subfamilies. Sequences representing entirely novel subfamilies are differentiated from those that can be classified to subfamilies in the input training set using logistic regression. Subfamily HMM parameters are estimated using an information-sharing protocol, enabling subfamilies containing even a single sequence to benefit from conservation patterns defining the family as a whole or in related subfamilies. SCI-PHY subfamilies correspond closely to functional subtypes defined by experts and to conserved clades found by phylogenetic analysis. Extensive comparisons of subfamily and family HMM performances show that subfamily HMMs dramatically improve the separation between homologous and non-homologous proteins in sequence database searches. Subfamily HMMs also provide extremely high specificity of classification and can be used to predict entirely novel subtypes. The SCI-PHY Web server at http://phylogenomics.berkeley.edu/SCI-PHY/ allows users to upload a multiple sequence alignment for subfamily identification and subfamily HMM construction. Biologists wishing to provide their own subfamily definitions can do so. Source code is available on the Web page. The Berkeley Phylogenomics Group PhyloFacts resource contains pre-calculated subfamily predictions and subfamily HMMs for more than 40,000 protein families and domains at http://phylogenomics.berkeley.edu/phylofacts/.'),
(83706, 2007, 'plos', 'Elucidating the altered transcriptional programs in breast cancer using independent component analysis', 'Teschendorff, Andrew E|Journée, Michel|Absil, Pierre A|Sepulchre, Rodolphe|Caldas, Carlos', 'Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. aet21@cam.ac.uk|Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. aet21@cam.ac.uk|Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. aet21@cam.ac.uk|Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. aet21@cam.ac.uk|Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. aet21@cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom', 79, 'Adaptation, Physiological|Algorithms|Breast Neoplasms|Gene Expression Profiling|Gene Expression Regulation, Neoplastic|Humans|Models, Genetic|Neoplasm Proteins|Oligonucleotide Array Sequence Analysis|Principal Component Analysis|Signal Transduction|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0030161', '17708679', 'The quantity of mRNA transcripts in a cell is determined by a complex interplay of cooperative and counteracting biological processes. Independent Component Analysis (ICA) is one of a few number of unsupervised algorithms that have been applied to microarray gene expression data in an attempt to understand phenotype differences in terms of changes in the activation/inhibition patterns of biological pathways. While the ICA model has been shown to outperform other linear representations of the data such as Principal Components Analysis (PCA), a validation using explicit pathway and regulatory element information has not yet been performed. We apply a range of popular ICA algorithms to six of the largest microarray cancer datasets and use pathway-knowledge and regulatory-element databases for validation. We show that ICA outperforms PCA and clustering-based methods in that ICA components map closer to known cancer-related pathways, regulatory modules, and cancer phenotypes. Furthermore, we identify cancer signalling and oncogenic pathways and regulatory modules that play a prominent role in breast cancer and relate the differential activation patterns of these to breast cancer phenotypes. Importantly, we find novel associations linking immune response and epithelial-mesenchymal transition pathways with estrogen receptor status and histological grade, respectively. In addition, we find associations linking the activity levels of biological pathways and transcription factors (NF1 and NFAT) with clinical outcome in breast cancer. ICA provides a framework for a more biologically relevant interpretation of genomewide transcriptomic data. Adopting ICA as the analysis tool of choice will help understand the phenotype-pathway relationship and thus help elucidate the molecular taxonomy of heterogeneous cancers and of other complex genetic diseases.'),
(83707, 2007, 'plos', 'Perceptual learning via modification of cortical top-down signals', 'Schäfer, Roland|Vasilaki, Eleni|Senn, Walter', 'Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.|Department of Physiology, University of Bern, Bern, Switzerland.', 'Switzerland|Switzerland|Switzerland', 15, 'Animals|Computational Biology|Electrophysiology|Feedback|Haplorhini|Learning|Models, Neurological|Models, Psychological|Visual Cortex|Visual Pathways|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.0030165', '17715996', 'The primary visual cortex (V1) is pre-wired to facilitate the extraction of behaviorally important visual features. Collinear edge detectors in V1, for instance, mutually enhance each other to improve the perception of lines against a noisy background. The same pre-wiring that facilitates line extraction, however, is detrimental when subjects have to discriminate the brightness of different line segments. How is it possible to improve in one task by unsupervised practicing, without getting worse in the other task? The classical view of perceptual learning is that practicing modulates the feedforward input stream through synaptic modifications onto or within V1. However, any rewiring of V1 would deteriorate other perceptual abilities different from the trained one. We propose a general neuronal model showing that perceptual learning can modulate top-down input to V1 in a task-specific way while feedforward and lateral pathways remain intact. Consistent with biological data, the model explains how context-dependent brightness discrimination is improved by a top-down recruitment of recurrent inhibition and a top-down induced increase of the neuronal gain within V1. Both the top-down modulation of inhibition and of neuronal gain are suggested to be universal features of cortical microcircuits which enable perceptual learning.'),
(83708, 2007, 'plos', 'Inferring function using patterns of native disorder in proteins', 'Lobley, Anna|Swindells, Mark B|Orengo, Christine A|Jones, David T', 'Bioinformatics Unit, Department of Computer Science, University College London, London, United Kingdom.|Bioinformatics Unit, Department of Computer Science, University College London, London, United Kingdom.|Bioinformatics Unit, Department of Computer Science, University College London, London, United Kingdom.|Bioinformatics Unit, Department of Computer Science, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 101, 'Amino Acid Sequence|Artificial Intelligence|Computer Simulation|Models, Biological|Models, Chemical|Models, Molecular|Molecular Sequence Data|Pattern Recognition, Automated|Protein Denaturation|Protein Folding|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030162', '17722973', 'Natively unstructured regions are a common feature of eukaryotic proteomes. Between 30% and 60% of proteins are predicted to contain long stretches of disordered residues, and not only have many of these regions been confirmed experimentally, but they have also been found to be essential for protein function. In this study, we directly address the potential contribution of protein disorder in predicting protein function using standard Gene Ontology (GO) categories. Initially we analyse the occurrence of protein disorder in the human proteome and report ontology categories that are enriched in disordered proteins. Pattern analysis of the distributions of disordered regions in human sequences demonstrated that the functions of intrinsically disordered proteins are both length- and position-dependent. These dependencies were then encoded in feature vectors to quantify the contribution of disorder in human protein function prediction using Support Vector Machine classifiers. The prediction accuracies of 26 GO categories relating to signalling and molecular recognition are improved using the disorder features. The most significant improvements were observed for kinase, phosphorylation, growth factor, and helicase categories. Furthermore, we provide predicted GO term assignments using these classifiers for a set of unannotated and orphan human proteins. In this study, the importance of capturing protein disorder information and its value in function prediction is demonstrated. The GO category classifiers generated can be used to provide more reliable predictions and further insights into the behaviour of orphan and unannotated proteins.'),
(83709, 2007, 'plos', 'A logical model provides insights into T cell receptor signaling', 'Saez-Rodriguez, Julio|Simeoni, Luca|Lindquist, Jonathan A|Hemenway, Rebecca|Bommhardt, Ursula|Arndt, Boerge|Haus, Utz-Uwe|Weismantel, Robert|Gilles, Ernst D|Klamt, Steffen|Schraven, Burkhart', 'Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.|Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany|Germany', 214, 'Computer Simulation|Logistic Models|Models, Immunological|Receptors, Antigen, T-Cell|Signal Transduction|T-Lymphocytes', 'Evaluation Studies', '10.1371/journal.pcbi.0030163', '17722974', 'Cellular decisions are determined by complex molecular interaction networks. Large-scale signaling networks are currently being reconstructed, but the kinetic parameters and quantitative data that would allow for dynamic modeling are still scarce. Therefore, computational studies based upon the structure of these networks are of great interest. Here, a methodology relying on a logical formalism is applied to the functional analysis of the complex signaling network governing the activation of T cells via the T cell receptor, the CD4/CD8 co-receptors, and the accessory signaling receptor CD28. Our large-scale Boolean model, which comprises 94 nodes and 123 interactions and is based upon well-established qualitative knowledge from primary T cells, reveals important structural features (e.g., feedback loops and network-wide dependencies) and recapitulates the global behavior of this network for an array of published data on T cell activation in wild-type and knock-out conditions. More importantly, the model predicted unexpected signaling events after antibody-mediated perturbation of CD28 and after genetic knockout of the kinase Fyn that were subsequently experimentally validated. Finally, we show that the logical model reveals key elements and potential failure modes in network functioning and provides candidates for missing links. In summary, our large-scale logical model for T cell activation proved to be a promising in silico tool, and it inspires immunologists to ask new questions. We think that it holds valuable potential in foreseeing the effects of drugs and network modifications.'),
(83710, 2007, 'plos', 'Design of multi-specificity in protein interfaces', 'Humphris, Elisabeth L|Kortemme, Tanja', 'Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.|Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States', 79, 'Binding Sites|Drug Delivery Systems|Drug Design|Protein Binding|Protein Interaction Mapping|Proteins|Sequence Alignment|Sequence Analysis, Protein|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030164', '17722975', 'Interactions in protein networks may place constraints on protein interface sequences to maintain correct and avoid unwanted interactions. Here we describe a multi-constraint protein design protocol to predict sequences optimized for multiple criteria, such as maintaining sets of interactions, and apply it to characterize the mechanism and extent to which 20 multi-specific proteins are constrained by binding to multiple partners. We find that multi-specific binding is accommodated by at least two distinct patterns. In the simplest case, all partners share key interactions, and sequences optimized for binding to either single or multiple partners recover only a subset of native amino acid residues as optimal. More interestingly, for signaling interfaces functioning as network hubs, we identify a different, multi-faceted mode, where each binding partner prefers its own subset of wild-type residues within the promiscuous binding site. Here, integration of preferences across all partners results in sequences much more native-like than seen in optimization for any single binding partner alone, suggesting these interfaces are substantially optimized for multi-specificity. The two strategies make distinct predictions for interface evolution and design. Shared interfaces may be better small molecule targets, whereas multi-faceted interactions may be more designable for altered specificity patterns. The computational methodology presented here is generalizable for examining how naturally occurring protein sequences have been selected to satisfy a variety of positive and negative constraints, as well as for rationally designing proteins to have desired patterns of altered specificity.'),
(83711, 2007, 'plos', 'Functional representation of enzymes by specific peptides', 'Kunik, Vered|Meroz, Yasmine|Solan, Zach|Sandbank, Ben|Weingart, Uri|Ruppin, Eytan|Horn, David', 'School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.|School of Computer Science, Tel Aviv University, Tel Aviv, Israel.', 'Israel|Israel|Israel|Israel|Israel|Israel|Israel', 16, 'Amino Acid Motifs|Amino Acid Sequence|Enzymes|Molecular Sequence Data|Peptides|Protein Structure, Tertiary|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030167', '17722976', 'Predicting the function of a protein from its sequence is a long-standing goal of bioinformatic research. While sequence similarity is the most popular tool used for this purpose, sequence motifs may also subserve this goal. Here we develop a motif-based method consisting of applying an unsupervised motif extraction algorithm (MEX) to all enzyme sequences, and filtering the results by the four-level classification hierarchy of the Enzyme Commission (EC). The resulting motifs serve as specific peptides (SPs), appearing on single branches of the EC. In contrast to previous motif-based methods, the new method does not require any preprocessing by multiple sequence alignment, nor does it rely on over-representation of motifs within EC branches. The SPs obtained comprise on average 8.4 +/- 4.5 amino acids, and specify the functions of 93% of all enzymes, which is much higher than the coverage of 63% provided by ProSite motifs. The SP classification thus compares favorably with previous function annotation methods and successfully demonstrates an added value in extreme cases where sequence similarity fails. Interestingly, SPs cover most of the annotated active and binding site amino acids, and occur in active-site neighboring 3-D pockets in a highly statistically significant manner. The latter are assumed to have strong biological relevance to the activity of the enzyme. Further filtering of SPs by biological functional annotations results in reduced small subsets of SPs that possess very large enzyme coverage. Overall, SPs both form a very useful tool for enzyme functional classification and bear responsibility for the catalytic biological function carried out by enzymes.'),
(83712, 2007, 'plos', 'Recent evolutions of multiple sequence alignment algorithms', 'Notredame, Cédric', 'Information Génomique et Structurale, CNRS UPR2589, Institute for Structural Biology and Microbiology, Parc Scientifique de Luminy, Marseille, France. cedric.notredame@europe.com', 'France', 142, 'Algorithms|Base Sequence|Chromosome Mapping|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030123', '17784778', '-'),
(83713, 2007, 'plos', 'A primer on learning in Bayesian networks for computational biology', 'Needham, Chris J|Bradford, James R|Bulpitt, Andrew J|Westhead, David R', 'School of Computing, University of Leeds, Leeds, United Kingdom. chrisn@comp.leeds.ac.uk|School of Computing, University of Leeds, Leeds, United Kingdom. chrisn@comp.leeds.ac.uk|School of Computing, University of Leeds, Leeds, United Kingdom. chrisn@comp.leeds.ac.uk|School of Computing, University of Leeds, Leeds, United Kingdom. chrisn@comp.leeds.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 176, 'Algorithms|Artificial Intelligence|Bayes Theorem|Computational Biology|Computer Simulation|Models, Biological|Models, Statistical|Pattern Recognition, Automated', 'Journal Article', '10.1371/journal.pcbi.0030129', '17784779', '-'),
(83714, 2007, 'plos', 'Slowness and sparseness lead to place, head-direction, and spatial-view cells', 'Franzius, Mathias|Sprekeler, Henning|Wiskott, Laurenz', 'Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. m.franzius@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. m.franzius@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt-Universität zu Berlin, Berlin, Germany. m.franzius@biologie.hu-berlin.de', 'Germany|Germany|Germany', 124, 'Animals|Computer Simulation|Head Movements|Hippocampus|Models, Neurological|Nerve Net|Neurons, Afferent|Orientation|Rats|Space Perception', 'Journal Article', '10.1371/journal.pcbi.0030166', '17784780', 'We present a model for the self-organized formation of place cells, head-direction cells, and spatial-view cells in the hippocampal formation based on unsupervised learning on quasi-natural visual stimuli. The model comprises a hierarchy of Slow Feature Analysis (SFA) nodes, which were recently shown to reproduce many properties of complex cells in the early visual system []. The system extracts a distributed grid-like representation of position and orientation, which is transcoded into a localized place-field, head-direction, or view representation, by sparse coding. The type of cells that develops depends solely on the relevant input statistics, i.e., the movement pattern of the simulated animal. The numerical simulations are complemented by a mathematical analysis that allows us to accurately predict the output of the top SFA layer.'),
(83715, 2007, 'plos', 'A numerical approach to ion channel modelling using whole-cell voltage-clamp recordings and a genetic algorithm', 'Gurkiewicz, Meron|Korngreen, Alon', 'The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.|The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.', 'Israel|Israel', 48, 'Action Potentials|Algorithms|Cell Membrane|Computer Simulation|Ion Channel Gating|Ion Channels|Membrane Potentials|Models, Genetic|Models, Neurological|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030169', '17784781', 'The activity of trans-membrane proteins such as ion channels is the essence of neuronal transmission. The currently most accurate method for determining ion channel kinetic mechanisms is single-channel recording and analysis. Yet, the limitations and complexities in interpreting single-channel recordings discourage many physiologists from using them. Here we show that a genetic search algorithm in combination with a gradient descent algorithm can be used to fit whole-cell voltage-clamp data to kinetic models with a high degree of accuracy. Previously, ion channel stimulation traces were analyzed one at a time, the results of these analyses being combined to produce a picture of channel kinetics. Here the entire set of traces from all stimulation protocols are analysed simultaneously. The algorithm was initially tested on simulated current traces produced by several Hodgkin-Huxley-like and Markov chain models of voltage-gated potassium and sodium channels. Currents were also produced by simulating levels of noise expected from actual patch recordings. Finally, the algorithm was used for finding the kinetic parameters of several voltage-gated sodium and potassium channels models by matching its results to data recorded from layer 5 pyramidal neurons of the rat cortex in the nucleated outside-out patch configuration. The minimization scheme gives electrophysiologists a tool for reproducing and simulating voltage-gated ion channel kinetics at the cellular level.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83716, 2007, 'plos', 'Buffering mechanisms in aging: a systems approach toward uncovering the genetic component of aging', 'Bergman, Aviv|Atzmon, Gil|Ye, Kenny|MacCarthy, Thomas|Barzilai, Nir', 'Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America. aviv@bergmanlab.org|Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America. aviv@bergmanlab.org|Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America. aviv@bergmanlab.org|Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America. aviv@bergmanlab.org|Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America. aviv@bergmanlab.org', 'United States|United States|United States|United States|United States', 83, 'Aging|Computer Simulation|Genetic Predisposition to Disease|Genetics, Population|Genotype|Humans|Longevity|Models, Genetic|Survival Rate', 'Journal Article', '10.1371/journal.pcbi.0030170', '17784782', 'An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the oldest old Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate-buffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar, thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.'),
(83717, 2007, 'plos', 'Pathway switching explains the sharp response characteristic of hypoxia response network', 'Yu, Yihai|Wang, Guanyu|Simha, Rahul|Peng, Weiqun|Turano, Frank|Zeng, Chen', 'Department of Physics, George Washington University, Washington, DC, United States of America.|Department of Physics, George Washington University, Washington, DC, United States of America.|Department of Physics, George Washington University, Washington, DC, United States of America.|Department of Physics, George Washington University, Washington, DC, United States of America.|Department of Physics, George Washington University, Washington, DC, United States of America.|Department of Physics, George Washington University, Washington, DC, United States of America.', 'United States|United States|United States|United States|United States|United States', 21, 'Adaptation, Physiological|Cell Hypoxia|Computer Simulation|Hypoxia-Inducible Factor 1|Models, Biological|Oxygen|Oxygen Consumption|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030171', '17784783', 'Hypoxia induces the expression of genes that alter metabolism through the hypoxia-inducible factor (HIF). A theoretical model based on differential equations of the hypoxia response network has been previously proposed in which a sharp response to changes in oxygen concentration was observed but not quantitatively explained. That model consisted of reactions involving 23 molecular species among which the concentrations of HIF and oxygen were linked through a complex set of reactions. In this paper, we analyze this previous model using a combination of mathematical tools to draw out the key components of the network and explain quantitatively how they contribute to the sharp oxygen response. We find that the switch-like behavior is due to pathway-switching wherein HIF degrades rapidly under normoxia in one pathway, while the other pathway accumulates HIF to trigger downstream genes under hypoxia. The analytic technique is potentially useful in studying larger biomedical networks.'),
(83718, 2007, 'plos', 'A balanced memory network', 'Roudi, Yasser|Latham, Peter E', 'Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. yasser@gatsby.ucl.ac.uk|Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom. yasser@gatsby.ucl.ac.uk', 'United Kingdom|United Kingdom', 51, 'Action Potentials|Computer Simulation|Information Storage and Retrieval|Memory|Models, Neurological|Nerve Net|Neuronal Plasticity|Neurons|Synaptic Transmission', 'Journal Article', '10.1371/journal.pcbi.0030141', '17845070', 'A fundamental problem in neuroscience is understanding how working memory--the ability to store information at intermediate timescales, like tens of seconds--is implemented in realistic neuronal networks. The most likely candidate mechanism is the attractor network, and a great deal of effort has gone toward investigating it theoretically. Yet, despite almost a quarter century of intense work, attractor networks are not fully understood. In particular, there are still two unanswered questions. First, how is it that attractor networks exhibit irregular firing, as is observed experimentally during working memory tasks? And second, how many memories can be stored under biologically realistic conditions? Here we answer both questions by studying an attractor neural network in which inhibition and excitation balance each other. Using mean-field analysis, we derive a three-variable description of attractor networks. From this description it follows that irregular firing can exist only if the number of neurons involved in a memory is large. The same mean-field analysis also shows that the number of memories that can be stored in a network scales with the number of excitatory connections, a result that has been suggested for simple models but never shown for realistic ones. Both of these predictions are verified using simulations with large networks of spiking neurons.'),
(83719, 2007, 'plos', 'Orthologous transcription factors in bacteria have different functions and regulate different genes', 'Price, Morgan N|Dehal, Paramvir S|Arkin, Adam P', 'Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. morgannprice@yahoo.com|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. morgannprice@yahoo.com|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. morgannprice@yahoo.com', 'United States|United States|United States', 68, 'Bacterial Proteins|Conserved Sequence|DNA Mutational Analysis|Evolution, Molecular|Gene Expression Regulation, Bacterial|Genetic Variation|Regulatory Sequences, Nucleic Acid|Structure-Activity Relationship|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0030175', '17845071', 'Transcription factors (TFs) form large paralogous gene families and have complex evolutionary histories. Here, we ask whether putative orthologs of TFs, from bidirectional best BLAST hits (BBHs), are evolutionary orthologs with conserved functions. We show that BBHs of TFs from distantly related bacteria are usually not evolutionary orthologs. Furthermore, the false orthologs usually respond to different signals and regulate distinct pathways, while the few BBHs that are evolutionary orthologs do have conserved functions. To test the conservation of regulatory interactions, we analyze expression patterns. We find that regulatory relationships between TFs and their regulated genes are usually not conserved for BBHs in Escherichia coli K12 and Bacillus subtilis. Even in the much more closely related bacteria Vibrio cholerae and Shewanella oneidensis MR-1, predicting regulation from E. coli BBHs has high error rates. Using gene-regulon correlations, we identify genes whose expression pattern differs between E. coli and S. oneidensis. Using literature searches and sequence analysis, we show that these changes in expression patterns reflect changes in gene regulation, even for evolutionary orthologs. We conclude that the evolution of bacterial regulation should be analyzed with phylogenetic trees, rather than BBHs, and that bacterial regulatory networks evolve more rapidly than previously thought.'),
(83720, 2007, 'plos', 'Signal propagation in proteins and relation to equilibrium fluctuations', 'Chennubhotla, Chakra|Bahar, Ivet', 'Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.', 'United States|United States', 156, 'Computer Simulation|Homeostasis|Information Storage and Retrieval|Models, Biological|Models, Statistical|Protein Interaction Mapping|Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030172', '17892319', 'Elastic network (EN) models have been widely used in recent years for describing protein dynamics, based on the premise that the motions naturally accessible to native structures are relevant to biological function. We posit that equilibrium motions also determine communication mechanisms inherent to the network architecture. To this end, we explore the stochastics of a discrete-time, discrete-state Markov process of information transfer across the network of residues. We measure the communication abilities of residue pairs in terms of hit and commute times, i.e., the number of steps it takes on an average to send and receive signals. Functionally active residues are found to possess enhanced communication propensities, evidenced by their short hit times. Furthermore, secondary structural elements emerge as efficient mediators of communication. The present findings provide us with insights on the topological basis of communication in proteins and design principles for efficient signal transduction. While hit/commute times are information-theoretic concepts, a central contribution of this work is to rigorously show that they have physical origins directly relevant to the equilibrium fluctuations of residues predicted by EN models.'),
(83721, 2007, 'plos', 'Excitability constraints on voltage-gated sodium channels', 'Angelino, Elaine|Brenner, Michael P', 'Systems Biology Graduate Program, Harvard University, Cambridge, Massachusetts, USA.|Systems Biology Graduate Program, Harvard University, Cambridge, Massachusetts, USA.', 'United States|United States', 21, 'Animals|Biological Evolution|Evolution, Molecular|Humans|Ion Channel Gating|Membrane Potentials|Sodium Channels', 'Journal Article', '10.1371/journal.pcbi.0030177', '17892320', 'We study how functional constraints bound and shape evolution through an analysis of mammalian voltage-gated sodium channels. The primary function of sodium channels is to allow the propagation of action potentials. Since Hodgkin and Huxley, mathematical models have suggested that sodium channel properties need to be tightly constrained for an action potential to propagate. There are nine mammalian genes encoding voltage-gated sodium channels, many of which are more than approximately 90% identical by sequence. This sequence similarity presumably corresponds to similarity of function, consistent with the idea that these properties must be tightly constrained. However, the multiplicity of genes encoding sodium channels raises the question: why are there so many? We demonstrate that the simplest theoretical constraints bounding sodium channel diversity--the requirements of membrane excitability and the uniqueness of the resting potential--act directly on constraining sodium channel properties. We compare the predicted constraints with functional data on mammalian sodium channel properties collected from the literature, including 172 different sets of measurements from 40 publications, wild-type and mutant, under a variety of conditions. The data from all channel types, including mutants, obeys the excitability constraint, on the other hand, channels expressed in muscle tend to obey the constraint of a unique resting potential, while channels expressed in neuronal tissue do not. The excitability properties alone distinguish the nine sodium channels into four different groups that are consistent with phylogenetic analysis. Our calculations suggest interpretations for the functional differences between these groups.'),
(83722, 2007, 'plos', 'Structure-templated predictions of novel protein interactions from sequence information', 'Betel, Doron|Breitkreuz, Kevin E|Isserlin, Ruth|Dewar-Darch, Danielle|Tyers, Mike|Hogue, Christopher W V', 'Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. betel@cbio.mskcc.org|Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. betel@cbio.mskcc.org|Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. betel@cbio.mskcc.org|Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. betel@cbio.mskcc.org|Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. betel@cbio.mskcc.org|Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada. betel@cbio.mskcc.org', 'Canada|Canada|Canada|Canada|Canada|Canada', 0, 'Algorithms|Amino Acid Sequence|Binding Sites|Computer Simulation|Conserved Sequence|Feasibility Studies|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Interaction Mapping|Protein Structure, Tertiary|Sequence Alignment|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0030182', '17892321', 'The multitude of functions performed in the cell are largely controlled by a set of carefully orchestrated protein interactions often facilitated by specific binding of conserved domains in the interacting proteins. Interacting domains commonly exhibit distinct binding specificity to short and conserved recognition peptides called binding profiles. Although many conserved domains are known in nature, only a few have well-characterized binding profiles. Here, we describe a novel predictive method known as domain-motif interactions from structural topology (D-MIST) for elucidating the binding profiles of interacting domains. A set of domains and their corresponding binding profiles were derived from extant protein structures and protein interaction data and then used to predict novel protein interactions in yeast. A number of the predicted interactions were verified experimentally, including new interactions of the mitotic exit network, RNA polymerases, nucleotide metabolism enzymes, and the chaperone complex. These results demonstrate that new protein interactions can be predicted exclusively from sequence information.'),
(83723, 2007, 'plos', 'Development of genomic sciences in Mexico: a good start and a long way to go', 'Palacios, Rafael|Collado-Vides, Julio', 'Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico. palacios@ccg.unam.mx|Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico. palacios@ccg.unam.mx', 'Mexico|Mexico', 0, 'Chromosome Mapping|Computational Biology|Genomics|Mexico|Research|Science', 'Journal Article', '10.1371/journal.pcbi.0030143', '17907791', '-'),
(83724, 2007, 'plos', 'From pathways databases to network models of switching behavior', 'Aguda, Baltazar D|Goryachev, Andrew B', 'Mathematical Biosciences Institute, Ohio State University, Columbus, Ohio, USA. bdaguda@mbi.osu.edu|Mathematical Biosciences Institute, Ohio State University, Columbus, Ohio, USA. bdaguda@mbi.osu.edu', 'United States|United States', 14, 'Computer Simulation|Databases, Genetic|Gene Expression Profiling|Gene Expression Regulation|Information Storage and Retrieval|Models, Biological|Proteome|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0030152', '17907792', '-'),
(83725, 2007, 'plos', 'Developing computational biology', 'Bourne, Philip E|Brenner, Steven E', 'Mathematical Biosciences Institute, Ohio State University, Columbus, Ohio, USA. bdaguda@mbi.osu.edu|Mathematical Biosciences Institute, Ohio State University, Columbus, Ohio, USA. bdaguda@mbi.osu.edu', 'United States|United States', 0, 'Computational Biology|Information Dissemination|Periodicals as Topic|United States', 'Editorial', '10.1371/journal.pcbi.0030157', '17907793', '-'),
(83726, 2007, 'plos', 'A computational approach to the functional screening of genomes', 'Chiarugi, Davide|Degano, Pierpaolo|Marangoni, Roberto', 'Dipartimento di Matematica e Informatica, Università di Siena, Siena, Italy.|Dipartimento di Matematica e Informatica, Università di Siena, Siena, Italy.|Dipartimento di Matematica e Informatica, Università di Siena, Siena, Italy.', 'Italy|Italy|Italy', 13, 'Algorithms|Biological Evolution|Cell Physiological Phenomena|Chromosome Mapping|Computer Simulation|Evolution, Molecular|Models, Genetic|Origin of Life', 'Journal Article', '10.1371/journal.pcbi.0030174', '17907794', 'Comparative genomics usually involves managing the functional aspects of genomes, by simply comparing gene-by-gene functions. Following this approach, Mushegian and Koonin proposed a hypothetical minimal genome, Minimal Gene Set (MGS), aiming for a possible oldest ancestor genome. They obtained MGS by comparing the genomes of two simple bacteria and eliminating duplicated or functionally identical genes. The authors raised the fundamental question of whether a hypothetical organism possessing MGS is able to live or not. We attacked this viability problem specifying in silico the metabolic pathways of the MGS-based prokaryote. We then performed a dynamic simulation of cellular metabolic activities in order to check whether the MGS-prokaryote reaches some equilibrium state and produces the necessary biomass. We assumed these two conditions to be necessary for a living organism. Our simulations clearly show that the MGS does not express an organism that is able to live. We then iteratively proceeded with functional replacements in order to obtain a genome composition that gives rise to equilibrium. We ruled out 76 of the original 254 genes in the MGS, because they resulted in duplication from a functional point of view. We also added seven genes not present in the MGS. These genes encode for enzymes involved in critical nodes of the metabolic network. These modifications led to a genome composed of 187 elements expressing a virtually living organism, Virtual Cell (ViCe), that exhibits homeostatic capabilities and produces biomass. Moreover, the steady-state distribution of the concentrations of virtual metabolites that resulted was similar to that experimentally measured in bacteria. We conclude then that ViCe is able to live in silico.'),
(83727, 2007, 'plos', 'What are lightness illusions and why do we see them?', 'Corney, David|Lotto, R Beau', 'UCL Institute of Ophthalmology, University College London, London, United Kingdom.|UCL Institute of Ophthalmology, University College London, London, United Kingdom.', 'United Kingdom|United Kingdom', 0, 'Artificial Intelligence|Biomimetics|Humans|Image Interpretation, Computer-Assisted|Nerve Net|Optical Illusions|Photometry|Visual Perception', 'Journal Article', '10.1371/journal.pcbi.0030180', '17907795', 'Lightness illusions are fundamental to human perception, and yet why we see them is still the focus of much research. Here we address the question by modelling not human physiology or perception directly as is typically the case but our natural visual world and the need for robust behaviour. Artificial neural networks were trained to predict the reflectance of surfaces in a synthetic ecology consisting of 3-D dead-leaves scenes under non-uniform illumination. The networks learned to solve this task accurately and robustly given only ambiguous sense data. In addition--and as a direct consequence of their experience--the networks also made systematic errors in their behaviour commensurate with human illusions, which includes brightness contrast and assimilation--although assimilation (specifically Whites illusion) only emerged when the virtual ecology included 3-D, as opposed to 2-D scenes. Subtle variations in these illusions, also found in human perception, were observed, such as the asymmetry of brightness contrast. These data suggest that illusions arise in humans because (i) natural stimuli are ambiguous, and (ii) this ambiguity is resolved empirically by encoding the statistical relationship between images and scenes in past visual experience. Since resolving stimulus ambiguity is a challenge faced by all visual systems, a corollary of these findings is that human illusions must be experienced by all visual animals regardless of their particular neural machinery. The data also provide a more formal definition of illusion: the condition in which the true source of a stimulus differs from what is its most likely (and thus perceived) source. As such, illusions are not fundamentally different from non-illusory percepts, all being direct manifestations of the statistical relationship between images and scenes.'),
(83728, 2007, 'plos', 'Organization and evolution of primate centromeric DNA from whole-genome shotgun sequence data', 'Alkan, Can|Ventura, Mario|Archidiacono, Nicoletta|Rocchi, Mariano|Sahinalp, S Cenk|Eichler, Evan E', 'Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.', 'United States|United States|United States|United States|United States|United States', 55, 'Animals|Base Sequence|Biological Evolution|Centromere|Chromosome Mapping|DNA, Satellite|Evolution, Molecular|Genome|Humans|Macaca|Molecular Sequence Data|Pan troglodytes|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0030181', '17907796', 'The major DNA constituent of primate centromeres is alpha satellite DNA. As much as 2%-5% of sequence generated as part of primate genome sequencing projects consists of this material, which is fragmented or not assembled as part of published genome sequences due to its highly repetitive nature. Here, we develop computational methods to rapidly recover and categorize alpha-satellite sequences from previously uncharacterized whole-genome shotgun sequence data. We present an algorithm to computationally predict potential higher-order array structure based on paired-end sequence data and then experimentally validate its organization and distribution by experimental analyses. Using whole-genome shotgun data from the human, chimpanzee, and macaque genomes, we examine the phylogenetic relationship of these sequences and provide further support for a model for their evolution and mutation over the last 25 million years. Our results confirm fundamental differences in the dispersal and evolution of centromeric satellites in the Old World monkey and ape lineages of evolution.'),
(83729, 2007, 'plos', 'Bistability and oscillations in the Huang-Ferrell model of MAPK signaling', 'Qiao, Liang|Nachbar, Robert B|Kevrekidis, Ioannis G|Shvartsman, Stanislav Y', 'Department of Chemical Engineering, Princeton University, Princeton, New Jersey, USA.|Department of Chemical Engineering, Princeton University, Princeton, New Jersey, USA.|Department of Chemical Engineering, Princeton University, Princeton, New Jersey, USA.|Department of Chemical Engineering, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey|Jersey', 0, 'Algorithms|Biological Clocks|Computer Simulation|Extracellular Signal-Regulated MAP Kinases|MAP Kinase Signaling System|Models, Biological', 'Journal Article', '10.1371/journal.pcbi.0030184', '17907797', 'Physicochemical models of signaling pathways are characterized by high levels of structural and parametric uncertainty, reflecting both incomplete knowledge about signal transduction and the intrinsic variability of cellular processes. As a result, these models try to predict the dynamics of systems with tens or even hundreds of free parameters. At this level of uncertainty, model analysis should emphasize statistics of systems-level properties, rather than the detailed structure of solutions or boundaries separating different dynamic regimes. Based on the combination of random parameter search and continuation algorithms, we developed a methodology for the statistical analysis of mechanistic signaling models. In applying it to the well-studied MAPK cascade model, we discovered a large region of oscillations and explained their emergence from single-stage bistability. The surprising abundance of strongly nonlinear (oscillatory and bistable) input/output maps revealed by our analysis may be one of the reasons why the MAPK cascade in vivo is embedded in more complex regulatory structures. We argue that this type of analysis should accompany nonlinear multiparameter studies of stationary as well as transient features in network dynamics.'),
(83730, 2007, 'plos', 'The origins of specificity in polyketide synthase protein interactions', 'Thattai, Mukund|Burak, Yoram|Shraiman, Boris I', 'National Centre for Biological Sciences, Bangalore, India. thattai@ncbs.res.in|National Centre for Biological Sciences, Bangalore, India. thattai@ncbs.res.in|National Centre for Biological Sciences, Bangalore, India. thattai@ncbs.res.in', 'India|India|India', 0, 'Amino Acid Sequence|Enzyme Activation|Evolution, Molecular|Molecular Sequence Data|Polyketide Synthases|Protein Interaction Mapping|Sequence Analysis, Protein|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.0030186', '17907798', 'Polyketides, a diverse group of heteropolymers with antibiotic and antitumor properties, are assembled in bacteria by multiprotein chains of modular polyketide synthase (PKS) proteins. Specific protein-protein interactions determine the order of proteins within a multiprotein chain, and thereby the order in which chemically distinct monomers are added to the growing polyketide product. Here we investigate the evolutionary and molecular origins of protein interaction specificity. We focus on the short, conserved N- and C-terminal docking domains that mediate interactions between modular PKS proteins. Our computational analysis, which combines protein sequence data with experimental protein interaction data, reveals a hierarchical interaction specificity code. PKS docking domains are descended from a single ancestral interacting pair, but have split into three phylogenetic classes that are mutually noninteracting. Specificity within one such compatibility class is determined by a few key residues, which can be used to define compatibility subclasses. We identify these residues using a novel, highly sensitive co-evolution detection algorithm called CRoSS (correlated residues of statistical significance). The residue pairs selected by CRoSS are involved in direct physical interactions in a docked-domain NMR structure. A single PKS system can use docking domain pairs from multiple classes, as well as domain pairs from multiple subclasses of any given class. The termini of individual proteins are frequently shuffled, but docking domain pairs straddling two interacting proteins are linked as an evolutionary module. The hierarchical and modular organization of the specificity code is intimately related to the processes by which bacteria generate new PKS pathways.'),
(83731, 2007, 'plos', 'Reply to Ten simple rules for getting published', 'Grosch, Eric', 'National Centre for Biological Sciences, Bangalore, India. thattai@ncbs.res.in', 'India', 0, 'Editorial Policies|Peer Review, Research|Periodicals as Topic|Publishing|Research|Writing', 'Comment', '10.1371/journal.pcbi.0030190', '17907799', '-'),
(83732, 2007, 'plos', 'Heat shock response in CHO mammalian cells is controlled by a nonlinear stochastic process', 'Lipan, Ovidiu|Navenot, Jean-Marc|Wang, Zixuan|Huang, Lei|Peiper, Stephen C', 'Department of Physics, University of Richmond, Richmond, Virginia, USA. olipan@richmond.edu|Department of Physics, University of Richmond, Richmond, Virginia, USA. olipan@richmond.edu|Department of Physics, University of Richmond, Richmond, Virginia, USA. olipan@richmond.edu|Department of Physics, University of Richmond, Richmond, Virginia, USA. olipan@richmond.edu|Department of Physics, University of Richmond, Richmond, Virginia, USA. olipan@richmond.edu', 'United States|United States|United States|United States|United States', 0, 'Animals|CHO Cells|Computer Simulation|Cricetinae|Cricetulus|Female|Gene Expression Regulation|Heat-Shock Proteins|Heat-Shock Response|Models, Biological|Nonlinear Dynamics|Numerical Analysis, Computer-Assisted|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0030187', '17922567', 'In many biological systems, the interactions that describe the coupling between different units in a genetic network are nonlinear and stochastic. We study the interplay between stochasticity and nonlinearity using the responses of Chinese hamster ovary (CHO) mammalian cells to different temperature shocks. The experimental data show that the mean value response of a cell population can be described by a mathematical expression (empirical law) which is valid for a large range of heat shock conditions. A nonlinear stochastic theoretical model was developed that explains the empirical law for the mean response. Moreover, the theoretical model predicts a specific biological probability distribution of responses for a cell population. The prediction was experimentally confirmed by measurements at the single-cell level. The computational approach can be used to study other nonlinear stochastic biological phenomena.'),
(83733, 2007, 'plos', 'Universally sloppy parameter sensitivities in systems biology models', 'Gutenkunst, Ryan N|Waterfall, Joshua J|Casey, Fergal P|Brown, Kevin S|Myers, Christopher R|Sethna, James P', 'Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca, New York, USA. rng7@cornell.edu|Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca, New York, USA. rng7@cornell.edu|Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca, New York, USA. rng7@cornell.edu|Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca, New York, USA. rng7@cornell.edu|Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca, New York, USA. rng7@cornell.edu|Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca, New York, USA. rng7@cornell.edu', 'United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Computer Simulation|Half-Life|Meta-Analysis as Topic|Metabolic Networks and Pathways|Models, Biological|Models, Statistical|Monte Carlo Method|Nonlinear Dynamics|Probability|Sensitivity and Specificity|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.0030189', '17922568', 'Quantitative computational models play an increasingly important role in modern biology. Such models typically involve many free parameters, and assigning their values is often a substantial obstacle to model development. Directly measuring in vivo biochemical parameters is difficult, and collectively fitting them to other experimental data often yields large parameter uncertainties. Nevertheless, in earlier work we showed in a growth-factor-signaling model that collective fitting could yield well-constrained predictions, even when it left individual parameters very poorly constrained. We also showed that the model had a sloppy spectrum of parameter sensitivities, with eigenvalues roughly evenly distributed over many decades. Here we use a collection of models from the literature to test whether such sloppy spectra are common in systems biology. Strikingly, we find that every model we examine has a sloppy spectrum of sensitivities. We also test several consequences of this sloppiness for building predictive models. In particular, sloppiness suggests that collective fits to even large amounts of ideal time-series data will often leave many parameters poorly constrained. Tests over our model collection are consistent with this suggestion. This difficulty with collective fits may seem to argue for direct parameter measurements, but sloppiness also implies that such measurements must be formidably precise and complete to usefully constrain many model predictions. We confirm this implication in our growth-factor-signaling model. Our results suggest that sloppy sensitivity spectra are universal in systems biology models. The prevalence of sloppiness highlights the power of collective fits and suggests that modelers should focus on predictions rather than on parameters.'),
(83734, 2007, 'plos', 'Metabolic reconstruction and modeling of nitrogen fixation in Rhizobium etli', 'Resendis-Antonio, Osbaldo|Reed, Jennifer L|Encarnación, Sergio|Collado-Vides, Julio|Palsson, Bernhard Ø', 'Bioengineering Department, University of California San Diego, La Jolla, California, USA.|Bioengineering Department, University of California San Diego, La Jolla, California, USA.|Bioengineering Department, University of California San Diego, La Jolla, California, USA.|Bioengineering Department, University of California San Diego, La Jolla, California, USA.|Bioengineering Department, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States|United States|United States', 0, 'Gene Expression Regulation, Bacterial|Genome, Bacterial|Metabolic Networks and Pathways|Models, Biological|Nitrogen Fixation|Rhizobium etli|Symbiosis', 'Journal Article', '10.1371/journal.pcbi.0030192', '17922569', 'Rhizobiaceas are bacteria that fix nitrogen during symbiosis with plants. This symbiotic relationship is crucial for the nitrogen cycle, and understanding symbiotic mechanisms is a scientific challenge with direct applications in agronomy and plant development. Rhizobium etli is a bacteria which provides legumes with ammonia (among other chemical compounds), thereby stimulating plant growth. A genome-scale approach, integrating the biochemical information available for R. etli, constitutes an important step toward understanding the symbiotic relationship and its possible improvement. In this work we present a genome-scale metabolic reconstruction (iOR363) for R. etli CFN42, which includes 387 metabolic and transport reactions across 26 metabolic pathways. This model was used to analyze the physiological capabilities of R. etli during stages of nitrogen fixation. To study the physiological capacities in silico, an objective function was formulated to simulate symbiotic nitrogen fixation. Flux balance analysis (FBA) was performed, and the predicted active metabolic pathways agreed qualitatively with experimental observations. In addition, predictions for the effects of gene deletions during nitrogen fixation in Rhizobia in silico also agreed with reported experimental data. Overall, we present some evidence supporting that FBA of the reconstructed metabolic network for R. etli provides results that are in agreement with physiological observations. Thus, as for other organisms, the reconstructed genome-scale metabolic network provides an important framework which allows us to compare model predictions with experimental measurements and eventually generate hypotheses on ways to improve nitrogen fixation.'),
(83735, 2007, 'plos', 'A statistical framework for modeling HLA-dependent T cell response data', 'Listgarten, Jennifer|Frahm, Nicole|Kadie, Carl|Brander, Christian|Heckerman, David', 'Microsoft Research, Redmond, Washington, USA.|Microsoft Research, Redmond, Washington, USA.|Microsoft Research, Redmond, Washington, USA.|Microsoft Research, Redmond, Washington, USA.|Microsoft Research, Redmond, Washington, USA.', 'United States|United States|United States|United States|United States', 0, 'Alleles|Computational Biology|Enzyme-Linked Immunosorbent Assay|Epitopes, T-Lymphocyte|False Positive Reactions|HLA Antigens|Humans|Models, Statistical|Models, Theoretical|Reproducibility of Results|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.0030188', '17937494', 'The identification of T cell epitopes and their HLA (human leukocyte antigen) restrictions is important for applications such as the design of cellular vaccines for HIV. Traditional methods for such identification are costly and time-consuming. Recently, a more expeditious laboratory technique using ELISpot assays has been developed that allows for rapid screening of specific responses. However, this assay does not directly provide information concerning the HLA restriction of a response, a critical piece of information for vaccine design. Thus, we introduce, apply, and validate a statistical model for identifying HLA-restricted epitopes from ELISpot data. By looking at patterns across a broad range of donors, in conjunction with our statistical model, we can determine (probabilistically) which of the HLA alleles are likely to be responsible for the observed reactivities. Additionally, we can provide a good estimate of the number of false positives generated by our analysis (i.e., the false discovery rate). This model allows us to learn about new HLA-restricted epitopes from ELISpot data in an efficient, cost-effective, and high-throughput manner. We applied our approach to data from donors infected with HIV and identified many potential new HLA restrictions. Among 134 such predictions, six were confirmed in the lab and the remainder could not be ruled as invalid. These results shed light on the extent of HLA class I promiscuity, which has significant implications for the understanding of HLA class I antigen presentation and vaccine development.'),
(83736, 2007, 'plos', 'Fast pairwise structural RNA alignments by pruning of the dynamical programming matrix', 'Havgaard, Jakob H|Torarinsson, Elfar|Gorodkin, Jan', 'Division of Genetics and Bioinformatics, University of Copenhagen, Frederiksberg, Denmark.|Division of Genetics and Bioinformatics, University of Copenhagen, Frederiksberg, Denmark.|Division of Genetics and Bioinformatics, University of Copenhagen, Frederiksberg, Denmark.', 'Denmark|Denmark|Denmark', 85, 'Algorithms|Animals|Computational Biology|Humans|Mice|Models, Statistical|Models, Theoretical|Nucleic Acid Conformation|RNA|RNA, Untranslated|Software|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0030193', '17937495', 'It has become clear that noncoding RNAs (ncRNA) play important roles in cells, and emerging studies indicate that there might be a large number of unknown ncRNAs in mammalian genomes. There exist computational methods that can be used to search for ncRNAs by comparing sequences from different genomes. One main problem with these methods is their computational complexity, and heuristics are therefore employed. Two heuristics are currently very popular: pre-folding and pre-aligning. However, these heuristics are not ideal, as pre-aligning is dependent on sequence similarity that may not be present and pre-folding ignores the comparative information. Here, pruning of the dynamical programming matrix is presented as an alternative novel heuristic constraint. All subalignments that do not exceed a length-dependent minimum score are discarded as the matrix is filled out, thus giving the advantage of providing the constraints dynamically. This has been included in a new implementation of the FOLDALIGN algorithm for pairwise local or global structural alignment of RNA sequences. It is shown that time and memory requirements are dramatically lowered while overall performance is maintained. Furthermore, a new divide and conquer method is introduced to limit the memory requirement during global alignment and backtrack of local alignment. All branch points in the computed RNA structure are found and used to divide the structure into smaller unbranched segments. Each segment is then realigned and backtracked in a normal fashion. Finally, the FOLDALIGN algorithm has also been updated with a better memory implementation and an improved energy model. With these improvements in the algorithm, the FOLDALIGN software package provides the molecular biologist with an efficient and user-friendly tool for searching for new ncRNAs. The software package is available for download at http://foldalign.ku.dk.'),
(83737, 2007, 'plos', 'Enzyme localization can drastically affect signal amplification in signal transduction pathways', 'van Albada, Siebe B|ten Wolde, Pieter Rein', 'FOM Institute for Atomic and Molecular Physics, Amsterdam, The Netherlands.|FOM Institute for Atomic and Molecular Physics, Amsterdam, The Netherlands.', 'Netherlands|Netherlands', 0, 'Animals|Cell Physiological Phenomena|Computational Biology|Cytoplasm|Enzymes|Kinetics|Models, Biological|Models, Statistical|Models, Theoretical|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.0030195', '17937496', 'Push-pull networks are ubiquitous in signal transduction pathways in both prokaryotic and eukaryotic cells. They allow cells to strongly amplify signals via the mechanism of zero-order ultrasensitivity. In a push-pull network, two antagonistic enzymes control the activity of a protein by covalent modification. These enzymes are often uniformly distributed in the cytoplasm. They can, however, also be colocalized in space, for instance, near the pole of the cell. Moreover, it is increasingly recognized that these enzymes can also be spatially separated, leading to gradients of the active form of the messenger protein. Here, we investigate the consequences of the spatial distributions of the enzymes for the amplification properties of push-pull networks. Our calculations reveal that enzyme localization by itself can have a dramatic effect on the gain. The gain is maximized when the two enzymes are either uniformly distributed or colocalized in one region in the cell. Depending on the diffusion constants, however, the sharpness of the response can be strongly reduced when the enzymes are spatially separated. We discuss how our predictions could be tested experimentally.'),
(83738, 2007, 'plos', 'Systems analysis of chaperone networks in the malarial parasite Plasmodium falciparum', 'Pavithra, Soundara Raghavan|Kumar, Ranjit|Tatu, Utpal', 'Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India.|Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India.|Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India.', 'India|India|India', 87, 'Animals|Computational Biology|Computer Simulation|Erythrocytes|Humans|Malaria|Models, Biological|Molecular Chaperones|Plasmodium falciparum|Protozoan Proteins', 'Journal Article', '10.1371/journal.pcbi.0030168', '17941702', 'Molecular chaperones participate in the maintenance of cellular protein homeostasis, cell growth and differentiation, signal transduction, and development. Although a vast body of information is available regarding individual chaperones, few studies have attempted a systems level analysis of chaperone function. In this paper, we have constructed a chaperone interaction network for the malarial parasite, Plasmodium falciparum. P. falciparum is responsible for several million deaths every year, and understanding the biology of the parasite is a top priority. The parasite regularly experiences heat shock as part of its life cycle, and chaperones have often been implicated in parasite survival and growth. To better understand the participation of chaperones in cellular processes, we created a parasite chaperone network by combining experimental interactome data with in silico analysis. We used interolog mapping to predict protein-protein interactions for parasite chaperones based on the interactions of corresponding human chaperones. This data was then combined with information derived from existing high-throughput yeast two-hybrid assays. Analysis of the network reveals the broad range of functions regulated by chaperones. The network predicts involvement of chaperones in chromatin remodeling, protein trafficking, and cytoadherence. Importantly, it allows us to make predictions regarding the functions of hypothetical proteins based on their interactions. It allows us to make specific predictions about Hsp70-Hsp40 interactions in the parasite and assign functions to members of the Hsp90 and Hsp100 families. Analysis of the network provides a rational basis for the anti-malarial activity of geldanamycin, a well-known Hsp90 inhibitor. Finally, analysis of the network provides a theoretical basis for further experiments designed toward understanding the involvement of this important class of molecules in parasite biology.'),
(83739, 2007, 'plos', 'Structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils', 'Cheon, Mookyung|Chang, Iksoo|Mohanty, Sandipan|Luheshi, Leila M|Dobson, Christopher M|Vendruscolo, Michele|Favrin, Giorgio', 'Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.|Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kingdom|United Kin', 0, 'Amino Acid Sequence|Amyloid|Binding Sites|Computer Simulation|Dimerization|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Conformation|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0030173', '17941703', 'Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of beta sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils.');
