INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83357, 2005, 'plos', 'Combinatorial pattern discovery approach for the folding trajectory analysis of a beta-hairpin', 'Parida, Laxmi|Zhou, Ruhong', 'Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, United States of America. parida@us.ibm.com|Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, United States of America. parida@us.ibm.com', 'United States|United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010008', '16103909', 'The study of protein folding mechanisms continues to be one of the most challenging problems in computational biology. Currently, the protein folding mechanism is often characterized by calculating the free energy landscape versus various reaction coordinates, such as the fraction of native contacts, the radius of gyration, RMSD from the native structure, and so on. In this paper, we present a combinatorial pattern discovery approach toward understanding the global state changes during the folding process. This is a first step toward an unsupervised (and perhaps eventually automated) approach toward identification of global states. The approach is based on computing biclusters (or patterned clusters)-each cluster is a combination of various reaction coordinates, and its signature pattern facilitates the computation of the Z-score for the cluster. For this discovery process, we present an algorithm of time complexity c in RO((N + nm) log n), where N is the size of the output patterns and (n x m) is the size of the input with n time frames and m reaction coordinates. To date, this is the best time complexity for this problem. We next apply this to a beta-hairpin folding trajectory and demonstrate that this approach extracts crucial information about protein folding intermediate states and mechanism. We make three observations about the approach: (1) The method recovers states previously obtained by visually analyzing free energy surfaces. (2) It also succeeds in extracting meaningful patterns and structures that had been overlooked in previous works, which provides a better understanding of the folding mechanism of the beta-hairpin. These new patterns also interconnect various states in existing free energy surfaces versus different reaction coordinates. (3) The approach does not require calculating the free energy values, yet it offers an analysis comparable to, and sometimes better than, the methods that use free energy landscapes, thus validating the choice of reaction coordinates. (An abstract version of this work was presented at the 2005 Asia Pacific Bioinformatics Conference [1].).'),
(83358, 2005, 'plos', 'Improving the precision of the structure-function relationship by considering phylogenetic context', 'Shakhnovich, Boris E', 'Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America. borya@acs.bu.edu', 'United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010009', '16103910', 'Understanding the relationship between protein structure and function is one of the foremost challenges in post-genomic biology. Higher conservation of structure could, in principle, allow researchers to extend current limitations of annotation. However, despite significant research in the area, a precise and quantitative relationship between biochemical function and protein structure has been elusive. Attempts to draw an unambiguous link have often been complicated by pleiotropy, variable transcriptional control, and adaptations to genomic context, all of which adversely affect simple definitions of function. In this paper, I report that integrating genomic information can be used to clarify the link between protein structure and function. First, I present a novel measure of functional proximity between protein structures (F-score). Then, using F-score and other entirely automatic methods measuring structure and phylogenetic similarity, I present a three-dimensional landscape describing their inter-relationship. The result is a well-shaped landscape that demonstrates the added value of considering genomic context in inferring function from structural homology. A generalization of methodology presented in this paper can be used to improve the precision of annotation of genes in current and newly sequenced genomes.'),
(83359, 2005, 'plos', 'Recognition of unknown conserved alternatively spliced exons', 'Ohler, Uwe|Shomron, Noam|Burge, Christopher B', 'Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. uwe.ohler@duke.edu|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. uwe.ohler@duke.edu|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. uwe.ohler@duke.edu', 'United States|United States|United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010015', '16110330', 'The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNA and protein isoforms from a single gene locus through the process of alternative splicing (AS). We propose a computational approach called UNCOVER based on a pair hidden Markov model to discover conserved coding exonic sequences subject to AS that have so far gone undetected. Applying UNCOVER to orthologous introns of known human and mouse genes predicts skipped exons or retained introns present in both species, while discriminating them from conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conserved AS events. The prediction of skipped exons in the approximately 1% of the human genome represented by the ENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencing analysis of 15 introns with strong UNCOVER predictions and lacking EST evidence. These results imply that a considerable number of conserved exonic sequences and associated isoforms are still completely missing from the current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention.'),
(83360, 2005, 'plos', 'Theoretical analysis of pre-receptor image conditioning in weakly electric fish', 'Migliaro, Adriana|Caputi, Angel A|Budelli, Ruben', 'Sección Biomatemática, Instituto de Biología, Facultad de Ciencias, Montevideo, Uruguay.|Sección Biomatemática, Instituto de Biología, Facultad de Ciencias, Montevideo, Uruguay.|Sección Biomatemática, Instituto de Biología, Facultad de Ciencias, Montevideo, Uruguay.', 'Uruguay|Uruguay|Uruguay', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010016', '16110331', 'Electroreceptive fish detect nearby objects by processing the information contained in the pattern of electric currents through the skin. The distribution of local transepidermal voltage or current density on the sensory surface of the fishs skin is the electric image of the surrounding environment. This article reports a model study of the quantitative effect of the conductance of the internal tissues and the skin on electric image generation in Gnathonemus petersii (Günther 1862). Using realistic modelling, we calculated the electric image of a metal object on a simulated fish having different combinations of internal tissues and skin conductances. An object perturbs an electric field as if it were a distribution of electric sources. The equivalent distribution of electric sources is referred to as an objects imprimence. The high conductivity of the fish body lowers the load resistance of a given objects imprimence, increasing the electric image. It also funnels the current generated by the electric organ in such a way that the field and the imprimence of objects in the vicinity of the rostral electric fovea are enhanced. Regarding skin conductance, our results show that the actual value is in the optimal range for transcutaneous voltage modulation by nearby objects. This result suggests that voltage is the answer to the long-standing question as to whether current or voltage is the effective stimulus for electroreceptors. Our analysis shows that the fish body should be conceived as an object that interacts with nearby objects, conditioning the electric image. The concept of imprimence can be extended to other sensory systems, facilitating the identification of features common to different perceptual systems.'),
(83361, 2005, 'plos', 'Computational ecology: from the complex to the simple and back', 'Pascual, Mercedes', 'Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, USA. pascual@umich.edu', 'United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010018', '16110332', '-'),
(83362, 2005, 'plos', 'Inflammatory aetiology of human myometrial activation tested using directed graphs', 'Bisits, Andrew M|Smith, Roger|Mesiano, Sam|Yeo, George|Kwek, Kenneth|MacIntyre, David|Chan, Eng C', 'Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.|Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.|Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.|Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.|Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.|Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.|Mothers and Babies Research Centre, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.', 'Australia|Australia|Australia|Australia|Australia|Australia|Australia', 37, '-', 'Journal Article', '10.1371/journal.pcbi.0010019', '16110333', 'There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the activation of human myometrium. The data provided quantitative RT-PCR results on key genes from samples taken before and during labour. Principal component analysis showed that pre-labour samples form a homogenous group compared to those during labour. We therefore modelled the alternative causal pathways in non-laboring samples using directed graphs and statistically compared the likelihood of the different models using structural equations and D-separation approaches. Using the computer program LISREL, inflammatory activation as a primary event was highly consistent with the data (p = 0.925), progesterone withdrawal, as a primary event, is plausible (p = 0.499), yet comparatively unlikely, oxytocin receptor mediated initiation is less compatible with the data (p = 0.091). DGraph, a software program that creates directed graphs, produced similar results (p= 0.684, p= 0.280, and p = 0.04, respectively). This outcome supports an inflammatory aetiology for human labour. Our results demonstrate the value of directed graphs in determining the likelihood of causal relationships in biology in situations where experiments are not possible.'),
(83363, 2005, 'plos', 'Molecular switches at the synapse emerge from receptor and kinase traffic', 'Hayer, Arnold|Bhalla, Upinder S', 'National Centre for Biological Sciences, Bangalore, India.|National Centre for Biological Sciences, Bangalore, India.', 'India|India', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010020', '16110334', 'Changes in the synaptic connection strengths between neurons are believed to play a role in memory formation. An important mechanism for changing synaptic strength is through movement of neurotransmitter receptors and regulatory proteins to and from the synapse. Several activity-triggered biochemical events control these movements. Here we use computer models to explore how these putative memory-related changes can be stabilised long after the initial trigger, and beyond the lifetime of synaptic molecules. We base our models on published biochemical data and experiments on the activity-dependent movement of a glutamate receptor, AMPAR, and a calcium-dependent kinase, CaMKII. We find that both of these molecules participate in distinct bistable switches. These simulated switches are effective for long periods despite molecular turnover and biochemical fluctuations arising from the small numbers of molecules in the synapse. The AMPAR switch arises from a novel self-recruitment process where the presence of sufficient receptors biases the receptor movement cycle to insert still more receptors into the synapse. The CaMKII switch arises from autophosphorylation of the kinase. The switches may function in a tightly coupled manner, or relatively independently. The latter case leads to multiple stable states of the synapse. We propose that similar self-recruitment cycles may be important for maintaining levels of many molecules that undergo regulated movement, and that these may lead to combinatorial possible stable states of systems like the synapse.'),
(83364, 2005, 'plos', 'The RNA silencing pathway: the bits and pieces that matter', 'Groenenboom, Marian A C|Marée, Athanasius F M|Hogeweg, Paulien', 'Theoretical Biology and Bioinformatics, University of Utrecht, Utrecht, The Netherlands. m.a.c.groenenboom@bio.uu.nl|Theoretical Biology and Bioinformatics, University of Utrecht, Utrecht, The Netherlands. m.a.c.groenenboom@bio.uu.nl|Theoretical Biology and Bioinformatics, University of Utrecht, Utrecht, The Netherlands. m.a.c.groenenboom@bio.uu.nl', 'Netherlands|Netherlands|Netherlands', 33, '-', 'Journal Article', '10.1371/journal.pcbi.0010021', '16110335', 'Cellular pathways are generally proposed on the basis of available experimental knowledge. The proposed pathways, however, may be inadequate to describe the phenomena they are supposed to explain. For instance, by means of concise mathematical models we are able to reveal shortcomings in the current description of the pathway of RNA silencing. The silencing pathway operates by cleaving siRNAs from dsRNA. siRNAs can associate with RISC, leading to the degradation of the target mRNA. We propose and analyze a few small extensions to the pathway: a siRNA degrading RNase, primed amplification of aberrant RNA pieces, and cooperation between aberrant RNA to trigger amplification. These extensions allow for a consistent explanation for various types of silencing phenomena, such as virus induced silencing, transgene and transposon induced silencing, and avoidance of self-reactivity, as well as for differences found between species groups.'),
(83365, 2005, 'plos', 'Combined evidence annotation of transposable elements in genome sequences', 'Quesneville, Hadi|Bergman, Casey M|Andrieu, Olivier|Autard, Delphine|Nouaud, Danielle|Ashburner, Michael|Anxolabehere, Dominique', 'Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr|Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr|Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr|Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr|Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr|Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr|Laboratoire Dynamique du Génome et Evolution, Institut Jacques Monod, Paris, France. hq@ccr.jussieu.fr', 'France|France|France|France|France|France|France', 183, '-', 'Journal Article', '10.1371/journal.pcbi.0010022', '16110336', 'Transposable elements (TEs) are mobile, repetitive sequences that make up significant fractions of metazoan genomes. Despite their near ubiquity and importance in genome and chromosome biology, most efforts to annotate TEs in genome sequences rely on the results of a single computational program, RepeatMasker. In contrast, recent advances in gene annotation indicate that high-quality gene models can be produced from combining multiple independent sources of computational evidence. To elevate the quality of TE annotations to a level comparable to that of gene models, we have developed a combined evidence-model TE annotation pipeline, analogous to systems used for gene annotation, by integrating results from multiple homology-based and de novo TE identification methods. As proof of principle, we have annotated TE models in Drosophila melanogaster Release 4 genomic sequences using the combined computational evidence derived from RepeatMasker, BLASTER, TBLASTX, all-by-all BLASTN, RECON, TE-HMM and the previous Release 3.1 annotation. Our system is designed for use with the Apollo genome annotation tool, allowing automatic results to be curated manually to produce reliable annotations. The euchromatic TE fraction of D. melanogaster is now estimated at 5.3% (cf. 3.86% in Release 3.1), and we found a substantially higher number of TEs (n = 6,013) than previously identified (n = 1,572). Most of the new TEs derive from small fragments of a few hundred nucleotides long and highly abundant families not previously annotated (e.g., INE-1). We also estimated that 518 TE copies (8.6%) are inserted into at least one other TE, forming a nest of elements. The pipeline allows rapid and thorough annotation of even the most complex TE models, including highly deleted and/or nested elements such as those often found in heterochromatic sequences. Our pipeline can be easily adapted to other genome sequences, such as those of the D. melanogaster heterochromatin or other species in the genus Drosophila.'),
(83366, 2005, 'plos', 'Bioinformatics for whole-genome shotgun sequencing of microbial communities', 'Chen, Kevin|Pachter, Lior', 'Department of Electrical Engineering and Computer Science, University of California, Berkeley, USA. kevinc@cs.berkeley.edu|Department of Electrical Engineering and Computer Science, University of California, Berkeley, USA. kevinc@cs.berkeley.edu', 'United States|United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010024', '16110337', 'The application of whole-genome shotgun sequencing to microbial communities represents a major development in metagenomics, the study of uncultured microbes via the tools of modern genomic analysis. In the past year, whole-genome shotgun sequencing projects of prokaryotic communities from an acid mine biofilm, the Sargasso Sea, Minnesota farm soil, three deep-sea whale falls, and deep-sea sediments have been reported, adding to previously published work on viral communities from marine and fecal samples. The interpretation of this new kind of data poses a wide variety of exciting and difficult bioinformatics problems. The aim of this review is to introduce the bioinformatics community to this emerging field by surveying existing techniques and promising new approaches for several of the most interesting of these computational problems.'),
(83367, 2005, 'plos', 'Prediction of transcriptional terminators in Bacillus subtilis and related species', 'de Hoon, Michiel J L|Makita, Yuko|Nakai, Kenta|Miyano, Satoru', 'Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. mdehoon@c2b2.columbia.edu|Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. mdehoon@c2b2.columbia.edu|Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. mdehoon@c2b2.columbia.edu|Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. mdehoon@c2b2.columbia.edu', 'Japan|Japan|Japan|Japan', 0, 'Bacillus subtilis|Base Sequence|Computational Biology|Escherichia coli|Genes, Bacterial|Rho Factor|Terminator Regions, Genetic|Thymine|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010025', '16110342', 'In prokaryotes, genes belonging to the same operon are transcribed in a single mRNA molecule. Transcription starts as the RNA polymerase binds to the promoter and continues until it reaches a transcriptional terminator. Some terminators rely on the presence of the Rho protein, whereas others function independently of Rho. Such Rho-independent terminators consist of an inverted repeat followed by a stretch of thymine residues, allowing us to predict their presence directly from the DNA sequence. Unlike in Escherichia coli, the Rho protein is dispensable in Bacillus subtilis, suggesting a limited role for Rho-dependent termination in this organism and possibly in other Firmicutes. We analyzed 463 experimentally known terminating sequences in B. subtilis and found a decision rule to distinguish Rho-independent transcriptional terminators from non-terminating sequences. The decision rule allowed us to find the boundaries of operons in B. subtilis with a sensitivity and specificity of about 94%. Using the same decision rule, we found an average sensitivity of 94% for 57 bacteria belonging to the Firmicutes phylum, and a considerably lower sensitivity for other bacteria. Our analysis shows that Rho-independent termination is dominant for Firmicutes in general, and that the properties of the transcriptional terminators are conserved. Terminator prediction can be used to reliably predict the operon structure in these organisms, even in the absence of experimentally known operons. Genome-wide predictions of Rho-independent terminators for the 57 Firmicutes are available in the Supporting Information section.'),
(83368, 2005, 'plos', 'Comparative genomics and disorder prediction identify biologically relevant SH3 protein interactions', 'Beltrao, Pedro|Serrano, Luis', 'EMBL Structural and Computational Biology, Heidelberg, Germany. beltrao@embl-heidelberg.de|EMBL Structural and Computational Biology, Heidelberg, Germany. beltrao@embl-heidelberg.de', 'Germany|Germany', 0, 'Base Sequence|Computational Biology|Conserved Sequence|Evolution, Molecular|Fungal Proteins|Genome, Fungal|Genomics|Ligands|Protein Binding|Protein Interaction Mapping|Protein Structure, Secondary|Time Factors|src Homology Domains', 'Comparative Study', '10.1371/journal.pcbi.0010026', '16110343', 'Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus), or a long time ago (Neurospora crassa and Schizosaccharomyces pombe), contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.'),
(83369, 2005, 'plos', 'Evidence of a double-lid movement in Pseudomonas aeruginosa lipase: insights from molecular dynamics simulations', 'Cherukuvada, Subbulakshmi Latha|Seshasayee, Aswin Sai Narain|Raghunathan, Krishnan|Anishetty, Sharmila|Pennathur, Gautam', 'Centre for Biotechnology, Anna University, Chennai, India.|Centre for Biotechnology, Anna University, Chennai, India.|Centre for Biotechnology, Anna University, Chennai, India.|Centre for Biotechnology, Anna University, Chennai, India.|Centre for Biotechnology, Anna University, Chennai, India.', 'India|India|India|India|India', 0, 'Computer Simulation|Hydrophobic and Hydrophilic Interactions|Lipase|Models, Molecular|Movement|Mutation|Protein Structure, Quaternary|Pseudomonas aeruginosa', 'Journal Article', '10.1371/journal.pcbi.0010028', '16110344', 'Pseudomonas aeruginosa lipase is a 29-kDa protein that, following the determination of its crystal structure, was postulated to have a lid that stretched between residues 125 and 148. In this paper, using molecular dynamics simulations, we propose that there exists, in addition to the above-mentioned lid, a novel second lid in this lipase. We further show that the second lid, covering residues 210-222, acts as a triggering lid for the movement of the first. We also investigate the role of hydrophobicity in the movement of the lids and show that two residues, Phe214 and Ala217, play important roles in lid movement. To our knowledge, this is the first time that a double-lid movement of the type described in our manuscript has been presented to the scientific community. This work also elucidates the interplay of hydrophobic interactions in the dynamics, and hence the function, of an enzyme.'),
(83370, 2005, 'plos', 'Comparative analyses of fundamental differences in membrane transport capabilities in prokaryotes and eukaryotes', 'Ren, Qinghu|Paulsen, Ian T', 'The Institute for Genomic Research, Rockville, Maryland, USA.|The Institute for Genomic Research, Rockville, Maryland, USA.', 'United States|United States', 0, 'Biological Transport|Computational Biology|Eukaryotic Cells|Genome|Membrane Transport Proteins|Phylogeny|Prokaryotic Cells|Substrate Specificity', 'Comparative Study', '10.1371/journal.pcbi.0010027', '16118665', 'Whole-genome transporter analyses have been conducted on 141 organisms whose complete genome sequences are available. For each organism, the complete set of membrane transport systems was identified with predicted functions, and classified into protein families based on the transporter classification system. Organisms with larger genome sizes generally possessed a relatively greater number of transport systems. In prokaryotes and unicellular eukaryotes, the significant factor in the increase in transporter content with genome size was a greater diversity of transporter types. In contrast, in multicellular eukaryotes, greater number of paralogs in specific transporter families was the more important factor in the increase in transporter content with genome size. Both eukaryotic and prokaryotic intracellular pathogens and endosymbionts exhibited markedly limited transport capabilities. Hierarchical clustering of phylogenetic profiles of transporter families, derived from the presence or absence of a certain transporter family, showed that clustering patterns of organisms were correlated to both their evolutionary history and their overall physiology and lifestyles.'),
(83371, 2005, 'plos', 'Functional coverage of the human genome by existing structures, structural genomics targets, and homology models', 'Xie, Lei|Bourne, Philip E', 'San Diego Supercomputer Center and Department of Pharmacology, University of California, San Diego, California, USA.|San Diego Supercomputer Center and Department of Pharmacology, University of California, San Diego, California, USA.', 'United States|United States', 0, 'Databases, Protein|Disease|Genome, Human|Genomics|Humans|Models, Molecular|Structural Homology, Protein', 'Journal Article', '10.1371/journal.pcbi.0010031', '16118666', 'The bias in protein structure and function space resulting from experimental limitations and targeting of particular functional classes of proteins by structural biologists has long been recognized, but never continuously quantified. Using the Enzyme Commission and the Gene Ontology classifications as a reference frame, and integrating structure data from the Protein Data Bank (PDB), target sequences from the structural genomics projects, structure homology derived from the SUPERFAMILY database, and genome annotations from Ensembl and NCBI, we provide a quantified view, both at the domain and whole-protein levels, of the current and projected coverage of protein structure and function space relative to the human genome. Protein structures currently provide at least one domain that covers 37% of the functional classes identified in the genome, whole structure coverage exists for 25% of the genome. If all the structural genomics targets were solved (twice the current number of structures in the PDB), it is estimated that structures of one domain would cover 69% of the functional classes identified and complete structure coverage would be 44%. Homology models from existing experimental structures extend the 37% coverage to 56% of the genome as single domains and 25% to 31% for complete structures. Coverage from homology models is not evenly distributed by protein family, reflecting differing degrees of sequence and structure divergence within families. While these data provide coverage, conversely, they also systematically highlight functional classes of proteins for which structures should be determined. Current key functional families without structure representation are highlighted here, updated information on the most wanted list that should be solved is available on a weekly basis from http://function.rcsb.org:8080/pdb/function_distribution/index.html.'),
(83372, 2005, 'plos', 'Molecular origin of polyglutamine aggregation in neurodegenerative diseases', 'Khare, Sagar D|Ding, Feng|Gwanmesia, Kenneth N|Dokholyan, Nikolay V', 'Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA.', 'United States|United States|United States|United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010030', '16158094', 'Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35-40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel beta-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the beta-helices observed in simulations, all residues adopt beta-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 +/- 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel beta-hairpins in their ground state, in agreement with experiments. The lower stability of mutant beta-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation.'),
(83373, 2005, 'plos', 'Evolution of genetic potential', 'Meyers, Lauren Ancel|Ancel, Fredric D|Lachmann, Michael', 'Section of Integrative Biology, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, USA. laurenmeyers@mail.utexas.edu|Section of Integrative Biology, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, USA. laurenmeyers@mail.utexas.edu|Section of Integrative Biology, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, USA. laurenmeyers@mail.utexas.edu', 'United States|United States|United States', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010032', '16158095', 'Organisms employ a multitude of strategies to cope with the dynamical environments in which they live. Homeostasis and physiological plasticity buffer changes within the lifetime of an organism, while stochastic developmental programs and hypermutability track changes on longer time-scales. An alternative long-term mechanism is genetic potential--a heightened sensitivity to the effects of mutation that facilitates rapid evolution to novel states. Using a transparent mathematical model, we illustrate the concept of genetic potential and show that as environmental variability decreases, the evolving population reaches three distinct steady state conditions: (1) organismal flexibility, (2) genetic potential, and (3) genetic robustness. As a specific example of this concept we examine fluctuating selection for hydrophobicity in a single amino acid. We see the same three stages, suggesting that environmental fluctuations can produce allele distributions that are distinct not only from those found under constant conditions, but also from the transient allele distributions that arise under isolated selective sweeps.'),
(83374, 2005, 'plos', 'Will a biological database be different from a biological journal?', 'Bourne, Philip', 'bourne@sdsc.edu', '-', 0, '-', 'Journal Article', '10.1371/journal.pcbi.0010034', '16158097', '-'),
(83375, 2005, 'plos', 'A biophysical model of the mitochondrial respiratory system and oxidative phosphorylation', 'Beard, Daniel A', 'Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America. dbeard@mcw.edu', 'United States', 175, 'Adenosine Triphosphate|Adenylate Kinase|Animals|Biophysical Phenomena|Biophysics|Cations|Cell Respiration|Computational Biology|Computer Simulation|Electron Transport|Magnesium|Mitochondria|Models, Biological|Oxidative Phosphorylation|Oxidoreductases|Oxygen|Phosphates|Rats|Substrate Specificity', 'Journal Article', '10.1371/journal.pcbi.0010036', '16163394', 'A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F1F0 ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K+/H+ antiporter and passive H+ and K+ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphate-dependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.'),
(83376, 2005, 'plos', 'Transition to quorum sensing in an Agrobacterium population: A stochastic model', 'Goryachev, Andrew B|Toh, Da-Jun|Wee, Keng Boon|Lee, Travis|Zhang, Hai-Bao|Zhang, Lian-Hui', 'Systems Biology Group, Bioinformatics Institute, Singapore. andrewg@bii-sg.org|Systems Biology Group, Bioinformatics Institute, Singapore. andrewg@bii-sg.org|Systems Biology Group, Bioinformatics Institute, Singapore. andrewg@bii-sg.org|Systems Biology Group, Bioinformatics Institute, Singapore. andrewg@bii-sg.org|Systems Biology Group, Bioinformatics Institute, Singapore. andrewg@bii-sg.org|Systems Biology Group, Bioinformatics Institute, Singapore. andrewg@bii-sg.org', 'Singapore|Singapore|Singapore|Singapore|Singapore|Singapore', 54, 'Agrobacterium tumefaciens|Bacterial Proteins|Biofilms|Cell Proliferation|Culture Media|Gene Expression Regulation, Bacterial|Models, Biological|Plasmids|Quorum Sensing|Sensitivity and Specificity|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0010037', '16170413', 'Understanding of the intracellular molecular machinery that is responsible for the complex collective behavior of multicellular populations is an exigent problem of modern biology. Quorum sensing, which allows bacteria to activate genetic programs cooperatively, provides an instructive and tractable example illuminating the causal relationships between the molecular organization of gene networks and the complex phenotypes they control. In this work we--to our knowledge for the first time--present a detailed model of the population-wide transition to quorum sensing using the example of Agrobacterium tumefaciens. We construct a model describing the Ti plasmid quorum-sensing gene network and demonstrate that it behaves as an on-off gene expression switch that is robust to molecular noise and that activates the plasmid conjugation program in response to the increase in autoinducer concentration. This intracellular model is then incorporated into an agent-based stochastic population model that also describes bacterial motion, cell division, and chemical communication. Simulating the transition to quorum sensing in a liquid medium and biofilm, we explain the experimentally observed gradual manifestation of the quorum-sensing phenotype by showing that the transition of individual model cells into the on state is spread stochastically over a broad range of autoinducer concentrations. At the same time, the population-averaged values of critical autoinducer concentration and the threshold population density are shown to be robust to variability between individual cells, predictable and specific to particular growth conditions. Our modeling approach connects intracellular and population scales of the quorum-sensing phenomenon and provides plausible answers to the long-standing questions regarding the ecological and evolutionary significance of the phenomenon. Thus, we demonstrate that the transition to quorum sensing requires a much higher threshold cell density in liquid medium than in biofilm, and on this basis we hypothesize that in Agrobacterium quorum sensing serves as the detector of biofilm formation.'),
(83377, 2005, 'plos', 'Analysis of a splice array experiment elucidates roles of chromatin elongation factor Spt4-5 in splicing', 'Xiao, Yuanyuan|Yang, Yee H|Burckin, Todd A|Shiue, Lily|Hartzog, Grant A|Segal, Mark R', 'Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, United States of America.|Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, University of California, San Francisco, California, United States of America.', 'United States|United States|United States|United States|United States|United States', 19, 'Chromatin|Chromosomal Proteins, Non-Histone|Databases, Genetic|Gene Expression Regulation, Fungal|Models, Genetic|Mutation|Nuclear Proteins|Oligonucleotide Array Sequence Analysis|RNA Splicing|RNA, Messenger|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Transcriptional Elongation Factors', 'Journal Article', '10.1371/journal.pcbi.0010039', '16172632', 'Splicing is an important process for regulation of gene expression in eukaryotes, and it has important functional links to other steps of gene expression. Two examples of these linkages include Ceg1, a component of the mRNA capping enzyme, and the chromatin elongation factors Spt4-5, both of which have recently been shown to play a role in the normal splicing of several genes in the yeast Saccharomyces cerevisiae. Using a genomic approach to characterize the roles of Spt4-5 in splicing, we used splicing-sensitive DNA microarrays to identify specific sets of genes that are mis-spliced in ceg1, spt4, and spt5 mutants. In the context of a complex, nested, experimental design featuring 22 dye-swap array hybridizations, comprising both biological and technical replicates, we applied five appropriate statistical models for assessing differential expression between wild-type and the mutants. To refine selection of differential expression genes, we then used a robust model-synthesizing approach, Differential Expression via Distance Synthesis, to integrate all five models. The resultant list of differentially expressed genes was then further analyzed with regard to select attributes: we found that highly transcribed genes with long introns were most sensitive to spt mutations. QPCR confirmation of differential expression was established for the limited number of genes evaluated. In this paper, we showcase splicing array technology, as well as powerful, yet general, statistical methodology for assessing differential expression, in the context of a real, complex experimental design. Our results suggest that the Spt4-Spt5 complex may help coordinate splicing with transcription under conditions that present kinetic challenges to spliceosome assembly or function.'),
(83378, 2005, 'plos', 'A digital atlas to characterize the mouse brain transcriptome', 'Carson, James P|Ju, Tao|Lu, Hui-Chen|Thaller, Christina|Xu, Mei|Pallas, Sarah L|Crair, Michael C|Warren, Joe|Chiu, Wah|Eichele, Gregor', 'Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu|Program in Structural and Computational Biology and Molecular Biophysics, National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, Texas, United States of America. james.carson@bcm.edu', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Anatomy, Artistic|Animals|Brain|Computational Biology|Computer Simulation|Databases, Factual|Gene Expression Profiling|In Situ Hybridization|Medical Illustration|Mice|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010041', '16184189', 'Massive amounts of data are being generated in an effort to represent for the brain the expression of all genes at cellular resolution. Critical to exploiting this effort is the ability to place these data into a common frame of reference. Here we have developed a computational method for annotating gene expression patterns in the context of a digital atlas to facilitate custom user queries and comparisons of this type of data. This procedure has been applied to 200 genes in the postnatal mouse brain. As an illustration of utility, we identify candidate genes that may be related to Parkinson disease by using the expression of a dopamine transporter in the substantia nigra as a search query pattern. In addition, we discover that transcription factor Rorb is down-regulated in the barrelless mutant relative to control mice by quantitative comparison of expression patterns in layer IV somatosensory cortex. The semi-automated annotation method developed here is applicable to a broad spectrum of complex tissues and data modalities.'),
(83379, 2005, 'plos', 'ReAS: Recovery of ancestral sequences for transposable elements from the unassembled reads of a whole genome shotgun', 'Li, Ruiqiang|Ye, Jia|Li, Songgang|Wang, Jing|Han, Yujun|Ye, Chen|Wang, Jian|Yang, Huanming|Yu, Jun|Wong, Gane Ka-Shu|Wang, Jun', 'James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.|James D. Watson Institute of Genome Sciences of Zhejiang University, Hangzhou, China.', 'China|China|China|China|China|China|China|China|China|China|China', 76, 'Algorithms|DNA Transposable Elements|Databases, Nucleic Acid|Evolution, Molecular|Gene Duplication|Genome, Plant|Oryza', 'Journal Article', '10.1371/journal.pcbi.0010043', '16184192', 'We describe an algorithm, ReAS, to recover ancestral sequences for transposable elements (TEs) from the unassembled reads of a whole genome shotgun. The main assumptions are that these TEs must exist at high copy numbers across the genome and must not be so old that they are no longer recognizable in comparison to their ancestral sequences. Tested on the japonica rice genome, ReAS was able to reconstruct all of the high copy sequences in the Repbase repository of known TEs, and increase the effectiveness of RepeatMasker in identifying TEs from genome sequences.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83380, 2005, 'plos', 'Inferring hypotheses on functional relationships of genes: Analysis of the Arabidopsis thaliana subtilase gene family', 'Rautengarten, Carsten|Steinhauser, Dirk|Büssis, Dirk|Stintzi, Annick|Schaller, Andreas|Kopka, Joachim|Altmann, Thomas', 'Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de|Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de|Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de|Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de|Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de|Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de|Institut für Biochemie und Biologie, Genetik, Universität Potsdam, Golm, Germany. rautengarten@mpimp-golm.mpg.de', 'Germany|Germany|Germany|Germany|Germany|Germany|Germany', 115, 'Animals|Arabidopsis|Chromosomes, Plant|Computational Biology|Gene Duplication|Gene Expression Regulation, Plant|Models, Genetic|Mutation|Oligonucleotide Array Sequence Analysis|Phylogeny|Substrate Specificity|Subtilisins|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010040', '16193095', 'The gene family of subtilisin-like serine proteases (subtilases) in Arabidopsis thaliana comprises 56 members, divided into six distinct subfamilies. Whereas the members of five subfamilies are similar to pyrolysins, two genes share stronger similarity to animal kexins. Mutant screens confirmed 144 T-DNA insertion lines with knockouts for 55 out of the 56 subtilases. Apart from SDD1, none of the confirmed homozygous mutants revealed any obvious visible phenotypic alteration during growth under standard conditions. Apart from this specific case, forward genetics gave us no hints about the function of the individual 54 non-characterized subtilase genes. Therefore, the main objective of our work was to overcome the shortcomings of the forward genetic approach and to infer alternative experimental approaches by using an integrative bioinformatics and biological approach. Computational analyses based on transcriptional co-expression and co-response pattern revealed at least two expression networks, suggesting that functional redundancy may exist among subtilases with limited similarity. Furthermore, two hubs were identified, which may be involved in signalling or may represent higher-order regulatory factors involved in responses to environmental cues. A particular enrichment of co-regulated genes with metabolic functions was observed for four subtilases possibly representing late responsive elements of environmental stress. The kexin homologs show stronger associations with genes of transcriptional regulation context. Based on the analyses presented here and in accordance with previously characterized subtilases, we propose three main functions of subtilases: involvement in (i) control of development, (ii) protein turnover, and (iii) action as downstream components of signalling cascades. Supplemental material is available in the Plant Subtilase Database (PSDB) (http://csbdb.mpimp-golm.mpg.de/psdb.html), as well as from the CSB.DB (http://csbdb.mpimp-golm.mpg.de).'),
(83381, 2005, 'plos', 'The human connectome: A structural description of the human brain', 'Sporns, Olaf|Tononi, Giulio|Kötter, Rolf', 'Department of Psychology, Indiana University, Bloomington, Indiana, United States of America. osporns@indiana.edu|Department of Psychology, Indiana University, Bloomington, Indiana, United States of America. osporns@indiana.edu|Department of Psychology, Indiana University, Bloomington, Indiana, United States of America. osporns@indiana.edu', 'India|India|India', 0, 'Animals|Brain|Humans|Nerve Net|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.0010042', '16201007', 'The connection matrix of the human brain (the human connectome) represents an indispensable foundation for basic and applied neurobiological research. However, the network of anatomical connections linking the neuronal elements of the human brain is still largely unknown. While some databases or collations of large-scale anatomical connection patterns exist for other mammalian species, there is currently no connection matrix of the human brain, nor is there a coordinated research effort to collect, archive, and disseminate this important information. We propose a research strategy to achieve this goal, and discuss its potential impact.'),
(83382, 2005, 'plos', 'Modeling the amplification dynamics of human Alu retrotransposons', 'Hedges, Dale J|Cordaux, Richard|Xing, Jinchuan|Witherspoon, David J|Rogers, Alan R|Jorde, Lynn B|Batzer, Mark A', 'Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.|Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.|Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.|Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.|Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.|Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.|Department of Biological Sciences, Biological Computation and Visualization Center, Center for Bio-Modular Microsystems, Louisiana State University, Baton Rouge, Louisiana, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 9, 'Alu Elements|Computational Biology|Computer Simulation|Gene Amplification|Genome, Human|Humans|Models, Genetic|Polymorphism, Genetic|Retroelements|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0010044', '16201008', 'Retrotransposons have had a considerable impact on the overall architecture of the human genome. Currently, there are three lineages of retrotransposons (Alu, L1, and SVA) that are believed to be actively replicating in humans. While estimates of their copy number, sequence diversity, and levels of insertion polymorphism can readily be obtained from existing genomic sequence data and population sampling, a detailed understanding of the temporal pattern of retrotransposon amplification remains elusive. Here we pose the question of whether, using genomic sequence and population frequency data from extant taxa, one can adequately reconstruct historical amplification patterns. To this end, we developed a computer simulation that incorporates several known aspects of primate Alu retrotransposon biology and accommodates sampling effects resulting from the methods by which mobile elements are typically discovered and characterized. By modeling a number of amplification scenarios and comparing simulation-generated expectations to empirical data gathered from existing Alu subfamilies, we were able to statistically reject a number of amplification scenarios for individual subfamilies, including that of a rapid expansion or explosion of Alu amplification at the time of human-chimpanzee divergence.'),
(83383, 2005, 'plos', 'Entropic stabilization of proteins and its proteomic consequences', 'Berezovsky, Igor N|Chen, William W|Choi, Paul J|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.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.', 'United States|United States|United States|United States', 62, 'Aminopeptidases|Arginine|Computational Biology|Computer Simulation|Cytochromes c|Endopeptidases|Entropy|Enzyme Stability|Escherichia coli|Genome|Lysine|Monte Carlo Method|Mutation|Protein Folding|Proteome|Proteomics|Temperature|Thermus thermophilus', 'Journal Article', '10.1371/journal.pcbi.0010047', '16201009', 'Evolutionary traces of thermophilic adaptation are manifest, on the whole-genome level, in compositional biases toward certain types of amino acids. However, it is sometimes difficult to discern their causes without a clear understanding of underlying physical mechanisms of thermal stabilization of proteins. For example, it is well-known that hyperthermophiles feature a greater proportion of charged residues, but, surprisingly, the excess of positively charged residues is almost entirely due to lysines but not arginines in the majority of hyperthermophilic genomes. All-atom simulations show that lysines have a much greater number of accessible rotamers than arginines of similar degree of burial in folded states of proteins. This finding suggests that lysines would preferentially entropically stabilize the native state. Indeed, we show in computational experiments that arginine-to-lysine amino acid substitutions result in noticeable stabilization of proteins. We then hypothesize that if evolution uses this physical mechanism as a complement to electrostatic stabilization in its strategies of thermophilic adaptation, then hyperthermostable organisms would have much greater content of lysines in their proteomes than comparably sized and similarly charged arginines. Consistent with that, high-throughput comparative analysis of complete proteomes shows extremely strong bias toward arginine-to-lysine replacement in hyperthermophilic organisms and overall much greater content of lysines than arginines in hyperthermophiles. This finding cannot be explained by genomic GC compositional biases or by the universal trend of amino acid gain and loss in protein evolution. We discovered here a novel entropic mechanism of protein thermostability due to residual dynamics of rotamer isomerization in native state and demonstrated its immediate proteomic implications. Our study provides an example of how analysis of a fundamental physical mechanism of thermostability helps to resolve a puzzle in comparative genomics as to why amino acid compositions of hyperthermophilic proteomes are significantly biased toward lysines but not similarly charged arginines.'),
(83384, 2005, 'plos', 'Protein molecular function prediction by Bayesian phylogenomics', 'Engelhardt, Barbara E|Jordan, Michael I|Muratore, Kathryn E|Brenner, Steven E', 'Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. bee@cs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. bee@cs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. bee@cs.berkeley.edu|Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. bee@cs.berkeley.edu', 'United States|United States|United States|United States', 0, 'Adenosine Deaminase|Algorithms|Animals|Computational Biology|Computer Graphics|Databases, Protein|Genomics|Phylogeny|Plasmodium falciparum|Programming Languages|Proteins|Proteomics|Sequence Alignment|Sequence Analysis, Protein|Software', 'Journal Article', '10.1371/journal.pcbi.0010045', '16217548', 'We present a statistical graphical model to infer specific molecular function for unannotated protein sequences using homology. Based on phylogenomic principles, SIFTER (Statistical Inference of Function Through Evolutionary Relationships) accurately predicts molecular function for members of a protein family given a reconciled phylogeny and available function annotations, even when the data are sparse or noisy. Our method produced specific and consistent molecular function predictions across 100 Pfam families in comparison to the Gene Ontology annotation database, BLAST, GOtcha, and Orthostrapper. We performed a more detailed exploration of functional predictions on the adenosine-5-monophosphate/adenosine deaminase family and the lactate/malate dehydrogenase family, in the former case comparing the predictions against a gold standard set of published functional characterizations. Given function annotations for 3% of the proteins in the deaminase family, SIFTER achieves 96% accuracy in predicting molecular function for experimentally characterized proteins as reported in the literature. The accuracy of SIFTER on this dataset is a significant improvement over other currently available methods such as BLAST (75%), GeneQuiz (64%), GOtcha (89%), and Orthostrapper (11%). We also experimentally characterized the adenosine deaminase from Plasmodium falciparum, confirming SIFTERs prediction. The results illustrate the predictive power of exploiting a statistical model of function evolution in phylogenomic problems. A software implementation of SIFTER is available from the authors.'),
(83385, 2005, 'plos', 'Structural evolution of the protein kinase-like superfamily', 'Scheeff, Eric D|Bourne, Philip E', 'San Diego Supercomputer Center, University of California, San Diego, California, United States of America. escheeff@sdsc.edu|San Diego Supercomputer Center, University of California, San Diego, California, United States of America. escheeff@sdsc.edu', 'United States|United States', 0, 'Adenosine Triphosphate|Amino Acid Sequence|Animals|Computational Biology|Databases, Protein|Evolution, Molecular|Humans|Molecular Sequence Data|Multigene Family|Phylogeny|Protein Kinases|Protein Structure, Secondary|Proteins|Proteomics|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0010049', '16244704', 'The protein kinase family is large and important, but it is only one family in a larger superfamily of homologous kinases that phosphorylate a variety of substrates and play important roles in all three superkingdoms of life. We used a carefully constructed structural alignment of selected kinases as the basis for a study of the structural evolution of the protein kinase-like superfamily. The comparison of structures revealed a universal core domain consisting only of regions required for ATP binding and the phosphotransfer reaction. Remarkably, even within the universal core some kinase structures display notable changes, while still retaining essential activity. Hence, the protein kinase-like superfamily has undergone substantial structural and sequence revision over long evolutionary timescales. We constructed a phylogenetic tree for the superfamily using a novel approach that allowed for the combination of sequence and structure information into a unified quantitative analysis. When considered against the backdrop of species distribution and other metrics, our tree provides a compelling scenario for the development of the various kinase families from a shared common ancestor. We propose that most of the so-called atypical kinases are not intermittently derived from protein kinases, but rather diverged early in evolution to form a distinct phyletic group. Within the atypical kinases, the aminoglycoside and choline kinase families appear to share the closest relationship. These two families in turn appear to be the most closely related to the protein kinase family. In addition, our analysis suggests that the actin-fragmin kinase, an atypical protein kinase, is more closely related to the phosphoinositide-3 kinase family than to the protein kinase family. The two most divergent families, alpha-kinases and phosphatidylinositol phosphate kinases (PIPKs), appear to have distinct evolutionary histories. While the PIPKs probably have an evolutionary relationship with the rest of the kinase superfamily, the relationship appears to be very distant (and perhaps indirect). Conversely, the alpha-kinases appear to be an exception to the scenario of early divergence for the atypical kinases: they apparently arose relatively recently in eukaryotes. We present possible scenarios for the derivation of the alpha-kinases from an extant kinase fold.'),
(83386, 2005, 'plos', 'Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs', 'Raman, Karthik|Rajagopalan, Preethi|Chandra, Nagasuma', 'Bioinformatics Centre, Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore, India.|Bioinformatics Centre, Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore, India.|Bioinformatics Centre, Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore, India.', 'India|India|India', 17, 'Algorithms|Antitubercular Agents|Bacterial Proteins|Chemistry, Pharmaceutical|Computational Biology|Drug Design|Gene Deletion|Humans|Models, Biological|Mycobacterium tuberculosis|Mycolic Acids|Oxidoreductases|Software', 'Journal Article', '10.1371/journal.pcbi.0010046', '16261191', 'Mycobacterium tuberculosis is the focus of several investigations for design of newer drugs, as tuberculosis remains a major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualities to mycolic acids, which are known to be important for their growth, survival, and pathogenicity. Mycolic acid biosynthesis has therefore been the focus of a number of biochemical and genetic studies. It also turns out to be the pathway inhibited by front-line anti-tubercular drugs such as isoniazid and ethionamide. Recent years have seen the emergence of systems-based methodologies that can be used to study microbial metabolism. Here, we seek to apply insights from flux balance analyses of the mycolic acid pathway (MAP) for the identification of anti-tubercular drug targets. We present a comprehensive model of mycolic acid synthesis in the pathogen M. tuberculosis involving 197 metabolites participating in 219 reactions catalysed by 28 proteins. Flux balance analysis (FBA) has been performed on the MAP model, which has provided insights into the metabolic capabilities of the pathway. In silico systematic gene deletions and inhibition of InhA by isoniazid, studied here, provide clues about proteins essential for the pathway and hence lead to a rational identification of possible drug targets. Feasibility studies using sequence analysis of the M. tuberculosis H37Rv and human proteomes indicate that, apart from the known InhA, potential targets for anti-tubercular drug design are AccD3, Fas, FabH, Pks13, DesA1/2, and DesA3. Proteins identified as essential by FBA correlate well with those previously identified experimentally through transposon site hybridisation mutagenesis. This study demonstrates the application of FBA for rational identification of potential anti-tubercular drug targets, which can indeed be a general strategy in drug design. The targets, chosen based on the critical points in the pathway, form a ready shortlist for experimental testing.'),
(83387, 2005, 'plos', 'Genomic variability within an organism exposes its cell lineage tree', 'Frumkin, Dan|Wasserstrom, Adam|Kaplan, Shai|Feige, Uriel|Shapiro, Ehud', 'Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.|Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.', 'Israel|Israel|Israel|Israel|Israel', 0, 'Animals|Caenorhabditis elegans|Cell Lineage|Computational Biology|Genes, Plant|Genetic Variation|Genome|Genomics|Humans|Infant, Newborn|Microsatellite Repeats|Models, Genetic|Models, Theoretical|Mutation|Proteomics', 'Journal Article', '10.1371/journal.pcbi.0010050', '16261192', 'What is the lineage relation among the cells of an organism? The answer is sought by developmental biology, immunology, stem cell research, brain research, and cancer research, yet complete cell lineage trees have been reconstructed only for simple organisms such as Caenorhabditis elegans. We discovered that somatic mutations accumulated during normal development of a higher organism implicitly encode its entire cell lineage tree with very high precision. Our mathematical analysis of known mutation rates in microsatellites (MSs) shows that the entire cell lineage tree of a human embryo, or a mouse, in which no cell is a descendent of more than 40 divisions, can be reconstructed from information on somatic MS mutations alone with no errors, with probability greater than 99.95%. Analyzing all approximately 1.5 million MSs of each cell of an organism may not be practical at present, but we also show that in a genetically unstable organism, analyzing only a few hundred MSs may suffice to reconstruct portions of its cell lineage tree. We demonstrate the utility of the approach by reconstructing cell lineage trees from DNA samples of a human cell line displaying MS instability. Our discovery and its associated procedure, which we have automated, may point the way to a future Human Cell Lineage Project that would aim to resolve fundamental open questions in biology and medicine by reconstructing ever larger portions of the human cell lineage tree.'),
(83388, 2005, 'plos', 'SNPdetector: a software tool for sensitive and accurate SNP detection', 'Zhang, Jinghui|Wheeler, David A|Yakub, Imtiaz|Wei, Sharon|Sood, Raman|Rowe, William|Liu, Paul P|Gibbs, Richard A|Buetow, Kenneth H', 'Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov|Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. jinghuiz@mail.nih.gov', 'United States|United States|United States|United States|United States|United States|United States|Un', 93, 'Algorithms|Alleles|Animals|Computational Biology|Gene Frequency|Genome|Genotype|Heterozygote|Humans|Polymorphism, Genetic|Polymorphism, Single Nucleotide|Reproducibility of Results|Sensitivity and Specificity|Software', 'Journal Article', '10.1371/journal.pcbi.0010053', '16261194', 'Identification of single nucleotide polymorphisms (SNPs) and mutations is important for the discovery of genetic predisposition to complex diseases. PCR resequencing is the method of choice for de novo SNP discovery. However, manual curation of putative SNPs has been a major bottleneck in the application of this method to high-throughput screening. Therefore it is critical to develop a more sensitive and accurate computational method for automated SNP detection. We developed a software tool, SNPdetector, for automated identification of SNPs and mutations in fluorescence-based resequencing reads. SNPdetector was designed to model the process of human visual inspection and has a very low false positive and false negative rate. We demonstrate the superior performance of SNPdetector in SNP and mutation analysis by comparing its results with those derived by human inspection, PolyPhred (a popular SNP detection tool), and independent genotype assays in three large-scale investigations. The first study identified and validated inter- and intra-subspecies variations in 4,650 traces of 25 inbred mouse strains that belong to either the Mus musculus species or the M. spretus species. Unexpected heterozygosity in CAST/Ei strain was observed in two out of 1,167 mouse SNPs. The second study identified 11,241 candidate SNPs in five ENCODE regions of the human genome covering 2.5 Mb of genomic sequence. Approximately 50% of the candidate SNPs were selected for experimental genotyping, the validation rate exceeded 95%. The third study detected ENU-induced mutations (at 0.04% allele frequency) in 64,896 traces of 1,236 zebra fish. Our analysis of three large and diverse test datasets demonstrated that SNPdetector is an effective tool for genome-scale research and for large-sample clinical studies. SNPdetector runs on Unix/Linux platform and is available publicly (http://lpg.nci.nih.gov).'),
(83389, 2005, 'plos', 'Ultrasensitization: switch-like regulation of cellular signaling by transcriptional induction', 'Legewie, Stefan|Blüthgen, Nils|Schäfer, Reinhold|Herzel, Hanspeter', 'Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de', 'Germany|Germany|Germany|Germany', 0, 'Animals|Cell Communication|Computational Biology|Humans|Kinetics|Models, Biological|Models, Statistical|Phosphorylation|Protein Kinases|Signal Transduction|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010054', '16261195', 'Cellular signaling networks are subject to transcriptional and proteolytic regulation under both physiological and pathological conditions. For example, the expression of proteins subject to covalent modification by phosphorylation is known to be altered upon cellular differentiation or during carcinogenesis. However, it is unclear how moderate alterations in protein expression can bring about large changes in signal transmission as, for example, observed in the case of haploinsufficiency, where halving the expression of signaling proteins abrogates cellular function. By modeling a fundamental motif of signal transduction, the phosphorylation-dephosphorylation cycle, we show that minor alterations in the concentration of the protein subject to phosphorylation (or the phosphatase) can affect signal transmission in a highly ultrasensitive fashion. This ultrasensitization is strongly favored by substrate sequestration on the catalyzing enzymes, and can be observed with experimentally measured enzymatic rate constants. Furthermore, we show that coordinated transcription of multiple proteins (i.e., synexpression) within a protein kinase cascade results in even more pronounced all-or-none behavior with respect to signal transmission. Finally, we demonstrate that ultrasensitization can account for specificity and modularity in the regulation of cellular signal transduction. Ultrasensitization can result in all-or-none cell-fate decisions and in highly specific cellular regulation. Additionally, switch-like phenomena such as ultrasensitization are known to contribute to bistability, oscillations, noise reduction, and cellular heterogeneity.'),
(83390, 2005, 'plos', 'Dissimilatory metabolism of nitrogen oxides in bacteria: comparative reconstruction of transcriptional networks', 'Rodionov, Dmitry A|Dubchak, Inna L|Arkin, Adam P|Alm, Eric J|Gelfand, Mikhail S', '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', '-|-|-|-|-', 50, 'Amino Acid Motifs|Bacteria|Bacterial Proteins|Computational Biology|Escherichia coli|Escherichia coli Proteins|Gene Expression Regulation, Bacterial|Genomics|Models, Biological|Multigene Family|Nitrites|Nitrogen Oxides|Oxidation-Reduction|Phylogeny|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010055', '16261196', 'Bacterial response to nitric oxide (NO) is of major importance since NO is an obligatory intermediate of the nitrogen cycle. Transcriptional regulation of the dissimilatory nitric oxides metabolism in bacteria is diverse and involves FNR-like transcription factors HcpR, DNR, and NnrR, two-component systems NarXL and NarQP, NO-responsive activator NorR, and nitrite-sensitive repressor NsrR. Using comparative genomics approaches, we predict DNA-binding motifs for these transcriptional factors and describe corresponding regulons in available bacterial genomes. Within the FNR family of regulators, we observed a correlation of two specificity-determining amino acids and contacting bases in corresponding DNA recognition motif. Highly conserved regulon HcpR for the hybrid cluster protein and some other redox enzymes is present in diverse anaerobic bacteria, including Clostridia, Thermotogales, and delta-proteobacteria. NnrR and DNR control denitrification in alpha- and beta-proteobacteria, respectively. Sigma-54-dependent NorR regulon found in some gamma- and beta-proteobacteria contains various enzymes involved in the NO detoxification. Repressor NsrR, which was previously known to control only nitrite reductase operon in Nitrosomonas spp., appears to be the master regulator of the nitric oxides metabolism, not only in most gamma- and beta-proteobacteria (including well-studied species such as Escherichia coli), but also in gram-positive Bacillus and Streptomyces species. Positional analysis and comparison of regulatory regions of NO detoxification genes allows us to propose the candidate NsrR-binding motif. The most conserved member of the predicted NsrR regulon is the NO-detoxifying flavohemoglobin Hmp. In enterobacteria, the regulon also includes two nitrite-responsive loci, nipAB (hcp-hcr) and nipC (dnrN), thus confirming the identity of the effector, i.e. nitrite. The proposed NsrR regulons in Neisseria and some other species are extended to include denitrification genes. As the result, we demonstrate considerable interconnection between various nitrogen-oxides-responsive regulatory systems for the denitrification and NO detoxification genes and evolutionary plasticity of this transcriptional network.'),
(83391, 2005, 'plos', 'Ten simple rules for getting published', 'Bourne, Philip E', 'Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia. rodionov@iitp.ru', '-', 0, 'Editorial Policies|Peer Review, Research|Periodicals as Topic|Publishing|Research|Writing', 'Editorial', '10.1371/journal.pcbi.0010057', '16261197', '-'),
(83392, 2005, 'plos', 'Use of artificial genomes in assessing methods for atypical gene detection', 'Azad, Rajeev K|Lawrence, Jeffrey G', 'Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.', 'United States|United States', 30, 'Algorithms|Base Composition|Base Sequence|Chimerism|Escherichia coli|Genes, Bacterial|Genetic Variation|Genome|Genome, Bacterial|Markov Chains|Models, Genetic|Open Reading Frames', 'Journal Article', '10.1371/journal.pcbi.0010056', '16292353', 'Parametric methods for identifying laterally transferred genes exploit the directional mutational biases unique to each genome. Yet the development of new, more robust methods--as well as the evaluation and proper implementation of existing methods--relies on an arbitrary assessment of performance using real genomes, where the evolutionary histories of genes are not known. We have used the framework of a generalized hidden Markov model to create artificial genomes modeled after genuine genomes. To model a genome, core genes--those displaying patterns of mutational biases shared among large numbers of genes--are identified by a novel gene clustering approach based on the Akaike information criterion. Gene models derived from multiple core gene clusters are used to generate an artificial genome that models the properties of a genuine genome. Chimeric artificial genomes--representing those having experienced lateral gene transfer--were created by combining genes from multiple artificial genomes, and the performance of the parametric methods for identifying atypical genes was assessed directly. We found that a hidden Markov model that included multiple gene models, each trained on sets of genes representing the range of genotypic variability within a genome, could produce artificial genomes that mimicked the properties of genuine genomes. Moreover, different methods for detecting foreign genes performed differently--i.e., they had different sets of strengths and weaknesses--when identifying atypical genes within chimeric artificial genomes.'),
(83393, 2005, 'plos', 'A guild of 45 CRISPR-associated (Cas) protein families and multiple CRISPR/Cas subtypes exist in prokaryotic genomes', 'Haft, Daniel H|Selengut, Jeremy|Mongodin, Emmanuel F|Nelson, Karen E', 'The Institute for Genomic Research, Rockville, Maryland, USA. haft@tigr.org|The Institute for Genomic Research, Rockville, Maryland, USA. haft@tigr.org|The Institute for Genomic Research, Rockville, Maryland, USA. haft@tigr.org|The Institute for Genomic Research, Rockville, Maryland, USA. haft@tigr.org', 'United States|United States|United States|United States', 0, 'Genes, Archaeal|Genes, Bacterial|Genes, Fungal|Genome|Genome, Bacterial|Haloarcula marismortui|Markov Chains|Multigene Family|Oligonucleotide Array Sequence Analysis|Phylogeny|Prokaryotic Cells|Proteins|Repetitive Sequences, Nucleic Acid|Yersinia pestis', 'Journal Article', '10.1371/journal.pcbi.0010060', '16292354', 'Clustered regularly interspaced short palindromic repeats (CRISPRs) are a family of DNA direct repeats found in many prokaryotic genomes. Repeats of 21-37 bp typically show weak dyad symmetry and are separated by regularly sized, nonrepetitive spacer sequences. Four CRISPR-associated (Cas) protein families, designated Cas1 to Cas4, are strictly associated with CRISPR elements and always occur near a repeat cluster. Some spacers originate from mobile genetic elements and are thought to confer immunity against the elements that harbor these sequences. In the present study, we have systematically investigated uncharacterized proteins encoded in the vicinity of these CRISPRs and found many additional protein families that are strictly associated with CRISPR loci across multiple prokaryotic species. Multiple sequence alignments and hidden Markov models have been built for 45 Cas protein families. These models identify family members with high sensitivity and selectivity and classify key regulators of development, DevR and DevS, in Myxococcus xanthus as Cas proteins. These identifications show that CRISPR/cas gene regions can be quite large, with up to 20 different, tandem-arranged cas genes next to a repeat cluster or filling the region between two repeat clusters. Distinctive subsets of the collection of Cas proteins recur in phylogenetically distant species and correlate with characteristic repeat periodicity. The analyses presented here support initial proposals of mobility of these units, along with the likelihood that loci of different subtypes interact with one another as well as with host cell defensive, replicative, and regulatory systems. It is evident from this analysis that CRISPR/cas loci are larger, more complex, and more heterogeneous than previously appreciated.'),
(83394, 2005, 'plos', 'The association of tetrameric acetylcholinesterase with ColQ tail: a block normal mode analysis', 'Zhang, Deqiang|McCammon, J Andrew', 'Howard Hughes Medical Institute, University of California, San Diego, California, USA. dzhang@mccammon.ucsd.edu|Howard Hughes Medical Institute, University of California, San Diego, California, USA. dzhang@mccammon.ucsd.edu', 'United States|United States', 0, 'Acetylcholinesterase|Animals|Collagen|Mice|Models, Molecular|Protein Binding|Protein Structure, Quaternary|Protein Subunits', 'Journal Article', '10.1371/journal.pcbi.0010062', '16299589', 'Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine in the neuromuscular junctions and other cholinergic synapses to terminate the neuronal signal. In physiological conditions, AChE exists as tetramers associated with the proline-rich attachment domain (PRAD) of either collagen-like Q subunit (ColQ) or proline-rich membrane-anchoring protein. Crystallographic studies have revealed that different tetramer forms may be present, and it is not clear whether one or both are relevant under physiological conditions. Recently, the crystal structure of the tryptophan amphiphilic tetramerization (WAT) domain of AChE associated with PRAD ([WAT]4PRAD), which mimics the interface between ColQ and AChE tetramer, became available. In this study we built a complete tetrameric mouse [AChE(T)]4-ColQ atomic structure model, based on the crystal structure of the [WAT]4PRAD complex. The structure was optimized using energy minimization. Block normal mode analysis was done to investigate the low-frequency motions of the complex and to correlate the structure model with the two known crystal structures of AChE tetramer. Significant low-frequency motions among the catalytic domains of the four AChE subunits were observed, while the [WAT]4PRAD part held the complex together. Normal mode involvement analysis revealed that the two lowest frequency modes were primarily involved in the conformational changes leading to the two crystal structures. The first 30 normal modes can account for more than 75% of the conformational changes in both cases. The evidence further supports the idea of a flexible tetramer model for AChE. This model can be used to study the implications of the association of AChE with ColQ.'),
(83395, 2005, 'plos', 'Stealth proteins: in silico identification of a novel protein family rendering bacterial pathogens invisible to host immune defense', 'Sperisen, Peter|Schmid, Christoph D|Bucher, Philipp|Zilian, Olav', 'Swiss Institute of Bioinformatics, Epalinges, Switzerland.|Swiss Institute of Bioinformatics, Epalinges, Switzerland.|Swiss Institute of Bioinformatics, Epalinges, Switzerland.|Swiss Institute of Bioinformatics, Epalinges, Switzerland.', 'Switzerland|Switzerland|Switzerland|Switzerland', 31, 'Amino Acid Sequence|Animals|Bacteria|Bacterial Infections|Computational Biology|Conserved Sequence|Evolution, Molecular|Genome|Humans|Molecular Sequence Data|Phylogeny|Proteins|Sequence Alignment|Streptomyces coelicolor|Virulence Factors', 'Journal Article', '10.1371/journal.pcbi.0010063', '16299590', 'There are a variety of bacterial defense strategies to survive in a hostile environment. Generation of extracellular polysaccharides has proved to be a simple but effective strategy against the hosts innate immune system. A comparative genomics approach led us to identify a new protein family termed Stealth, most likely involved in the synthesis of extracellular polysaccharides. This protein family is characterized by a series of domains conserved across phylogeny from bacteria to eukaryotes. In bacteria, Stealth (previously characterized as SacB, XcbA, or WefC) is encoded by subsets of strains mainly colonizing multicellular organisms, with evidence for a protective effect against the host innate immune defense. More specifically, integrating all the available information about Stealth proteins in bacteria, we propose that Stealth is a D-hexose-1-phosphoryl transferase involved in the synthesis of polysaccharides. In the animal kingdom, Stealth is strongly conserved across evolution from social amoebas to simple and complex multicellular organisms, such as Dictyostelium discoideum, hydra, and human. Based on the occurrence of Stealth in most Eukaryotes and a subset of Prokaryotes together with its potential role in extracellular polysaccharide synthesis, we propose that metazoan Stealth functions to regulate the innate immune system. Moreover, there is good reason to speculate that the acquisition and spread of Stealth could be responsible for future epidemic outbreaks of infectious diseases caused by a large variety of eubacterial pathogens. Our in silico identification of a homologous protein in the human host will help to elucidate the causes of Stealth-dependent virulence. At a more basic level, the characterization of the molecular and cellular function of Stealth proteins may shed light on fundamental mechanisms of innate immune defense against microbial invasion.'),
(83396, 2005, 'plos', 'Bioinformatics education--perspectives and challenges', 'Ranganathan, Shoba', 'Macquarie University, Sydney, Australia. shoba.ranganathan@mq.edu.au', 'Australia', 36, 'Computational Biology|Internet', 'Journal Article', '10.1371/journal.pcbi.0010052', '16322761', '-'),
(83397, 2005, 'plos', 'NIH Roadmap interdisciplinary research initiatives', 'Huerta, Michael F|Farber, Gregory K|Wilder, Elizabeth L|Kleinman, Dushanka V|Grady, Patricia A|Schwartz, David A|Tabak, Lawrence A', 'National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov|National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov|National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov|National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov|National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov|National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov|National Institute of Mental Health, Bethesda, Maryland, United States of America. mhuert1@mail.nih.gov', 'United States|United States|United States|United States|United States|United States|United States', 12, 'Internet|National Institutes of Health (U.S.)|Research|United States', 'Comment', '10.1371/journal.pcbi.0010059', '16322762', '-'),
(83398, 2005, 'plos', 'Quasispecies made simple', 'Bull, J J|Meyers, Lauren Ancel|Lachmann, Michael', 'Institute for Cellular and Molecular Biology, Section of Integrative Biology, University of Texas, Austin, Texas, United States of America.|Institute for Cellular and Molecular Biology, Section of Integrative Biology, University of Texas, Austin, Texas, United States of America.|Institute for Cellular and Molecular Biology, Section of Integrative Biology, University of Texas, Austin, Texas, United States of America.', 'United States|United States|United States', 112, 'Genes, Lethal|Genotype|Models, Genetic|Mutation|RNA Viruses|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010061', '16322763', 'Quasispecies are clouds of genotypes that appear in a population at mutation-selection balance. This concept has recently attracted the attention of virologists, because many RNA viruses appear to generate high levels of genetic variation that may enhance the evolution of drug resistance and immune escape. The literature on these important evolutionary processes is, however, quite challenging. Here we use simple models to link mutation-selection balance theory to the most novel property of quasispecies: the error threshold-a mutation rate below which populations equilibrate in a traditional mutation-selection balance and above which the population experiences an error catastrophe, that is, the loss of the favored genotype through frequent deleterious mutations. These models show that a single fitness landscape may contain multiple, hierarchically organized error thresholds and that an error threshold is affected by the extent of back mutation and redundancy in the genotype-to-phenotype map. Importantly, an error threshold is distinct from an extinction threshold, which is the complete loss of the population through lethal mutations. Based on this framework, we argue that the lethal mutagenesis of a viral infection by mutation-inducing drugs is not a true error catastophe, but is an extinction catastrophe.'),
(83399, 2005, 'plos', 'Quantitative analysis of genetic and neuronal multi-perturbation experiments', 'Kaufman, Alon|Keinan, Alon|Meilijson, Isaac|Kupiec, Martin|Ruppin, Eytan', 'Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. kalon@post.tau.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. kalon@post.tau.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. kalon@post.tau.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. kalon@post.tau.ac.il|Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel. kalon@post.tau.ac.il', 'Israel|Israel|Israel|Israel|Israel', 27, 'Algorithms|Animals|Caenorhabditis elegans|Chemotaxis|DNA Repair|Gene Deletion|Models, Biological|Molecular Sequence Data|Mutagenesis|Neurons|Phenotype|Saccharomyces cerevisiae|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.0010064', '16322764', 'Perturbation studies, in which functional performance is measured after deletion, mutation, or lesion of elements of a biological system, have been traditionally employed in many fields in biology. The vast majority of these studies have been qualitative and have employed single perturbations, often resulting in little phenotypic effect. Recently, newly emerging experimental techniques have allowed researchers to carry out concomitant multi-perturbations and to uncover the causal functional contributions of system elements. This study presents a rigorous and quantitative multi-perturbation analysis of gene knockout and neuronal ablation experiments. In both cases, a quantification of the elements contributions, and new insights and predictions, are provided. Multi-perturbation analysis has a potentially wide range of applications and is gradually becoming an essential tool in biology.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83400, 2005, 'plos', 'Allele-specific amplification in cancer revealed by SNP array analysis', 'LaFramboise, Thomas|Weir, Barbara A|Zhao, Xiaojun|Beroukhim, Rameen|Li, Cheng|Harrington, David|Sellers, William R|Meyerson, Matthew', 'Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 91, 'Alleles|Cell Line, Tumor|Chromosomes, Human|DNA, Neoplasm|ErbB Receptors|Gene Amplification|Gene Dosage|Gene Expression Regulation, Neoplastic|Haplotypes|Humans|Models, Genetic|Neoplasms|Oligonucleotide Array Sequence Analysis|Polymorphism, Single Nucleotide', 'Journal Article', '10.1371/journal.pcbi.0010065', '16322765', 'Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ.'),
(83401, 2005, 'plos', 'Refining protein subcellular localization', 'Scott, Michelle S|Calafell, Sara J|Thomas, David Y|Hallett, Michael T', 'McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada.|McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada.|McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada.|McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada.', 'Canada|Canada|Canada|Canada', 62, 'Amino Acid Motifs|Computational Biology|Databases, Protein|Protein Binding|Protein Transport|Proteins|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.0010066', '16322766', 'The study of protein subcellular localization is important to elucidate protein function. Even in well-studied organisms such as yeast, experimental methods have not been able to provide a full coverage of localization. The development of bioinformatic predictors of localization can bridge this gap. We have created a Bayesian network predictor called PSLT2 that considers diverse protein characteristics, including the combinatorial presence of InterPro motifs and protein interaction data. We compared the localization predictions of PSLT2 to high-throughput experimental localization datasets. Disagreements between these methods generally involve proteins that transit through or reside in the secretory pathway. We used our multi-compartmental predictions to refine the localization annotations of yeast proteins primarily by distinguishing between soluble lumenal proteins and soluble proteins peripherally associated with organelles. To our knowledge, this is the first tool to provide this functionality. We used these sub-compartmental predictions to characterize cellular processes on an organellar scale. The integration of diverse protein characteristics and protein interaction data in an appropriate setting can lead to high-quality detailed localization annotations for whole proteomes. This type of resource is instrumental in developing models of whole organelles that provide insight into the extent of interaction and communication between organelles and help define organellar functionality.'),
(83402, 2005, 'plos', 'Revealing posttranscriptional regulatory elements through network-level conservation', 'Chan, Chang S|Elemento, Olivier|Tavazoie, Saeed', 'Department of Molecular Biology and The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology and The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.|Department of Molecular Biology and The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.', 'Jersey|Jersey|Jersey', 0, '3 Untranslated Regions|Animals|Base Sequence|Caenorhabditis|Conserved Sequence|Drosophila|Genome|MicroRNAs|Protein Processing, Post-Translational|Regulatory Sequences, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0010069', '16355253', 'We used network-level conservation between pairs of fly (Drosophila melanogaster/D. pseudoobscura) and worm (Caenorhabditis elegans/C. briggsae) genomes to detect highly conserved mRNA motifs in 3 untranslated regions. Many of these elements are complementary to the 5 extremity of known microRNAs (miRNAs), and likely correspond to their target sites. We also identify known targets of RNA-binding proteins, and many novel sites not yet known to be functional. Coherent sets of genes with similar function often bear the same conserved elements, providing new insights into their cellular functions. We also show that target sites for distinct miRNAs are often simultaneously conserved, suggesting combinatorial regulation by multiple miRNAs. A genome-wide search for conserved stem-loops, containing complementary sequences to the novel sites, revealed many new candidate miRNAs that likely target them. We also provide evidence that posttranscriptional networks have undergone extensive rewiring across distant phyla, despite strong conservation of regulatory elements themselves.'),
(83403, 2005, 'plos', 'Folding free energies of 5-UTRs impact post-transcriptional regulation on a genomic scale in yeast', 'Ringnér, Markus|Krogh, Morten', 'Complex Systems Division, Department of Theoretical Physics, Lund University, Lund, Sweden. markus@thep.lu.se|Complex Systems Division, Department of Theoretical Physics, Lund University, Lund, Sweden. markus@thep.lu.se', 'Sweden|Sweden', 0, '5 Untranslated Regions|Base Sequence|Gene Expression Regulation, Fungal|Genome, Fungal|Molecular Sequence Data|Nucleic Acid Conformation|Protein Biosynthesis|RNA-Binding Proteins|Ribosomes|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Thermodynamics|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0010072', '16355254', 'Using high-throughput technologies, abundances and other features of genes and proteins have been measured on a genome-wide scale in Saccharomyces cerevisiae. In contrast, secondary structure in 5-untranslated regions (UTRs) of mRNA has only been investigated for a limited number of genes. Here, the aim is to study genome-wide regulatory effects of mRNA 5-UTR folding free energies. We performed computations of secondary structures in 5-UTRs and their folding free energies for all verified genes in S. cerevisiae. We found significant correlations between folding free energies of 5-UTRs and various transcript features measured in genome-wide studies of yeast. In particular, mRNAs with weakly folded 5-UTRs have higher translation rates, higher abundances of the corresponding proteins, longer half-lives, and higher numbers of transcripts, and are upregulated after heat shock. Furthermore, 5-UTRs have significantly higher folding free energies than other genomic regions and randomized sequences. We also found a positive correlation between transcript half-life and ribosome occupancy that is more pronounced for short-lived transcripts, which supports a picture of competition between translation and degradation. Among the genes with strongly folded 5-UTRs, there is a huge overrepresentation of uncharacterized open reading frames. Based on our analysis, we conclude that (i) there is a widespread bias for 5-UTRs to be weakly folded, (ii) folding free energies of 5-UTRs are correlated with mRNA translation and turnover on a genomic scale, and (iii) transcripts with strongly folded 5-UTRs are often rare and hard to find experimentally.'),
(83404, 2005, 'plos', 'The activity reaction core and plasticity of metabolic networks', 'Almaas, Eivind|Oltvai, Zoltán N|Barabási, Albert-László', 'Microbial Systems Division, Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.|Microbial Systems Division, Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.|Microbial Systems Division, Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.', 'United States|United States|United States', 0, 'Escherichia coli|Helicobacter pylori|Models, Biological|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.0010068', '16362071', 'Understanding the system-level adaptive changes taking place in an organism in response to variations in the environment is a key issue of contemporary biology. Current modeling approaches, such as constraint-based flux-balance analysis, have proved highly successful in analyzing the capabilities of cellular metabolism, including its capacity to predict deletion phenotypes, the ability to calculate the relative flux values of metabolic reactions, and the capability to identify properties of optimal growth states. Here, we use flux-balance analysis to thoroughly assess the activity of Escherichia coli, Helicobacter pylori, and Saccharomyces cerevisiae metabolism in 30,000 diverse simulated environments. We identify a set of metabolic reactions forming a connected metabolic core that carry non-zero fluxes under all growth conditions, and whose flux variations are highly correlated. Furthermore, we find that the enzymes catalyzing the core reactions display a considerably higher fraction of phenotypic essentiality and evolutionary conservation than those catalyzing noncore reactions. Cellular metabolism is characterized by a large number of species-specific conditionally active reactions organized around an evolutionary conserved, but always active, metabolic core. Finally, we find that most current antibiotics interfering with bacterial metabolism target the core enzymes, indicating that our findings may have important implications for antimicrobial drug-target discovery.'),
(83405, 2005, 'plos', 'Comparing the Dictyostelium and Entamoeba genomes reveals an ancient split in the Conosa lineage', 'Song, Jie|Xu, Qikai|Olsen, Rolf|Loomis, William F|Shaulsky, Gad|Kuspa, Adam|Sucgang, Richard', 'Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Animals|Dictyostelium|Entamoeba|Genes, Protozoan|Genome, Protozoan|Humans|Multigene Family|Phylogeny|Proteome|Protozoan Proteins|Time Factors', 'Comparative Study', '10.1371/journal.pcbi.0010071', '16362072', 'The Amoebozoa are a sister clade to the fungi and the animals, but are poorly sampled for completely sequenced genomes. The social amoeba Dictyostelium discoideum and amitochondriate pathogen Entamoeba histolytica are the first Amoebozoa with genomes completely sequenced. Both organisms are classified under the Conosa subphylum. To identify Amoebozoa-specific genomic elements, we compared these two genomes to each other and to other eukaryotic genomes. An expanded phylogenetic tree built from the complete predicted proteomes of 23 eukaryotes places the two amoebae in the same lineage, although the divergence is estimated to be greater than that between animals and fungi, and probably happened shortly after the Amoebozoa split from the opisthokont lineage. Most of the 1,500 orthologous gene families shared between the two amoebae are also shared with plant, animal, and fungal genomes. We found that only 42 gene families are distinct to the amoeba lineage, among these are a large number of proteins that contain repeats of the FNIP domain, and a putative transcription factor essential for proper cell type differentiation in D. discoideum. These Amoebozoa-specific genes may be useful in the design of novel diagnostics and therapies for amoebal pathologies.'),
(83406, 2005, 'plos', 'Selective constraint on noncoding regions of hominid genomes', 'Bush, Eliot C|Lahn, Bruce T', 'Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.|Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.', 'United States|United States', 0, 'Animals|Evolution, Molecular|Genome|Hominidae|Humans|RNA, Untranslated', 'Journal Article', '10.1371/journal.pcbi.0010073', '16362073', 'An important challenge for human evolutionary biology is to understand the genetic basis of human-chimpanzee differences. One influential idea holds that such differences depend, to a large extent, on adaptive changes in gene expression. An important step in assessing this hypothesis involves gaining a better understanding of selective constraint on noncoding regions of hominid genomes. In noncoding sequence, functional elements are frequently small and can be separated by large nonfunctional regions. For this reason, constraint in hominid genomes is likely to be patchy. Here we use conservation in more distantly related mammals and amniotes as a way of identifying small sequence windows that are likely to be functional. We find that putatively functional noncoding elements defined in this manner are subject to significant selective constraint in hominids.'),
(83407, 2005, 'plos', 'Genome trees from conservation profiles', 'Tekaia, Fredj|Yeramian, Edouard', 'Unité de Génétique Moléculaire des Levures (URA 2171 CNRS and UFR927 Univ. P.M. Curie), Institut Pasteur, Paris, France. tekaia@pasteur.fr|Unité de Génétique Moléculaire des Levures (URA 2171 CNRS and UFR927 Univ. P.M. Curie), Institut Pasteur, Paris, France. tekaia@pasteur.fr', 'France|France', 19, 'Animals|Conserved Sequence|Evolution, Molecular|Genome|Humans|Phylogeny|Proteins', 'Journal Article', '10.1371/journal.pcbi.0010075', '16362074', 'The concept of the genome tree depends on the potential evolutionary significance in the clustering of species according to similarities in the gene content of their genomes. In this respect, genome trees have often been identified with species trees. With the rapid expansion of genome sequence data it becomes of increasing importance to develop accurate methods for grasping global trends for the phylogenetic signals that mutually link the various genomes. We therefore derive here the methodological concept of genome trees based on protein conservation profiles in multiple species. The basic idea in this derivation is that the multi-component presence-absence protein conservation profiles permit tracking of common evolutionary histories of genes across multiple genomes. We show that a significant reduction in informational redundancy is achieved by considering only the subset of distinct conservation profiles. Beyond these basic ideas, we point out various pitfalls and limitations associated with the data handling, paving the way for further improvements. As an illustration for the methods, we analyze a genome tree based on the above principles, along with a series of other trees derived from the same data and based on pair-wise comparisons (ancestral duplication-conservation and shared orthologs). In all trees we observe a sharp discrimination between the three primary domains of life: Bacteria, Archaea, and Eukarya. The new genome tree, based on conservation profiles, displays a significant correspondence with classically recognized taxonomical groupings, along with a series of departures from such conventional clusterings.'),
(83408, 2005, 'plos', 'Segregation of the brain into gray and white matter: a design minimizing conduction delays', 'Wen, Quan|Chklovskii, Dmitri B', 'Department of Physics and Astronomy, State University of New York at Stony Brook, Stony Brook, New York, United States of America.|Department of Physics and Astronomy, State University of New York at Stony Brook, Stony Brook, New York, United States of America.', 'United States|United States', 0, 'Animals|Brain|Color|Models, Neurological|Neural Pathways', 'Journal Article', '10.1371/journal.pcbi.0010078', '16389299', 'A ubiquitous feature of the vertebrate anatomy is the segregation of the brain into white and gray matter. Assuming that evolution maximized brain functionality, what is the reason for such segregation? To answer this question, we posit that brain functionality requires high interconnectivity and short conduction delays. Based on this assumption we searched for the optimal brain architecture by comparing different candidate designs. We found that the optimal design depends on the number of neurons, interneuronal connectivity, and axon diameter. In particular, the requirement to connect neurons with many fast axons drives the segregation of the brain into white and gray matter. These results provide a possible explanation for the structure of various regions of the vertebrate brain, such as the mammalian neocortex and neostriatum, the avian telencephalon, and the spinal cord.'),
(83409, 2005, 'plos', 'New maximum likelihood estimators for eukaryotic intron evolution', 'Nguyen, Hung D|Yoshihama, Maki|Kenmochi, Naoya', 'Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.|Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.|Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.', 'Japan|Japan|Japan', 62, 'Animals|Conserved Sequence|Eukaryotic Cells|Evolution, Molecular|Humans|Introns|Likelihood Functions|Spliceosomes', 'Journal Article', '10.1371/journal.pcbi.0010079', '16389300', 'The evolution of spliceosomal introns remains poorly understood. Although many approaches have been used to infer intron evolution from the patterns of intron position conservation, the results to date have been contradictory. In this paper, we address the problem using a novel maximum likelihood method, which allows estimation of the frequency of intron insertion target sites, together with the rates of intron gain and loss. We analyzed the pattern of 10,044 introns (7,221 intron positions) in the conserved regions of 684 sets of orthologs from seven eukaryotes. We determined that there is an average of one target site per 11.86 base pairs (bp) (95% confidence interval, 9.27 to 14.39 bp). In addition, our results showed that: (i) overall intron gains are approximately 25% greater than intron losses, although specific patterns vary with time and lineage, (ii) parallel gains account for approximately 18.5% of shared intron positions, and (iii) reacquisition following loss accounts for approximately 0.5% of all intron positions. Our results should assist in resolving the long-standing problem of inferring the evolution of spliceosomal introns.'),
(83410, 2006, 'plos', 'Genome-wide identification of human functional DNA using a neutral indel model', 'Lunter, Gerton|Ponting, Chris P|Hein, Jotun', 'MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. lunter@stats.ox.ac.uk|MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. lunter@stats.ox.ac.uk|MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. lunter@stats.ox.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 136, 'Animals|Base Composition|Base Sequence|DNA|Genetic Variation|Genome, Human|Genomics|Humans|Models, Genetic|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020005', '16410828', 'It has become clear that a large proportion of functional DNA in the human genome does not code for protein. Identification of this non-coding functional sequence using comparative approaches is proving difficult and has previously been thought to require deep sequencing of multiple vertebrates. Here we introduce a new model and comparative method that, instead of nucleotide substitutions, uses the evolutionary imprint of insertions and deletions (indels) to infer the past consequences of selection. The model predicts the distribution of indels under neutrality, and shows an excellent fit to human-mouse ancestral repeat data. Across the genome, many unusually long ungapped regions are detected that are unaccounted for by the neutral model, and which we predict to be highly enriched in functional DNA that has been subject to purifying selection with respect to indels. We use the model to determine the proportion under indel-purifying selection to be between 2.56% and 3.25% of human euchromatin. Since annotated protein-coding genes comprise only 1.2% of euchromatin, these results lend further weight to the proposition that more than half the functional complement of the human genome is non-protein-coding. The method is surprisingly powerful at identifying selected sequence using only two or three mammalian genomes. Applying the method to the human, mouse, and dog genomes, we identify 90 Mb of human sequence under indel-purifying selection, at a predicted 10% false-discovery rate and 75% sensitivity. As expected, most of the identified sequence represents unannotated material, while the recovered proportions of known protein-coding and microRNA genes closely match the predicted sensitivity of the method. The methods high sensitivity to functional sequence such as microRNAs suggest that as yet unannotated microRNA genes are enriched among the sequences identified. Furthermore, its independence of substitutions allowed us to identify sequence that has been subject to heterogeneous selection, that is, sequence subject to both positive selection with respect to substitutions and purifying selection with respect to indels. The ability to identify elements under heterogeneous selection enables, for the first time, the genome-wide investigation of positive selection on functional elements other than protein-coding genes.'),
(83411, 2006, 'plos', 'Long-range periodic patterns in microbial genomes indicate significant multi-scale chromosomal organization', 'Allen, Timothy E|Price, Nathan D|Joyce, Andrew R|Palsson, Bernhard Ø', 'Department of Bioengineering, University of California San Diego, La Jolla, California, USA.|Department of Bioengineering, University of California San Diego, La Jolla, California, USA.|Department of Bioengineering, University of California San Diego, La Jolla, California, USA.|Department of Bioengineering, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States|United States', 34, 'Bacterial Proteins|Base Sequence|Cell Shape|Chromosomes, Bacterial|Databases, Genetic|Evolution, Molecular|Gene Expression Regulation, Bacterial|Genome, Bacterial|Nuclear Proteins|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.0020002', '16410829', 'Genome organization can be studied through analysis of chromosome position-dependent patterns in sequence-derived parameters. A comprehensive analysis of such patterns in prokaryotic sequences and genome-scale functional data has yet to be performed. We detected spatial patterns in sequence-derived parameters for 163 chromosomes occurring in 135 bacterial and 16 archaeal organisms using wavelet analysis. Pattern strength was found to correlate with organism-specific features such as genome size, overall GC content, and the occurrence of known motility and chromosomal binding proteins. Given additional functional data for Escherichia coli, we found significant correlations among chromosome position dependent patterns in numerous properties, some of which are consistent with previously experimentally identified chromosome macrodomains. These results demonstrate that the large-scale organization of most sequenced genomes is significantly nonrandom, and, moreover, that this organization is likely linked to genome size, nucleotide composition, and information transfer processes. Constraints on genome evolution and design are thus not solely dependent upon information content, but also upon an intricate multi-parameter, multi-length-scale organization of the chromosome.'),
(83412, 2006, 'plos', 'Unusual intron conservation near tissue-regulated exons found by splicing microarrays', 'Sugnet, Charles W|Srinivasan, Karpagam|Clark, Tyson A|OBrien, Georgeann|Cline, Melissa S|Wang, Hui|Williams, Alan|Kulp, David|Blume, John E|Haussler, David|Ares, Manuel', 'Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 151, 'Adaptor Proteins, Signal Transducing|Alternative Splicing|Animals|Base Sequence|Brain|Conserved Sequence|Evolution, Molecular|Exons|Humans|Introns|Membrane Proteins|Mice|Molecular Sequence Data|Muscles|Neuropeptides|Oligonucleotide Array Sequence Analysis|Organ Specificity|Protein Isoforms|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.0020004', '16424921', 'Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5 splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.'),
(83413, 2006, 'plos', 'Computational analysis and prediction of the binding motif and protein interacting partners of the Abl SH3 domain', 'Hou, Tingjun|Chen, Ken|McLaughlin, William A|Lu, Benzhuo|Wang, Wei', 'Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.', 'United States|United States|United States|United States|United States', 119, 'Amino Acid Motifs|Amino Acid Sequence|Binding Sites|Computational Biology|Databases, Protein|Humans|Ligands|Models, Molecular|Molecular Sequence Data|Peptides|Protein Binding|Protein Structure, Tertiary|Proto-Oncogene Proteins c-abl|Reproducibility of Results|Static Electricity|src Homology Domains', 'Journal Article', '10.1371/journal.pcbi.0020001', '16446784', 'Protein-protein interactions, particularly weak and transient ones, are often mediated by peptide recognition domains, such as Src Homology 2 and 3 (SH2 and SH3) domains, which bind to specific sequence and structural motifs. It is important but challenging to determine the binding specificity of these domains accurately and to predict their physiological interacting partners. In this study, the interactions between 35 peptide ligands (15 binders and 20 non-binders) and the Abl SH3 domain were analyzed using molecular dynamics simulation and the Molecular Mechanics/Poisson-Boltzmann Solvent Area method. The calculated binding free energies correlated well with the rank order of the binding peptides and clearly distinguished binders from non-binders. Free energy component analysis revealed that the van der Waals interactions dictate the binding strength of peptides, whereas the binding specificity is determined by the electrostatic interaction and the polar contribution of desolvation. The binding motif of the Abl SH3 domain was then determined by a virtual mutagenesis method, which mutates the residue at each position of the template peptide relative to all other 19 amino acids and calculates the binding free energy difference between the template and the mutated peptides using the Molecular Mechanics/Poisson-Boltzmann Solvent Area method. A single position mutation free energy profile was thus established and used as a scoring matrix to search peptides recognized by the Abl SH3 domain in the human genome. Our approach successfully picked ten out of 13 experimentally determined binding partners of the Abl SH3 domain among the top 600 candidates from the 218,540 decapeptides with the PXXP motif in the SWISS-PROT database. We expect that this physical-principle based method can be applied to other protein domains as well.'),
(83414, 2006, 'plos', 'Signal processing in the TGF-beta superfamily ligand-receptor network', 'Vilar, Jose M G|Jansen, Ronald|Sander, Chris', 'Integrative Biological Modeling Laboratory, Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. vilar@cbio.mskcc.org|Integrative Biological Modeling Laboratory, Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. vilar@cbio.mskcc.org|Integrative Biological Modeling Laboratory, Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. vilar@cbio.mskcc.org', 'United States|United States|United States', 96, 'Computer Simulation|Kinetics|Ligands|Models, Biological|Neoplasms|Protein Binding|Protein Transport|Receptors, Transforming Growth Factor beta|Signal Transduction|Transforming Growth Factor beta', 'Journal Article', '10.1371/journal.pcbi.0020003', '16446785', 'The TGF-beta pathway plays a central role in tissue homeostasis and morphogenesis. It transduces a variety of extracellular signals into intracellular transcriptional responses that control a plethora of cellular processes, including cell growth, apoptosis, and differentiation. We use computational modeling to show that coupling of signaling with receptor trafficking results in a highly versatile signal-processing unit, able to sense by itself absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This coupling controls whether the response of the receptor module is transient or permanent and whether or not different signaling channels behave independently of each other. Our computational approach unifies seemingly disparate experimental observations and suggests specific changes in receptor trafficking patterns that can lead to phenotypes that favor tumor progression.'),
(83415, 2006, 'plos', 'Traditional biomolecular structure determination by NMR spectroscopy allows for major errors', 'Nabuurs, Sander B|Spronk, Chris A E M|Vuister, Geerten W|Vriend, Gert', 'Center for Molecular and Biomolecular Informatics, Nijmegen Center for Molecular Life Sciences, Radboud University, Nijmegen, Netherlands.|Center for Molecular and Biomolecular Informatics, Nijmegen Center for Molecular Life Sciences, Radboud University, Nijmegen, Netherlands.|Center for Molecular and Biomolecular Informatics, Nijmegen Center for Molecular Life Sciences, Radboud University, Nijmegen, Netherlands.|Center for Molecular and Biomolecular Informatics, Nijmegen Center for Molecular Life Sciences, Radboud University, Nijmegen, Netherlands.', 'Netherlands|Netherlands|Netherlands|Netherlands', 67, 'Amino Acid Sequence|Cytoplasmic Dyneins|Data Interpretation, Statistical|Dyneins|Humans|Image Processing, Computer-Assisted|Magnetic Resonance Spectroscopy|Molecular Conformation|Molecular Sequence Data|Neoplasm Proteins|Protein Conformation|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0020009', '16462939', 'One of the major goals of structural genomics projects is to determine the three-dimensional structure of representative members of as many different fold families as possible. Comparative modeling is expected to fill the remaining gaps by providing structural models of homologs of the experimentally determined proteins. However, for such an approach to be successful it is essential that the quality of the experimentally determined structures is adequate. In an attempt to build a homology model for the protein dynein light chain 2A (DLC2A) we found two potential templates, both experimentally determined nuclear magnetic resonance (NMR) structures originating from structural genomics efforts. Despite their high sequence identity (96%), the folds of the two structures are markedly different. This urged us to perform in-depth analyses of both structure ensembles and the deposited experimental data, the results of which clearly identify one of the two models as largely incorrect. Next, we analyzed the quality of a large set of recent NMR-derived structure ensembles originating from both structural genomics projects and individual structure determination groups. Unfortunately, a visual inspection of structures exhibiting lower quality scores than DLC2A reveals that the seriously flawed DLC2A structure is not an isolated incident. Overall, our results illustrate that the quality of NMR structures cannot be reliably evaluated using only traditional experimental input data and overall quality indicators as a reference and clearly demonstrate the urgent need for a tight integration of more sophisticated structure validation tools in NMR structure determination projects. In contrast to common methodologies where structures are typically evaluated as a whole, such tools should preferentially operate on a per-residue basis.'),
(83416, 2006, 'plos', 'Seriation in paleontological data using markov chain Monte Carlo methods', 'Puolamäki, Kai|Fortelius, Mikael|Mannila, Heikki', 'Laboratory of Computer and Information Science, Helsinki University of Technology, Espoo, Finland. Kai.Puolamaki@hut.fi|Laboratory of Computer and Information Science, Helsinki University of Technology, Espoo, Finland. Kai.Puolamaki@hut.fi|Laboratory of Computer and Information Science, Helsinki University of Technology, Espoo, Finland. Kai.Puolamaki@hut.fi', 'Finland|Finland|Finland', 0, 'Animals|Computational Biology|Fossils|Likelihood Functions|Mammals|Markov Chains|Models, Biological|Models, Statistical|Models, Theoretical|Monte Carlo Method|Paleontology|Phylogeny|Population Dynamics|Probability|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020006', '16477311', 'Given a collection of fossil sites with data about the taxa that occur in each site, the task in biochronology is to find good estimates for the ages or ordering of sites. We describe a full probabilistic model for fossil data. The parameters of the model are natural: the ordering of the sites, the origination and extinction times for each taxon, and the probabilities of different types of errors. We show that the posterior distributions of these parameters can be estimated reliably by using Markov chain Monte Carlo techniques. The posterior distributions of the model parameters can be used to answer many different questions about the data, including seriation (finding the best ordering of the sites) and outlier detection. We demonstrate the usefulness of the model and estimation method on synthetic data and on real data on large late Cenozoic mammals. As an example, for the sites with large number of occurrences of common genera, our methods give orderings, whose correlation with geochronologic ages is 0.95.'),
(83417, 2005, 'plos', 'PhyloGibbs: a Gibbs sampling motif finder that incorporates phylogeny', 'Siddharthan, Rahul|Siggia, Eric D|van Nimwegen, Erik', 'Center for Studies in Physics and Biology, The Rockefeller University, New York, New York, United States of America.|Center for Studies in Physics and Biology, The Rockefeller University, New York, New York, United States of America.|Center for Studies in Physics and Biology, The Rockefeller University, New York, New York, United States of America.', 'United States|United States|United States', 0, 'Algorithms|Base Sequence|Binding Sites|Computational Biology|DNA, Intergenic|Genome, Fungal|Models, Genetic|Molecular Sequence Data|Phylogeny|Response Elements|Saccharomyces cerevisiae|Sequence Alignment|Software|Transcription Factors', 'Comparative Study', '10.1371/journal.pcbi.0010067', '16477324', 'A central problem in the bioinformatics of gene regulation is to find the binding sites for regulatory proteins. One of the most promising approaches toward identifying these short and fuzzy sequence patterns is the comparative analysis of orthologous intergenic regions of related species. This analysis is complicated by various factors. First, one needs to take the phylogenetic relationship between the species into account in order to distinguish conservation that is due to the occurrence of functional sites from spurious conservation that is due to evolutionary proximity. Second, one has to deal with the complexities of multiple alignments of orthologous intergenic regions, and one has to consider the possibility that functional sites may occur outside of conserved segments. Here we present a new motif sampling algorithm, PhyloGibbs, that runs on arbitrary collections of multiple local sequence alignments of orthologous sequences. The algorithm searches over all ways in which an arbitrary number of binding sites for an arbitrary number of transcription factors (TFs) can be assigned to the multiple sequence alignments. These binding site configurations are scored by a Bayesian probabilistic model that treats aligned sequences by a model for the evolution of binding sites and background intergenic DNA. This model takes the phylogenetic relationship between the species in the alignment explicitly into account. The algorithm uses simulated annealing and Monte Carlo Markov-chain sampling to rigorously assign posterior probabilities to all the binding sites that it reports. In tests on synthetic data and real data from five Saccharomyces species our algorithm performs significantly better than four other motif-finding algorithms, including algorithms that also take phylogeny into account. Our results also show that, in contrast to the other algorithms, PhyloGibbs can make realistic estimates of the reliability of its predictions. Our tests suggest that, running on the five-species multiple alignment of a single genes upstream region, PhyloGibbs on average recovers over 50% of all binding sites in S. cerevisiae at a specificity of about 50%, and 33% of all binding sites at a specificity of about 85%. We also tested PhyloGibbs on collections of multiple alignments of intergenic regions that were recently annotated, based on ChIP-on-chip data, to contain binding sites for the same TF. We compared PhyloGibbss results with the previous analysis of these data using six other motif-finding algorithms. For 16 of 21 TFs for which all other motif-finding methods failed to find a significant motif, PhyloGibbs did recover a motif that matches the literature consensus. In 11 cases where there was disagreement in the results we compiled lists of known target genes from the literature, and found that running PhyloGibbs on their regulatory regions yielded a binding motif matching the literature consensus in all but one of the cases. Interestingly, these literature gene lists had little overlap with the targets annotated based on the ChIP-on-chip data. The PhyloGibbs code can be downloaded from http://www.biozentrum.unibas.ch/~nimwegen/cgi-bin/phylogibbs.cgi or http://www.imsc.res.in/~rsidd/phylogibbs. The full set of predicted sites from our tests on yeast are available at http://www.swissregulon.unibas.ch.'),
(83418, 2005, 'plos', 'Functional alignment of regulatory networks: a study of temperate phages', 'Trusina, Ala|Sneppen, Kim|Dodd, Ian B|Shearwin, Keith E|Egan, J Barry', 'Department of Theoretical Physics, Umeå University, Umeå, Sweden. trusina@tp.umu.se|Department of Theoretical Physics, Umeå University, Umeå, Sweden. trusina@tp.umu.se|Department of Theoretical Physics, Umeå University, Umeå, Sweden. trusina@tp.umu.se|Department of Theoretical Physics, Umeå University, Umeå, Sweden. trusina@tp.umu.se|Department of Theoretical Physics, Umeå University, Umeå, Sweden. trusina@tp.umu.se', 'Sweden|Sweden|Sweden|Sweden|Sweden', 0, 'Bacteriophages|Gene Expression Regulation, Viral|Models, Biological|Molecular Sequence Data|Phylogeny|Signal Transduction', 'Comparative Study', '10.1371/journal.pcbi.0010074', '16477325', 'The relationship between the design and functionality of molecular networks is now a key issue in biology. Comparison of regulatory networks performing similar tasks can provide insights into how network architecture is constrained by the functions it directs. Here, we discuss methods of network comparison based on network architecture and signaling logic. Introducing local and global signaling scores for the difference between two networks, we quantify similarities between evolutionarily closely and distantly related bacteriophages. Despite the large evolutionary separation between phage lambda and 186, their networks are found to be similar when difference is measured in terms of global signaling. We finally discuss how network alignment can be used to pinpoint protein similarities viewed from the network perspective.'),
(83419, 2006, 'plos', 'Structure modeling of all identified G protein-coupled receptors in the human genome', 'Zhang, Yang|Devries, Mark E|Skolnick, Jeffrey', 'Center of Excellence in Bioinformatics, University at Buffalo, Buffalo, New York, USA.|Center of Excellence in Bioinformatics, University at Buffalo, Buffalo, New York, USA.|Center of Excellence in Bioinformatics, University at Buffalo, Buffalo, New York, USA.', 'United States|United States|United States', 178, 'Algorithms|Animals|Cattle|Cluster Analysis|Computational Biology|Databases, Protein|Genome, Human|Humans|Internet|Models, Molecular|Molecular Conformation|Protein Conformation|Receptors, G-Protein-Coupled|Software', 'Journal Article', '10.1371/journal.pcbi.0020013', '16485037', 'G protein-coupled receptors (GPCRs), encoded by about 5% of human genes, comprise the largest family of integral membrane proteins and act as cell surface receptors responsible for the transduction of endogenous signal into a cellular response. Although tertiary structural information is crucial for function annotation and drug design, there are few experimentally determined GPCR structures. To address this issue, we employ the recently developed threading assembly refinement (TASSER) method to generate structure predictions for all 907 putative GPCRs in the human genome. Unlike traditional homology modeling approaches, TASSER modeling does not require solved homologous template structures, moreover, it often refines the structures closer to native. These features are essential for the comprehensive modeling of all human GPCRs when close homologous templates are absent. Based on a benchmarked confidence score, approximately 820 predicted models should have the correct folds. The majority of GPCR models share the characteristic seven-transmembrane helix topology, but 45 ORFs are predicted to have different structures. This is due to GPCR fragments that are predominantly from extracellular or intracellular domains as well as database annotation errors. Our preliminary validation includes the automated modeling of bovine rhodopsin, the only solved GPCR in the Protein Data Bank. With homologous templates excluded, the final model built by TASSER has a global C(alpha) root-mean-squared deviation from native of 4.6 angstroms, with a root-mean-squared deviation in the transmembrane helix region of 2.1 angstroms. Models of several representative GPCRs are compared with mutagenesis and affinity labeling data, and consistent agreement is demonstrated. Structure clustering of the predicted models shows that GPCRs with similar structures tend to belong to a similar functional class even when their sequences are diverse. These results demonstrate the usefulness and robustness of the in silico models for GPCR functional analysis. All predicted GPCR models are freely available for noncommercial users on our Web site (http://www.bioinformatics.buffalo.edu/GPCR).');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83420, 2006, 'plos', 'Dependency map of proteins in the small ribosomal subunit', 'Hamacher, Kay|Trylska, Joanna|McCammon, J Andrew', 'Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA. hamacher_at_ctbp.ucsd.edu|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA. hamacher_at_ctbp.ucsd.edu|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA. hamacher_at_ctbp.ucsd.edu', 'United States|United States|United States', 36, 'Computational Biology|Entropy|Escherichia coli|Models, Biological|Models, Statistical|Monte Carlo Method|Peptides|Ribosomal Proteins|Ribosomes|Software|Thermodynamics|Thermus thermophilus', 'Journal Article', '10.1371/journal.pcbi.0020010', '16485038', 'The assembly of the ribosome has recently become an interesting target for antibiotics in several bacteria. In this work, we extended an analytical procedure to determine native state fluctuations and contact breaking to investigate the protein stability dependence in the 30S small ribosomal subunit of Thermus thermophilus. We determined the causal influence of the presence and absence of proteins in the 30S complex on the binding free energies of other proteins. The predicted dependencies are in overall agreement with the experimentally determined assembly map for another organism, Escherichia coli. We found that the causal influences result from two distinct mechanisms: one is pure internal energy change, the other originates from the entropy change. We discuss the implications on how to target the ribosomal assembly most effectively by suggesting six proteins as targets for mutations or other hindering of their binding. Our results show that by blocking one out of this set of proteins, the association of other proteins is eventually reduced, thus reducing the translation efficiency even more. We could additionally determine the binding dependency of THX--a peptide not present in the ribosome of E. coli--and suggest its assembly path.'),
(83421, 2006, 'plos', 'Ten simple rules for getting grants', 'Bourne, Philip E|Chalupa, Leo M', 'Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA. hamacher_at_ctbp.ucsd.edu|Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA. hamacher_at_ctbp.ucsd.edu', 'United States|United States', 16, 'Financing, Government|Financing, Organized|Fund Raising|Research|Research Support as Topic|United States', 'Editorial', '10.1371/journal.pcbi.0020012', '16501664', '-'),
(83422, 2006, 'plos', 'The fragile breakage versus random breakage models of chromosome evolution', 'Peng, Qian|Pevzner, Pavel A|Tesler, Glenn', 'Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA.|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA.|Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States', 66, 'Algorithms|Animals|Chromosome Breakage|Chromosomes|Chromosomes, Human|Chromosomes, Human, X|Computational Biology|DNA Damage|Evolution, Molecular|Humans|Mice|Models, Biological|Models, Statistical|X Chromosome', 'Journal Article', '10.1371/journal.pcbi.0020014', '16501665', 'For many years, studies of chromosome evolution were dominated by the random breakage theory, which implies that there are no rearrangement hot spots in the human genome. In 2003, Pevzner and Tesler argued against the random breakage model and proposed an alternative fragile breakage model of chromosome evolution. In 2004, Sankoff and Trinh argued against the fragile breakage model and raised doubts that Pevzner and Tesler provided any evidence of rearrangement hot spots. We investigate whether Sankoff and Trinh indeed revealed a flaw in the arguments of Pevzner and Tesler. We show that Sankoff and Trinhs synteny block identification algorithm makes erroneous identifications even in small toy examples and that their parameters do not reflect the realities of the comparative genomic architecture of human and mouse. We further argue that if Sankoff and Trinh had fixed these problems, their arguments in support of the random breakage model would disappear. Finally, we study the link between rearrangements and regulatory regions and argue that long regulatory regions and inhomogeneity of gene distribution in mammalian genomes may be responsible for the breakpoint reuse phenomenon.'),
(83423, 2006, 'plos', 'Large-scale trends in the evolution of gene structures within 11 animal genomes', 'Yandell, Mark|Mungall, Chris J|Smith, Chris|Prochnik, Simon|Kaminker, Joshua|Hartzell, George|Lewis, Suzanna|Rubin, Gerald M', 'Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah|Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA. myandell@genetics.utah', 'United States|United States|United States|United States|United States|United States|United States|United States', 59, 'Animals|Anopheles|Caenorhabditis elegans|Ciona intestinalis|Computational Biology|Drosophila melanogaster|Evolution, Molecular|Genome|Humans|Mice|Phylogeny|Proteomics|Species Specificity', 'Journal Article', '10.1371/journal.pcbi.0020015', '16518452', 'We have used the annotations of six animal genomes (Homo sapiens, Mus musculus, Ciona intestinalis, Drosophila melanogaster, Anopheles gambiae, and Caenorhabditis elegans) together with the sequences of five unannotated Drosophila genomes to survey changes in protein sequence and gene structure over a variety of timescales--from the less than 5 million years since the divergence of D. simulans and D. melanogaster to the more than 500 million years that have elapsed since the Cambrian explosion. To do so, we have developed a new open-source software library called CGL (for Comparative Genomics Library). Our results demonstrate that change in intron-exon structure is gradual, clock-like, and largely independent of coding-sequence evolution. This means that genome annotations can be used in new ways to inform, corroborate, and test conclusions drawn from comparative genomics analyses that are based upon protein and nucleotide sequence similarities.'),
(83424, 2006, 'plos', 'Circadian clocks are resounding in peripheral tissues', 'Ptitsyn, Andrey A|Zvonic, Sanjin|Conrad, Steven A|Scott, L Keith|Mynatt, Randall L|Gimble, Jeffrey M', 'Experimental Obesity Laboratory, Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.|Experimental Obesity Laboratory, Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.|Experimental Obesity Laboratory, Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.|Experimental Obesity Laboratory, Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.|Experimental Obesity Laboratory, Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.|Experimental Obesity Laboratory, Louisiana State University Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.', 'United States|United States|United States|United States|United States|United States', 103, 'Adipose Tissue|Algorithms|Animals|Circadian Rhythm|Computational Biology|Gene Expression Regulation|Liver|Mice|Models, Statistical|Obesity|Oligonucleotide Array Sequence Analysis|Oscillometry|Stochastic Processes|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020016', '16532060', 'Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%-10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity.'),
(83425, 2006, 'plos', 'A third approach to gene prediction suggests thousands of additional human transcribed regions', 'Glusman, Gustavo|Qin, Shizhen|El-Gewely, M Raafat|Siegel, Andrew F|Roach, Jared C|Hood, Leroy|Smit, Arian F A', 'Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org|Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org|Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org|Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org|Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org|Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org|Institute for Systems Biology, Seattle, Washington, USA. Gustavo@SystemsBiology.org', 'United States|United States|United States|United States|United States|United States|United States', 0, 'Algorithms|Computational Biology|DNA Repair|Evolution, Molecular|Gene Expression Profiling|Humans|Models, Statistical|Mutation|Sequence Analysis, DNA|Software|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020018', '16543943', 'The identification and characterization of the complete ensemble of genes is a main goal of deciphering the digital information stored in the human genome. Many algorithms for computational gene prediction have been described, ultimately derived from two basic concepts: (1) modeling gene structure and (2) recognizing sequence similarity. Successful hybrid methods combining these two concepts have also been developed. We present a third orthogonal approach to gene prediction, based on detecting the genomic signatures of transcription, accumulated over evolutionary time. We discuss four algorithms based on this third concept: Greens and CHOWDER, which quantify mutational strand biases caused by transcription-coupled DNA repair, and ROAST and PASTA, which are based on strand-specific selection against polyadenylation signals. We combined these algorithms into an integrated method called FEAST, which we used to predict the location and orientation of thousands of putative transcription units not overlapping known genes. Many of the newly predicted transcriptional units do not appear to code for proteins. The new algorithms are particularly apt at detecting genes with long introns and lacking sequence conservation. They therefore complement existing gene prediction methods and will help identify functional transcripts within many apparent genomic deserts.'),
(83426, 2006, 'plos', 'Role of mechanical factors in the morphology of the primate cerebral cortex', 'Hilgetag, Claus C|Barbas, Helen', 'School of Engineering and Science, International University Bremen, Bremen, Germany. c.hilgetag@iu-bremen.de|School of Engineering and Science, International University Bremen, Bremen, Germany. c.hilgetag@iu-bremen.de', 'Germany|Germany', 191, 'Algorithms|Animals|Autistic Disorder|Axons|Brain Mapping|Cerebral Cortex|Computational Biology|Humans|Macaca mulatta|Models, Statistical|Neural Pathways|Neurons|Prefrontal Cortex|Schizophrenia', 'Journal Article', '10.1371/journal.pcbi.0020022', '16557292', 'The convoluted cortex of primates is instantly recognizable in its principal morphologic features, yet puzzling in its complex finer structure. Various hypotheses have been proposed about the mechanisms of its formation. Based on the analysis of databases of quantitative architectonic and connection data for primate prefrontal cortices, we offer support for the hypothesis that tension exerted by corticocortical connections is a significant factor in shaping the cerebral cortical landscape. Moreover, forces generated by cortical folding influence laminar morphology, and appear to have a previously unsuspected impact on cellular migration during cortical development. The evidence for a significant role of mechanical factors in cortical morphology opens the possibility of constructing computational models of cortical development based on physical principles. Such models are particularly relevant for understanding the relationship of cortical morphology to the connectivity of normal brains, and structurally altered brains in diseases of developmental origin, such as schizophrenia and autism.'),
(83427, 2006, 'plos', 'The emergence of Up and Down states in cortical networks', 'Holcman, David|Tsodyks, Misha', 'Department of Mathematics, Weizmann Institute of Science, Rehovot, Israel. david.holcman@weizmann.ac.il|Department of Mathematics, Weizmann Institute of Science, Rehovot, Israel. david.holcman@weizmann.ac.il', 'Israel|Israel', 0, 'Action Potentials|Animals|Cerebral Cortex|Membrane Potentials|Models, Neurological|Models, Theoretical|Nerve Net|Neural Pathways|Neuronal Plasticity|Neurons|Synapses', 'Journal Article', '10.1371/journal.pcbi.0020023', '16557293', 'The cerebral cortex is continuously active in the absence of external stimuli. An example of this spontaneous activity is the voltage transition between an Up and a Down state, observed simultaneously at individual neurons. Since this phenomenon could be of critical importance for working memory and attention, its explanation could reveal some fundamental properties of cortical organization. To identify a possible scenario for the dynamics of Up-Down states, we analyze a reduced stochastic dynamical system that models an interconnected network of excitatory neurons with activity-dependent synaptic depression. The model reveals that when the total synaptic connection strength exceeds a certain threshold, the phase space of the dynamical system contains two attractors, interpreted as Up and Down states. In that case, synaptic noise causes transitions between the states. Moreover, an external stimulation producing a depolarization increases the time spent in the Up state, as observed experimentally. We therefore propose that the existence of Up-Down states is a fundamental and inherent property of a noisy neural ensemble with sufficiently strong synaptic connections.'),
(83428, 2006, 'plos', 'A model for integrating elementary neural functions into delayed-response behavior', 'Gisiger, Thomas|Kerszberg, Michel', 'Récepteurs et Cognition, Institut Pasteur, Paris, France.|Récepteurs et Cognition, Institut Pasteur, Paris, France.', 'France|France', 0, 'Algorithms|Animals|Basal Ganglia|Brain|Brain Mapping|Computer Simulation|Electrophysiology|Haplorhini|Humans|Learning|Memory, Short-Term|Models, Neurological|Nerve Net|Prefrontal Cortex', 'Journal Article', '10.1371/journal.pcbi.0020025', '16604158', 'It is well established that various cortical regions can implement a wide array of neural processes, yet the mechanisms which integrate these processes into behavior-producing, brain-scale activity remain elusive. We propose that an important role in this respect might be played by executive structures controlling the traffic of information between the cortical regions involved. To illustrate this hypothesis, we present a neural network model comprising a set of interconnected structures harboring stimulus-related activity (visual representation, working memory, and planning), and a group of executive units with task-related activity patterns that manage the information flowing between them. The resulting dynamics allows the network to perform the dual task of either retaining an image during a delay (delayed-matching to sample task), or recalling from this image another one that has been associated with it during training (delayed-pair association task). The model reproduces behavioral and electrophysiological data gathered on the inferior temporal and prefrontal cortices of primates performing these same tasks. It also makes predictions on how neural activity coding for the recall of the image associated with the sample emerges and becomes prospective during the training phase. The network dynamics proves to be very stable against perturbations, and it exhibits signs of scale-invariant organization and cooperativity. The present network represents a possible neural implementation for active, top-down, prospective memory retrieval in primates. The model suggests that brain activity leading to performance of cognitive tasks might be organized in modular fashion, simple neural functions becoming integrated into more complex behavior by executive structures harbored in prefrontal cortex and/or basal ganglia.'),
(83429, 2006, 'plos', 'Understanding the degradation of hominid gene control', 'Keightley, Peter D|Lercher, Martin J|Eyre-Walker, Adam', 'Récepteurs et Cognition, Institut Pasteur, Paris, France.|Récepteurs et Cognition, Institut Pasteur, Paris, France.|Récepteurs et Cognition, Institut Pasteur, Paris, France.', 'France|France|France', 5, 'Animals|DNA|Gene Expression Regulation|Genetics, Medical|Genome|Hominidae|Humans|Introns|Mammals', 'Letter', '10.1371/journal.pcbi.0020019', '16604186', '-'),
(83430, 2006, 'plos', 'Spatiotemporal expression control correlates with intragenic scaffold matrix attachment regions (S/MARs) in Arabidopsis thaliana', 'Tetko, Igor V|Haberer, Georg|Rudd, Stephen|Meyers, Blake|Mewes, Hans-Werner|Mayer, Klaus F X', 'GSF National Research Center for Environment and Health, MIPS, Institute for Bioinformatics, Neuherberg, Germany.|GSF National Research Center for Environment and Health, MIPS, Institute for Bioinformatics, Neuherberg, Germany.|GSF National Research Center for Environment and Health, MIPS, Institute for Bioinformatics, Neuherberg, Germany.|GSF National Research Center for Environment and Health, MIPS, Institute for Bioinformatics, Neuherberg, Germany.|GSF National Research Center for Environment and Health, MIPS, Institute for Bioinformatics, Neuherberg, Germany.|GSF National Research Center for Environment and Health, MIPS, Institute for Bioinformatics, Neuherberg, Germany.', 'Germany|Germany|Germany|Germany|Germany|Germany', 0, 'Arabidopsis|Cell Nucleus|Chromatin|DNA, Plant|Gene Expression Regulation, Plant|Genes, Plant|Oligonucleotide Array Sequence Analysis|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020021', '16604187', 'Scaffold/matrix attachment regions (S/MARs) are essential for structural organization of the chromatin within the nucleus and serve as anchors of chromatin loop domains. A significant fraction of genes in Arabidopsis thaliana contains intragenic S/MAR elements and a significant correlation of S/MAR presence and overall expression strength has been demonstrated. In this study, we undertook a genome scale analysis of expression level and spatiotemporal expression differences in correlation with the presence or absence of genic S/MAR elements. We demonstrate that genes containing intragenic S/MARs are prone to pronounced spatiotemporal expression regulation. This characteristic is found to be even more pronounced for transcription factor genes. Our observations illustrate the importance of S/MARs in transcriptional regulation and the role of chromatin structural characteristics for gene regulation. Our findings open new perspectives for the understanding of tissue- and organ-specific regulation of gene expression.'),
(83431, 2006, 'plos', 'Estimating Costs and Benefits of CTL Escape Mutations in SIV/HIV Infection', 'Ganusov, Vitaly V|De Boer, Rob J', 'Theoretical Biology, Utrecht University, Utrecht, Netherlands. V.V.Ganusov@bio.uu.nl|Theoretical Biology, Utrecht University, Utrecht, Netherlands. V.V.Ganusov@bio.uu.nl', 'Netherlands|Netherlands', 0, 'Animals|CD8-Positive T-Lymphocytes|HIV|HIV Infections|Humans|Mutation|Simian Acquired Immunodeficiency Syndrome|Simian Immunodeficiency Virus|T-Lymphocytes, Cytotoxic', 'Journal Article', '10.1371/journal.pcbi.0020024', '16604188', 'Mutations that allow SIV/HIV to avoid the cytotoxic T lymphocyte (CTL) response are well documented. Recently, there have been a few attempts at estimating the costs of CTL escape mutations in terms of the reduction in viral fitness and the killing rate at which the CTL response specific to one viral epitope clears virus-infected cells. Using a mathematical model we show that estimation of both parameters depends critically on the underlying changes in the replication rate of the virus and the changes in the killing rate over time (which in previous studies were assumed to be constant). We provide a theoretical basis for estimation of these parameters using in vivo data. In particular, we show that 1) by assuming unlimited virus growth one can obtain a minimal estimate of the fitness cost of the escape mutation, and 2) by assuming no virus growth during the escape, one can obtain a minimal estimate of the average killing rate. We also discuss the conditions under which better estimates of the average killing rate can be obtained.'),
(83432, 2006, 'plos', 'Dynamical principles of two-component genetic oscillators', 'Guantes, Raúl|Poyatos, Juan F', 'Instituto Nicolás Cabrera, Facultad de Ciencias C-XVI, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto Nicolás Cabrera, Facultad de Ciencias C-XVI, Universidad Autónoma de Madrid, Madrid, Spain.', 'Spain|Spain', 85, 'Animals|Genetic Variation|Models, Genetic|Oscillometry|Protein Biosynthesis|Protein Processing, Post-Translational|Proteins|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020030', '16604190', 'Genetic oscillators based on the interaction of a small set of molecular components have been shown to be involved in the regulation of the cell cycle, the circadian rhythms, or the response of several signaling pathways. Uncovering the functional properties of such oscillators then becomes important for the understanding of these cellular processes and for the characterization of fundamental properties of more complex clocks. Here, we show how the dynamics of a minimal two-component oscillator is drastically affected by its genetic implementation. We consider a repressor and activator element combined in a simple logical motif. While activation is always exerted at the transcriptional level, repression is alternatively operating at the transcriptional (Design I) or post-translational (Design II) level. These designs display differences on basic oscillatory features and on their behavior with respect to molecular noise or entrainment by periodic signals. In particular, Design I induces oscillations with large activator amplitudes and arbitrarily small frequencies, and acts as an integrator of external stimuli, while Design II shows emergence of oscillations with finite, and less variable, frequencies and smaller amplitudes, and detects better frequency-encoded signals (resonator). Similar types of stimulus response are observed in neurons, and thus this work enables us to connect very different biological contexts. These dynamical principles are relevant for the characterization of the physiological roles of simple oscillator motifs, the understanding of core machineries of complex clocks, and the bio-engineering of synthetic oscillatory circuits.'),
(83433, 2006, 'plos', 'Folding very short peptides using molecular dynamics', 'Ho, Bosco K|Dill, Ken A', 'Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA. bosco@maxwell.ucsf.edu|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA. bosco@maxwell.ucsf.edu', 'United States|United States', 60, 'Biophysical Phenomena|Biophysics|Computational Biology|Computer Simulation|Entropy|Kinetics|Models, Molecular|Models, Statistical|Molecular Conformation|Peptides|Protein Conformation|Protein Folding|Protein Structure, Secondary|Proteomics|Solvents', 'Journal Article', '10.1371/journal.pcbi.0020027', '16617376', 'Peptides often have conformational preferences. We simulated 133 peptide 8-mer fragments from six different proteins, sampled by replica-exchange molecular dynamics using Amber7 with a GB/SA (generalized-Born/solvent-accessible electrostatic approximation to water) implicit solvent. We found that 85 of the peptides have no preferred structure, while 48 of them converge to a preferred structure. In 85% of the converged cases (41 peptides), the structures found by the simulations bear some resemblance to their native structures, based on a coarse-grained backbone description. In particular, all seven of the beta hairpins in the native structures contain a fragment in the turn that is highly structured. In the eight cases where the bioinformatics-based I-sites library picks out native-like structures, the present simulations are largely in agreement. Such physics-based modeling may be useful for identifying early nuclei in folding kinetics and for assisting in protein-structure prediction methods that utilize the assembly of peptide fragments.'),
(83434, 2006, 'plos', 'Conformational changes in protein loops and helices induced by post-translational phosphorylation', 'Groban, Eli S|Narayanan, Arjun|Jacobson, Matthew P', 'Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.', 'United States|United States|United States', 102, 'Algorithms|Animals|Aspartic Acid|Computational Biology|Cyclin-Dependent Kinase 2|Databases, Protein|Glutamic Acid|Humans|Molecular Conformation|Phosphorylation|Protein Conformation|Protein Processing, Post-Translational|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.0020032', '16628247', 'Post-translational phosphorylation is a ubiquitous mechanism for modulating protein activity and protein-protein interactions. In this work, we examine how phosphorylation can modulate the conformation of a protein by changing the energy landscape. We present a molecular mechanics method in which we phosphorylate proteins in silico and then predict how the conformation of the protein will change in response to phosphorylation. We apply this method to a test set comprised of proteins with both phosphorylated and non-phosphorylated crystal structures, and demonstrate that it is possible to predict localized phosphorylation-induced conformational changes, or the absence of conformational changes, with near-atomic accuracy in most cases. Examples of proteins used for testing our methods include kinases and prokaryotic response regulators. Through a detailed case study of cyclin-dependent kinase 2, we also illustrate how the computational methods can be used to provide new understanding of how phosphorylation drives conformational change, why substituting Glu or Asp for a phosphorylated amino acid does not always mimic the effects of phosphorylation, and how a phosphatase can capture a phosphorylated amino acid. This work illustrates how computational methods can be used to elucidate principles and mechanisms of post-translational phosphorylation, which can ultimately help to bridge the gap between the number of known sites of phosphorylation and the number of structures of phosphorylated proteins.'),
(83435, 2006, 'plos', 'Identification and classification of conserved RNA secondary structures in the human genome', 'Pedersen, Jakob Skou|Bejerano, Gill|Siepel, Adam|Rosenbloom, Kate|Lindblad-Toh, Kerstin|Lander, Eric S|Kent, Jim|Miller, Webb|Haussler, David', 'Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu|Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, USA. jsp@soe.ucsc.edu', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 385, '3 Untranslated Regions|Animals|Chickens|Computational Biology|Conserved Sequence|Dogs|Genome|Genome, Human|Humans|Mice|MicroRNAs|Nucleic Acid Conformation|Rats|Sequence Analysis, RNA|Tetraodontiformes|Zebrafish', 'Journal Article', '10.1371/journal.pcbi.0020033', '16628248', 'The discoveries of microRNAs and riboswitches, among others, have shown functional RNAs to be biologically more important and genomically more prevalent than previously anticipated. We have developed a general comparative genomics method based on phylogenetic stochastic context-free grammars for identifying functional RNAs encoded in the human genome and used it to survey an eight-way genome-wide alignment of the human, chimpanzee, mouse, rat, dog, chicken, zebra-fish, and puffer-fish genomes for deeply conserved functional RNAs. At a loose threshold for acceptance, this search resulted in a set of 48,479 candidate RNA structures. This screen finds a large number of known functional RNAs, including 195 miRNAs, 62 histone 3UTR stem loops, and various types of known genetic recoding elements. Among the highest-scoring new predictions are 169 new miRNA candidates, as well as new candidate selenocysteine insertion sites, RNA editing hairpins, RNAs involved in transcript auto regulation, and many folds that form singletons or small functional RNA families of completely unknown function. While the rate of false positives in the overall set is difficult to estimate and is likely to be substantial, the results nevertheless provide evidence for many new human functional RNAs and present specific predictions to facilitate their further characterization.'),
(83436, 2006, 'plos', 'Genome-wide survey for biologically functional pseudogenes', 'Svensson, Orjan|Arvestad, Lars|Lagergren, Jens', 'Stockholm Bioinformatics Centre, Royal Institute of Technology, Albanova University Center, Stockholm, Sweden. osv@sbc.su.se|Stockholm Bioinformatics Centre, Royal Institute of Technology, Albanova University Center, Stockholm, Sweden. osv@sbc.su.se|Stockholm Bioinformatics Centre, Royal Institute of Technology, Albanova University Center, Stockholm, Sweden. osv@sbc.su.se', 'Sweden|Sweden|Sweden', 54, 'Animals|Base Sequence|Conserved Sequence|Evolution, Molecular|Gene Expression|Genome|Genomics|Humans|Likelihood Functions|Mice|Molecular Sequence Data|Pan troglodytes|Phylogeny|Pseudogenes|RNA, Messenger|Sequence Alignment', 'Journal Article', '10.1371/journal.pcbi.0020046', '16680195', 'According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human-mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human-mouse species split, and also a larger group of primate-specific ones found from human-chimpanzee searches. Two processed sequences are notable, their conservation since the human-mouse split being as high as most protein-coding genes, one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios.'),
(83437, 2006, 'plos', 'Fold designability, distribution, and disease', 'Wong, Philip|Frishman, Dmitrij', 'Institute for Bioinformatics, GSF--National Research Center for Environment and Health, Neuherberg, Germany.|Institute for Bioinformatics, GSF--National Research Center for Environment and Health, Neuherberg, Germany.', 'Germany|Germany', 0, 'Animals|Cell Proliferation|Cellular Senescence|Disease|Humans|Mice|Proteins|Saccharomyces cerevisiae', 'Journal Article', '10.1371/journal.pcbi.0020040', '16680196', 'Fold designability has been estimated by the number of families contained in that fold. Here, we show that among orthologous proteins, sequence divergence is higher for folds with greater numbers of families. Folds with greater numbers of families also tend to have families that appear more often in the proteome and greater promiscuity (the number of unique partner folds that the fold is found with within the same protein). We also find that many disease-related proteins have folds with relatively few families. In particular, a number of these proteins are associated with diseases occurring at high frequency. These results suggest that family counts reflect how certain structures are distributed in nature and is an important characteristic associated with many human diseases.'),
(83438, 2006, 'plos', 'SAGE2Splice: unmapped SAGE tags reveal novel splice junctions', 'Kuo, Byron Yu-Lin|Chen, Ying|Bohacec, Slavita|Johansson, Ojvind|Wasserman, Wyeth W|Simpson, Elizabeth M', 'Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.|Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada', 9, 'Algorithms|Animals|Base Sequence|Gene Expression Profiling|Introns|Mice|Models, Genetic|Molecular Sequence Data|RNA Splice Sites|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.0020034', '16683015', 'Serial analysis of gene expression (SAGE) not only is a method for profiling the global expression of genes, but also offers the opportunity for the discovery of novel transcripts. SAGE tags are mapped to known transcripts to determine the gene of origin. Tags that map neither to a known transcript nor to the genome were hypothesized to span a splice junction, for which the exon combination or exon(s) are unknown. To test this hypothesis, we have developed an algorithm, SAGE2Splice, to efficiently map SAGE tags to potential splice junctions in a genome. The algorithm consists of three search levels. A scoring scheme was designed based on position weight matrices to assess the quality of candidates. Using optimized parameters for SAGE2Splice analysis and two sets of SAGE data, candidate junctions were discovered for 5%-6% of unmapped tags. Candidates were classified into three categories, reflecting the previous annotations of the putative splice junctions. Analysis of predicted tags extracted from EST sequences demonstrated that candidate junctions having the splice junction located closer to the center of the tags are more reliable. Nine of these 12 candidates were validated by RT-PCR and sequencing, and among these, four revealed previously uncharacterized exons. Thus, SAGE2Splice provides a new functionality for the identification of novel transcripts and exons. SAGE2Splice is available online at http://www.cisreg.ca.'),
(83439, 2006, 'plos', 'The signal in the genomes', 'Sankoff, David', 'Genetics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada', 24, 'Animals|Genome|Genomics|Humans|Mice|Synteny', 'Comment', '10.1371/journal.pcbi.0020035', '16683016', '-'),
(83440, 2006, 'plos', 'Practical strategies for discovering regulatory DNA sequence motifs', 'MacIsaac, Kenzie D|Fraenkel, Ernest', 'Department of Electrical Engineering and Computer Science, Cambridge, Massachusetts, United States of America.|Department of Electrical Engineering and Computer Science, Cambridge, Massachusetts, United States of America.', 'United States|United States', 115, 'Algorithms|Animals|Base Sequence|Computational Biology|DNA|Gene Expression Regulation|Humans|Models, Genetic|Phylogeny|Regulatory Sequences, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0020036', '16683017', '-'),
(83441, 2006, 'plos', 'Codon usage domains over bacterial chromosomes', 'Bailly-Bechet, Marc|Danchin, Antoine|Iqbal, Mudassar|Marsili, Matteo|Vergassola, Massimo', 'CNRS URA 2171, Institute Pasteur, Unité Génétique in silico, Paris, France.|CNRS URA 2171, Institute Pasteur, Unité Génétique in silico, Paris, France.|CNRS URA 2171, Institute Pasteur, Unité Génétique in silico, Paris, France.|CNRS URA 2171, Institute Pasteur, Unité Génétique in silico, Paris, France.|CNRS URA 2171, Institute Pasteur, Unité Génétique in silico, Paris, France.', 'France|France|France|France|France', 35, 'Amino Acids|Bacillus subtilis|Base Sequence|Chromosomes, Bacterial|Codon|Escherichia coli|Gene Expression Regulation, Bacterial|Multigene Family|Operon', 'Journal Article', '10.1371/journal.pcbi.0020037', '16683018', 'The geography of codon bias distributions over prokaryotic genomes and its impact upon chromosomal organization are analyzed. To this aim, we introduce a clustering method based on information theory, specifically designed to cluster genes according to their codon usage and apply it to the coding sequences of Escherichia coli and Bacillus subtilis. One of the clusters identified in each of the organisms is found to be related to expression levels, as expected, but other groups feature an over-representation of genes belonging to different functional groups, namely horizontally transferred genes, motility, and intermediary metabolism. Furthermore, we show that genes with a similar bias tend to be close to each other on the chromosome and organized in coherent domains, more extended than operons, demonstrating a role of translation in structuring bacterial chromosomes. It is argued that a sizeable contribution to this effect comes from the dynamical compartimentalization induced by the recycling of tRNAs, leading to gene expression rates dependent on their genomic and expression context.'),
(83442, 2006, 'plos', 'Positive selection, relaxation, and acceleration in the evolution of the human and chimp genome', 'Arbiza, Leonardo|Dopazo, Joaquín|Dopazo, Hernán', 'Pharmacogenomics and Comparative Genomics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Pharmacogenomics and Comparative Genomics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.|Pharmacogenomics and Comparative Genomics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.', 'Spain|Spain|Spain', 0, 'Adaptation, Biological|Animals|Evolution, Molecular|Genome|Humans|Pan troglodytes|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020038', '16683019', 'For years evolutionary biologists have been interested in searching for the genetic bases underlying humanness. Recent efforts at a large or a complete genomic scale have been conducted to search for positively selected genes in human and in chimp. However, recently developed methods allowing for a more sensitive and controlled approach in the detection of positive selection can be employed. Here, using 13,198 genes, we have deduced the sets of genes involved in rate acceleration, positive selection, and relaxation of selective constraints in human, in chimp, and in their ancestral lineage since the divergence from murids. Significant deviations from the strict molecular clock were observed in 469 human and in 651 chimp genes. The more stringent branch-site test of positive selection detected 108 human and 577 chimp positively selected genes. An important proportion of the positively selected genes did not show a significant acceleration in rates, and similarly, many of the accelerated genes did not show significant signals of positive selection. Functional differentiation of genes under rate acceleration, positive selection, and relaxation was not statistically significant between human and chimp with the exception of terms related to G-protein coupled receptors and sensory perception. Both of these were over-represented under relaxation in human in relation to chimp. Comparing differences between derived and ancestral lineages, a more conspicuous change in trends seems to have favored positive selection in the human lineage. Since most of the positively selected genes are different under the same functional categories between these species, we suggest that the individual roles of the alternative positively selected genes may be an important factor underlying biological differences between these species.'),
(83443, 2006, 'plos', 'Changing cellular location of CheZ predicted by molecular simulations', 'Lipkow, Karen', 'Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. KL280@cam.ac.uk', 'United Kingdom', 0, 'Bacterial Proteins|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Histidine Kinase|Membrane Proteins|Methyl-Accepting Chemotaxis Proteins|Models, Biological|Protein Binding|Protein Structure, Quaternary|Protein Transport|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0020039', '16683020', 'In the chemotaxis pathway of the bacterium Escherichia coli, signals are carried from a cluster of receptors to the flagellar motors by the diffusion of the protein CheY-phosphate (CheYp) through the cytoplasm. A second protein, CheZ, which promotes dephosphorylation of CheYp, partially colocalizes with receptors in the plasma membrane. CheZ is normally dimeric in solution but has been suggested to associate into highly active oligomers in the presence of CheYp. A model is presented here and supported by Brownian dynamics simulations, which accounts for these and other experimental data: A minority component of the receptor cluster (dimers of CheA(short)) nucleates CheZ oligomerization and CheZ molecules move from the cytoplasm to a bound state at the receptor cluster depending on the current level of cellular stimulation. The corresponding simulations suggest that dynamic CheZ localization will sharpen cellular responses to chemoeffectors, increase the range of detectable ligand concentrations, and make adaptation more precise and robust. The localization and activation of CheZ constitute a negative feedback loop that provides a second tier of adaptation to the system. Subtle adjustments of this kind are likely to be found in many other signaling pathways.'),
(83444, 2006, 'plos', 'Designing a nanotube using naturally occurring protein building blocks', 'Tsai, Chung-Jung|Zheng, Jie|Nussinov, Ruth', 'Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research, Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.|Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research, Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.|Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research, Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.', 'United States|United States|United States', 0, 'HIV-1|Models, Molecular|Molecular Conformation|Nanotubes|Peptides|Viral Proteins', 'Journal Article', '10.1371/journal.pcbi.0020042', '16683021', 'Here our goal is to carry out nanotube design using naturally occurring protein building blocks. Inspection of the protein structural database reveals the richness of the conformations of proteins, their parts, and their chemistry. Given target functional protein nanotube geometry, our strategy involves scanning a library of candidate building blocks, combinatorially assembling them into the shape and testing its stability. Since self-assembly takes place on time scales not affordable for computations, here we propose a strategy for the very first step in protein nanotube design: we map the candidate building blocks onto a planar sheet and wrap the sheet around a cylinder with the target dimensions. We provide examples of three nanotubes, two peptide and one protein, in atomistic model detail for which there are experimental data. The nanotube models can be used to verify a nanostructure observed by low-resolution experiments, and to study the mechanism of tube formation.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83445, 2006, 'plos', 'Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays', 'Beroukhim, Rameen|Lin, Ming|Park, Yuhyun|Hao, Ke|Zhao, Xiaojun|Garraway, Levi A|Fox, Edward A|Hochberg, Ephraim P|Mellinghoff, Ingo K|Hofer, Matthias D|Descazeaud, Aurelien|Rubin, Mark A|Meyerson, Matthew|Wong, Wing Hung|Sellers, William R|Li, Cheng', 'Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 0, 'Alleles|Chromosomes, Human, Y|Gene Dosage|Haplotypes|Humans|Loss of Heterozygosity|Male|Models, Genetic|Oligonucleotide Array Sequence Analysis|Polymorphism, Single Nucleotide|Probability|Prostatic Neoplasms|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.0020041', '16699594', 'Loss of heterozygosity (LOH) of chromosomal regions bearing tumor suppressors is a key event in the evolution of epithelial and mesenchymal tumors. Identification of these regions usually relies on genotyping tumor and counterpart normal DNA and noting regions where heterozygous alleles in the normal DNA become homozygous in the tumor. However, paired normal samples for tumors and cell lines are often not available. With the advent of oligonucleotide arrays that simultaneously assay thousands of single-nucleotide polymorphism (SNP) markers, genotyping can now be done at high enough resolution to allow identification of LOH events by the absence of heterozygous loci, without comparison to normal controls. Here we describe a hidden Markov model-based method to identify LOH from unpaired tumor samples, taking into account SNP intermarker distances, SNP-specific heterozygosity rates, and the haplotype structure of the human genome. When we applied the method to data genotyped on 100 K arrays, we correctly identified 99% of SNP markers as either retention or loss. We also correctly identified 81% of the regions of LOH, including 98% of regions greater than 3 megabases. By integrating copy number analysis into the method, we were able to distinguish LOH from allelic imbalance. Application of this method to data from a set of prostate samples without paired normals identified known regions of prevalent LOH. We have developed a method for analyzing high-density oligonucleotide SNP array data to accurately identify of regions of LOH and retention in tumors without the need for paired normal samples.'),
(83446, 2006, 'plos', 'Differential repression of alternative transcripts: a screen for miRNA targets', 'Legendre, Matthieu|Ritchie, William|Lopez, Fabrice|Gautheret, Daniel', 'INSERM ERM 206, Université de la Méditerranée, Marseille, France.|INSERM ERM 206, Université de la Méditerranée, Marseille, France.|INSERM ERM 206, Université de la Méditerranée, Marseille, France.|INSERM ERM 206, Université de la Méditerranée, Marseille, France.', 'France|France|France|France', 49, 'Animals|Base Sequence|Down-Regulation|Expressed Sequence Tags|Humans|Mice|MicroRNAs|Organ Specificity|Protein Isoforms|RNA, Messenger|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020043', '16699595', 'Alternative polyadenylation sites produce transcript isoforms with 3 untranslated regions (UTRs) of different lengths. If a microRNA (miRNA) target is present in the UTR, then only those target-containing isoforms should be sensitive to control by a cognate miRNA. We carried out a systematic examination of 3 UTRs containing multiple poly(A) sites and putative miRNA targets. Based on expressed sequence tag (EST) counts and EST library information, we observed that levels of isoforms containing targets for miR-1 or miR-124, two miRNAs causing downregulation of transcript levels, were reduced in tissues expressing the corresponding miRNA. This analysis was repeated for all conserved 7-mers in 3 UTRs, resulting in a selection of 312 motifs. We show that this set is significantly enriched in known miRNA targets and mRNA-destabilizing elements, which validates our initial hypothesis. We scanned the human genome for possible cognate miRNAs and identified phylogenetically conserved precursors matching our motifs. This analysis can help identify target-miRNA couples that went undetected in previous screens, but it may also reveal targets for other types of regulatory factors.'),
(83447, 2006, 'plos', 'Spatial regulation and the rate of signal transduction activation', 'Batada, Nizar N|Shepp, Larry A|Siegmund, David O|Levitt, Michael', 'Program in Biophysics, Stanford University, Stanford, California, USA. nizar.batada@utoronto.ca|Program in Biophysics, Stanford University, Stanford, California, USA. nizar.batada@utoronto.ca|Program in Biophysics, Stanford University, Stanford, California, USA. nizar.batada@utoronto.ca|Program in Biophysics, Stanford University, Stanford, California, USA. nizar.batada@utoronto.ca', 'United States|United States|United States|United States', 0, 'Animals|Cytoplasm|Dimerization|Models, Biological|Proteins|Signal Transduction|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020044', '16699596', 'Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement.'),
(83448, 2006, 'plos', 'Dynamic changes in subgraph preference profiles of crucial transcription factors', 'Zhang, Zhihua|Liu, Changning|Skogerbø, Geir|Zhu, Xiaopeng|Lu, Hongchao|Chen, Lan|Shi, Baochen|Zhang, Yong|Wang, Jie|Wu, Tao|Chen, Runsheng', 'Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.', 'China|China|China|China|China|China|China|China|China|China|China', 11, 'Cell Cycle|Gene Expression Regulation, Fungal|Saccharomyces cerevisiae|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020047', '16699597', 'Transcription factors with a large number of target genes--transcription hub(s), or THub(s)--are usually crucial components of the regulatory system of a cell, and the different patterns through which they transfer the transcriptional signal to downstream cascades are of great interest. By profiling normalized abundances (A(N)) of basic regulatory patterns of individual THubs in the yeast Saccharomyces cerevisiae transcriptional regulation network under five different cellular states and environmental conditions, we have investigated their preferences for different basic regulatory patterns. Subgraph-normalized abundances downstream of individual THubs often differ significantly from that of the network as a whole, and conversely, certain over-represented subgraphs are not preferred by any THub. The THub preferences changed substantially when the cellular or environmental conditions changed. This switching of regulatory pattern preferences suggests that a change in conditions does not only elicit a change in response by the regulatory network, but also a change in the mechanisms by which the response is mediated. The THub subgraph preference profile thus provides a novel tool for description of the structure and organization between the large-scale exponents and local regulatory patterns.'),
(83449, 2006, 'plos', 'Statistics of knots, geometry of conformations, and evolution of proteins', 'Lua, Rhonald C|Grosberg, Alexander Y', 'Department of Physics, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Physics, University of Minnesota, Minneapolis, Minnesota, USA.', 'United States|United States', 114, 'Evolution, Molecular|Models, Molecular|Molecular Weight|Probability|Protein Conformation|Protein Folding|Proteins', 'Journal Article', '10.1371/journal.pcbi.0020045', '16710448', 'Like shoelaces, the backbones of proteins may get entangled and form knots. However, only a few knots in native proteins have been identified so far. To more quantitatively assess the rarity of knots in proteins, we make an explicit comparison between the knotting probabilities in native proteins and in random compact loops. We identify knots in proteins statistically, applying the mathematics of knot invariants to the loops obtained by complementing the protein backbone with an ensemble of random closures, and assigning a certain knot type to a given protein if and only if this knot dominates the closure statistics (which tells us that the knot is determined by the protein and not by a particular method of closure). We also examine the local fractal or geometrical properties of proteins via computational measurements of the end-to-end distance and the degree of interpenetration of its subchains. Although we did identify some rather complex knots, we show that native conformations of proteins have statistically fewer knots than random compact loops, and that the local geometrical properties, such as the crumpled character of the conformations at a certain range of scales, are consistent with the rarity of knots. From these, we may conclude that the known protein universe (set of native conformations) avoids knots. However, the precise reason for this is unknown--for instance, if knots were removed by evolution due to their unfavorable effect on protein folding or function or due to some other unidentified property of protein evolution.'),
(83450, 2006, 'plos', 'Reverse engineering the gap gene network of Drosophila melanogaster', 'Perkins, Theodore J|Jaeger, Johannes|Reinitz, John|Glass, Leon', 'McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada. perkins@mcb.mcgill.ca|McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada. perkins@mcb.mcgill.ca|McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada. perkins@mcb.mcgill.ca|McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada. perkins@mcb.mcgill.ca', 'Canada|Canada|Canada|Canada', 132, 'Animals|Computational Biology|Computer Simulation|Drosophila Proteins|Drosophila melanogaster|Gene Expression Regulation, Developmental|Models, Genetic|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020051', '16710449', 'A fundamental problem in functional genomics is to determine the structure and dynamics of genetic networks based on expression data. We describe a new strategy for solving this problem and apply it to recently published data on early Drosophila melanogaster development. Our method is orders of magnitude faster than current fitting methods and allows us to fit different types of rules for expressing regulatory relationships. Specifically, we use our approach to fit models using a smooth nonlinear formalism for modeling gene regulation (gene circuits) as well as models using logical rules based on activation and repression thresholds for transcription factors. Our technique also allows us to infer regulatory relationships de novo or to test network structures suggested by the literature. We fit a series of models to test several outstanding questions about gap gene regulation, including regulation of and by hunchback and the role of autoactivation. Based on our modeling results and validation against the experimental literature, we propose a revised network structure for the gap gene system. Interestingly, some relationships in standard textbook models of gap gene regulation appear to be unnecessary for or even inconsistent with the details of gap gene expression during wild-type development.'),
(83451, 2006, 'plos', 'Iterative reconstruction of transcriptional regulatory networks: an algorithmic approach', 'Barrett, Christian L|Palsson, Bernhard O', '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', 0, 'Algorithms|Computer Simulation|Databases, Genetic|Gene Expression Regulation|Models, Genetic|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020052', '16710450', 'The number of complete, publicly available genome sequences is now greater than 200, and this number is expected to rapidly grow in the near future as metagenomic and environmental sequencing efforts escalate and the cost of sequencing drops. In order to make use of this data for understanding particular organisms and for discerning general principles about how organisms function, it will be necessary to reconstruct their various biochemical reaction networks. Principal among these will be transcriptional regulatory networks. Given the physical and logical complexity of these networks, the various sources of (often noisy) data that can be utilized for their elucidation, the monetary costs involved, and the huge number of potential experiments approximately 10(12)) that can be performed, experiment design algorithms will be necessary for synthesizing the various computational and experimental data to maximize the efficiency of regulatory network reconstruction. This paper presents an algorithm for experimental design to systematically and efficiently reconstruct transcriptional regulatory networks. It is meant to be applied iteratively in conjunction with an experimental laboratory component. The algorithm is presented here in the context of reconstructing transcriptional regulation for metabolism in Escherichia coli, and, through a retrospective analysis with previously performed experiments, we show that the produced experiment designs conform to how a human would design experiments. The algorithm is able to utilize probability estimates based on a wide range of computational and experimental sources to suggest experiments with the highest potential of discovering the greatest amount of new regulatory knowledge.'),
(83452, 2006, 'plos', 'Predicting Shine-Dalgarno sequence locations exposes genome annotation errors', 'Starmer, J|Stomp, A|Vouk, M|Bitzer, D', 'Bioinformatics Program, North Carolina State University, Raleigh, North Carolina, USA. jdstarme@ncsu.edu|Bioinformatics Program, North Carolina State University, Raleigh, North Carolina, USA. jdstarme@ncsu.edu|Bioinformatics Program, North Carolina State University, Raleigh, North Carolina, USA. jdstarme@ncsu.edu|Bioinformatics Program, North Carolina State University, Raleigh, North Carolina, USA. jdstarme@ncsu.edu', 'United States|United States|United States|United States', 0, 'Base Sequence|Codon, Initiator|Computational Biology|Escherichia coli|Gene Expression Regulation, Bacterial|Genome, Bacterial|Hydrogen Bonding|Models, Genetic|Peptide Chain Initiation, Translational|RNA, Messenger|RNA, Ribosomal|Research Design', 'Journal Article', '10.1371/journal.pcbi.0020057', '16710451', 'In prokaryotes, Shine-Dalgarno (SD) sequences, nucleotides upstream from start codons on messenger RNAs (mRNAs) that are complementary to ribosomal RNA (rRNA), facilitate the initiation of protein synthesis. The location of SD sequences relative to start codons and the stability of the hybridization between the mRNA and the rRNA correlate with the rate of synthesis. Thus, accurate characterization of SD sequences enhances our understanding of how an organisms transcriptome relates to its cellular proteome. We implemented the Individual Nearest Neighbor Hydrogen Bond model for oligo-oligo hybridization and created a new metric, relative spacing (RS), to identify both the location and the hybridization potential of SD sequences by simulating the binding between mRNAs and single-stranded 16S rRNA 3 tails. In 18 prokaryote genomes, we identified 2,420 genes out of 58,550 where the strongest binding in the translation initiation region included the start codon, deviating from the expected location for the SD sequence of five to ten bases upstream. We designated these as RS+1 genes. Additional analysis uncovered an unusual bias of the start codon in that the majority of the RS+1 genes used GUG, not AUG. Furthermore, of the 624 RS+1 genes whose SD sequence was associated with a free energy release of less than -8.4 kcal/mol (strong RS+1 genes), 384 were within 12 nucleotides upstream of in-frame initiation codons. The most likely explanation for the unexpected location of the SD sequence for these 384 genes is mis-annotation of the start codon. In this way, the new RS metric provides an improved method for gene sequence annotation. The remaining strong RS+1 genes appear to have their SD sequences in an unexpected location that includes the start codon. Thus, our RS metric provides a new way to explore the role of rRNA-mRNA nucleotide hybridization in translation initiation.'),
(83453, 2006, 'plos', 'Protein family expansions and biological complexity', 'Vogel, Christine|Chothia, Cyrus', 'Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. cvogel@mail.utexas.edu|Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. cvogel@mail.utexas.edu', 'United Kingdom|United Kingdom', 0, 'Animals|Biological Evolution|Cluster Analysis|Computational Biology|Databases, Factual|Evolution, Molecular|Genes, Fungal|Genes, Plant|Humans|Models, Biological|Software', 'Journal Article', '10.1371/journal.pcbi.0020048', '16733546', 'During the course of evolution, new proteins are produced very largely as the result of gene duplication, divergence and, in many cases, combination. This means that proteins or protein domains belong to families or, in cases where their relationships can only be recognised on the basis of structure, superfamilies whose members descended from a common ancestor. The size of superfamilies can vary greatly. Also, during the course of evolution organisms of increasing complexity have arisen. In this paper we determine the identity of those superfamilies whose relative sizes in different organisms are highly correlated to the complexity of the organisms. As a measure of the complexity of 38 uni- and multicellular eukaryotes we took the number of different cell types of which they are composed. Of 1,219 superfamilies, there are 194 whose sizes in the 38 organisms are strongly correlated with the number of cell types in the organisms. We give outline descriptions of these superfamilies. Half are involved in extracellular processes or regulation and smaller proportions in other types of activity. Half of all superfamilies have no significant correlation with complexity. We also determined whether the expansions of large superfamilies correlate with each other. We found three large clusters of correlated expansions: one involves expansions in both vertebrates and plants, one just in vertebrates, and one just in plants. Our work identifies important protein families and provides one explanation of the discrepancy between the total number of genes and the apparent physiological complexity of eukaryotic organisms.'),
(83454, 2006, 'plos', 'Transcription factor map alignment of promoter regions', 'Blanco, Enrique|Messeguer, Xavier|Smith, Temple F|Guigó, Roderic', 'Research Group in Biomedical Informatics, Institut Municipal dInvestigació Mèdica/Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.|Research Group in Biomedical Informatics, Institut Municipal dInvestigació Mèdica/Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.|Research Group in Biomedical Informatics, Institut Municipal dInvestigació Mèdica/Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.|Research Group in Biomedical Informatics, Institut Municipal dInvestigació Mèdica/Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.', 'Spain|Spain|Spain|Spain', 0, 'Algorithms|Animals|Chromosome Mapping|Computational Biology|Humans|Mice|Models, Statistical|Promoter Regions, Genetic|Restriction Mapping|Software|Species Specificity|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0020049', '16733547', 'We address the problem of comparing and characterizing the promoter regions of genes with similar expression patterns. This remains a challenging problem in sequence analysis, because often the promoter regions of co-expressed genes do not show discernible sequence conservation. In our approach, thus, we have not directly compared the nucleotide sequence of promoters. Instead, we have obtained predictions of transcription factor binding sites, annotated the predicted sites with the labels of the corresponding binding factors, and aligned the resulting sequences of labels--to which we refer here as transcription factor maps (TF-maps). To obtain the global pairwise alignment of two TF-maps, we have adapted an algorithm initially developed to align restriction enzyme maps. We have optimized the parameters of the algorithm in a small, but well-curated, collection of human-mouse orthologous gene pairs. Results in this dataset, as well as in an independent much larger dataset from the CISRED database, indicate that TF-map alignments are able to uncover conserved regulatory elements, which cannot be detected by the typical sequence alignments.'),
(83455, 2006, 'plos', 'Expression-guided in silico evaluation of candidate cis regulatory codes for Drosophila muscle founder cells', 'Philippakis, Anthony A|Busser, Brian W|Gisselbrecht, Stephen S|He, Fangxue Sherry|Estrada, Beatriz|Michelson, Alan M|Bulyk, Martha L', 'Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States|United States', 59, 'Amino Acid Motifs|Animals|Cluster Analysis|Computational Biology|Drosophila melanogaster|Gene Expression Regulation, Developmental|Mesoderm|Models, Biological|Muscles|Oligonucleotide Array Sequence Analysis|Promoter Regions, Genetic|Regulatory Sequences, Nucleic Acid|Wings, Animal', 'Journal Article', '10.1371/journal.pcbi.0020053', '16733548', 'While combinatorial models of transcriptional regulation can be inferred for metazoan systems from a priori biological knowledge, validation requires extensive and time-consuming experimental work. Thus, there is a need for computational methods that can evaluate hypothesized cis regulatory codes before the difficult task of experimental verification is undertaken. We have developed a novel computational framework (termed CodeFinder) that integrates transcription factor binding site and gene expression information to evaluate whether a hypothesized transcriptional regulatory model (TRM, i.e., a set of co-regulating transcription factors) is likely to target a given set of co-expressed genes. Our basic approach is to simultaneously predict cis regulatory modules (CRMs) associated with a given gene set and quantify the enrichment for combinatorial subsets of transcription factor binding site motifs comprising the hypothesized TRM within these predicted CRMs. As a model system, we have examined a TRM experimentally demonstrated to drive the expression of two genes in a sub-population of cells in the developing Drosophila mesoderm, the somatic muscle founder cells. This TRM was previously hypothesized to be a general mode of regulation for genes expressed in this cell population. In contrast, the present analyses suggest that a modified form of this cis regulatory code applies to only a subset of founder cell genes, those whose gene expression responds to specific genetic perturbations in a similar manner to the gene on which the original model was based. We have confirmed this hypothesis by experimentally discovering six (out of 12 tested) new CRMs driving expression in the embryonic mesoderm, four of which drive expression in founder cells.'),
(83456, 2006, 'plos', 'Evolutionary potential of a duplicated repressor-operator pair: simulating pathways using mutation data', 'Poelwijk, Frank J|Kiviet, Daniel J|Tans, Sander J', 'FOM Institute for Atomic and Molecular Physics (AMOLF), Amsterdam, Netherlands.|FOM Institute for Atomic and Molecular Physics (AMOLF), Amsterdam, Netherlands.|FOM Institute for Atomic and Molecular Physics (AMOLF), Amsterdam, Netherlands.', 'Netherlands|Netherlands|Netherlands', 0, 'Computational Biology|DNA|Escherichia coli|Evolution, Molecular|Genetic Techniques|Models, Genetic|Mutation|Operator Regions, Genetic|Phenotype|Protein Binding|Repressor Proteins', 'Journal Article', '10.1371/journal.pcbi.0020058', '16733549', 'Ample evidence has accumulated for the evolutionary importance of duplication events. However, little is known about the ensuing step-by-step divergence process and the selective conditions that allow it to progress. Here we present a computational study on the divergence of two repressors after duplication. A central feature of our approach is that intermediate phenotypes can be quantified through the use of in vivo measured repression strengths of Escherichia coli lac mutants. Evolutionary pathways are constructed by multiple rounds of single base pair substitutions and selection for tight and independent binding. Our analysis indicates that when a duplicated repressor co-diverges together with its binding site, the fitness landscape allows funneling to a new regulatory interaction with early increases in fitness. We find that neutral mutations do not play an essential role, which is important for substantial divergence probabilities. By varying the selective pressure we can pinpoint the necessary ingredients for the observed divergence. Our findings underscore the importance of coevolutionary mechanisms in regulatory networks, and should be relevant for the evolution of protein-DNA as well as protein-protein interactions.'),
(83457, 2005, 'plos', 'Time to organize the bioinformatics resourceome', 'Cannata, Nicola|Merelli, Emanuela|Altman, Russ B', 'Centro Ricerca Interdipartimentale Biotecnologie Innovative, Università di Padova, Padova, Italy.|Centro Ricerca Interdipartimentale Biotecnologie Innovative, Università di Padova, Padova, Italy.|Centro Ricerca Interdipartimentale Biotecnologie Innovative, Università di Padova, Padova, Italy.', 'Italy|Italy|Italy', 0, 'Algorithms|Animals|Computational Biology|Databases, Factual|Databases, Genetic|Genomics|Humans|Internet|Molecular Biology|Proteomics|Software', 'Journal Article', '10.1371/journal.pcbi.0010076', '16738704', '-'),
(83458, 2006, 'plos', 'The G protein-coupled receptor subset of the chicken genome', 'Lagerström, Malin C|Hellström, Anders R|Gloriam, David E|Larsson, Thomas P|Schiöth, Helgi B|Fredriksson, Robert', 'Department of Neuroscience, Uppsala University, Uppsala, Sweden.|Department of Neuroscience, Uppsala University, Uppsala, Sweden.|Department of Neuroscience, Uppsala University, Uppsala, Sweden.|Department of Neuroscience, Uppsala University, Uppsala, Sweden.|Department of Neuroscience, Uppsala University, Uppsala, Sweden.|Department of Neuroscience, Uppsala University, Uppsala, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden|Sweden', 83, 'Animals|Automation|Chickens|Computational Biology|Databases, Protein|Genome|Genome, Human|Humans|Phylogeny|Receptors, G-Protein-Coupled|Sequence Alignment|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0020054', '16741557', 'G protein-coupled receptors (GPCRs) are one of the largest families of proteins, and here we scan the recently sequenced chicken genome for GPCRs. We use a homology-based approach, utilizing comparisons with all human GPCRs, to detect and verify chicken GPCRs from translated genomic alignments and Genscan predictions. We present 557 manually curated sequences for GPCRs from the chicken genome, of which 455 were previously not annotated. More than 60% of the chicken Genscan gene predictions with a human ortholog needed curation, which drastically changed the average percentage identity between the human-chicken orthologous pairs (from 56.3% to 72.9%). Of the non-olfactory chicken GPCRs, 79% had a one-to-one orthologous relationship to a human GPCR. The Frizzled, Secretin, and subgroups of the Rhodopsin families have high proportions of orthologous pairs, although the percentage of amino acid identity varies. Other groups show large differences, such as the Adhesion family and GPCRs that bind exogenous ligands. The chicken has only three bitter Taste 2 receptors, and it also lacks an ortholog to human TAS1R2 (one of three GPCRs in the human genome in the Taste 1 receptor family [TAS1R]), implying that the chickens ability and mode of detecting both bitter and sweet taste may differ from the humans. The chicken genome contains at least 229 olfactory receptors, and the majority of these (218) originate from a chicken-specific expansion. To our knowledge, this dataset of chicken GPCRs is the largest curated dataset from a single gene family from a non-mammalian vertebrate. Both the updated human GPCR dataset, as well the chicken GPCR dataset, are available for download.'),
(83459, 2005, 'plos', 'ISMB 2005 Conference Report', 'Morrison McKay, B J', 'Department of Neuroscience, Uppsala University, Uppsala, Sweden.', 'Sweden', 0, 'Alternative Splicing|Computational Biology|Humans|Molecular Biology|Pharmacology|Programming Languages', 'Congress', '10.1371/journal.pcbi.0010033', '16758003', '-'),
(83460, 2005, 'plos', 'The eighth annual bio-ontologies meeting', 'Lord, Phillip|Stevens, Robert|Butler, James A|McEntire, Robin', 'University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk|University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk|University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk|University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Computational Biology|Internet|Molecular Biology|Software', 'Congress', '10.1371/journal.pcbi.0010077', '16758004', '-'),
(83461, 2006, 'plos', 'ISMB 2006', 'Neshich, Goran|Bourne, Philip E|Brunak, Søren', 'University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk|University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk|University of Newcastle upon Tyne, Newcastle, United Kingdom. bio-ont-sig@cs.man.ac.uk', 'United Kingdom|United Kingdom|United Kingdom', 0, 'Animals|Biology|Computational Biology|Congresses as Topic|Databases, Genetic|Expert Systems|Genomics|Humans|Molecular Biology', 'Journal Article', '10.1371/journal.pcbi.0020011', '16758006', '-'),
(83462, 2006, 'plos', 'Ultra-fast evaluation of protein energies directly from sequence', 'Grigoryan, Gevorg|Zhou, Fei|Lustig, Steve R|Ceder, Gerbrand|Morgan, Dane|Keating, Amy E', 'Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.', 'United States|United States|United States|United States|United States|United States', 38, 'Algorithms|Computer Simulation|Computer Systems|Energy Transfer|Models, Chemical|Models, Molecular|Protein Conformation|Proteins|Sequence Analysis, Protein|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0020063', '16789811', 'The structure, function, stability, and many other properties of a protein in a fixed environment are fully specified by its sequence, but in a manner that is difficult to discern. We present a general approach for rapidly mapping sequences directly to their energies on a pre-specified rigid backbone, an important sub-problem in computational protein design and in some methods for protein structure prediction. The cluster expansion (CE) method that we employ can, in principle, be extended to model any computable or measurable protein property directly as a function of sequence. Here we show how CE can be applied to the problem of computational protein design, and use it to derive excellent approximations of physical potentials. The approach provides several attractive advantages. First, following a one-time derivation of a CE expansion, the amount of time necessary to evaluate the energy of a sequence adopting a specified backbone conformation is reduced by a factor of 10(7) compared to standard full-atom methods for the same task. Second, the agreement between two full-atom methods that we tested and their CE sequence-based expressions is very high (root mean square deviation 1.1-4.7 kcal/mol, R2 = 0.7-1.0). Third, the functional form of the CE energy expression is such that individual terms of the expansion have clear physical interpretations. We derived expressions for the energies of three classic protein design targets-a coiled coil, a zinc finger, and a WW domain-as functions of sequence, and examined the most significant terms. Single-residue and residue-pair interactions are sufficient to accurately capture the energetics of the dimeric coiled coil, whereas higher-order contributions are important for the two more globular folds. For the task of designing novel zinc-finger sequences, a CE-derived energy function provides significantly better solutions than a standard design protocol, in comparable computation time. Given these advantages, CE is likely to find many uses in computational structural modeling.'),
(83463, 2006, 'plos', 'How does cross-reactive stimulation affect the longevity of CD8+ T cell memory?', 'Ganusov, Vitaly V|Pilyugin, Sergei S|Ahmed, Rafi|Antia, Rustom', 'Department of Biology, Emory University, Atlanta, Georgia, USA.|Department of Biology, Emory University, Atlanta, Georgia, USA.|Department of Biology, Emory University, Atlanta, Georgia, USA.|Department of Biology, Emory University, Atlanta, Georgia, USA.', 'Georgia|Georgia|Georgia|Georgia', 0, 'Animals|CD8-Positive T-Lymphocytes|Cell Lineage|Immunologic Memory|Mice|Mice, Inbred BALB C|Mice, Inbred C57BL|Models, Immunological|Models, Statistical|Models, Theoretical|Vertebrates', 'Journal Article', '10.1371/journal.pcbi.0020055', '16789812', 'Immunological memory--the ability to remember previously encountered pathogens and respond faster upon re-exposure is a central feature of the immune response in vertebrates. The cross-reactive stimulation hypothesis for the maintenance of memory proposes that memory cells specific for a given pathogen are maintained by cross-reactive stimulation following infections with other (unrelated) pathogens. We use mathematical models to examine the cross-reactive stimulation hypothesis. We find that: (i) the direct boosting of cross-reactive lineages only provides a very small increase in the average longevity of immunological memory, (ii) the expansion of cross-reactive lineages can indirectly increase the longevity of memory by reducing the magnitude of expansion of new naive lineages which occupy space in the memory compartment and are responsible for the decline in memory, (iii) cross-reactive stimulation results in variation in the rates of decline of different lineages of memory cells and enrichment of memory cell population for cells that are cross-reactive for the pathogens to which the individual has been exposed.'),
(83464, 2006, 'plos', 'Prioritizing genomic drug targets in pathogens: application to Mycobacterium tuberculosis', 'Hasan, Samiul|Daugelat, Sabine|Rao, P S Srinivasa|Schreiber, Mark', 'Novartis Institute for Tropical Diseases (NITD), Chromos, Singapore.|Novartis Institute for Tropical Diseases (NITD), Chromos, Singapore.|Novartis Institute for Tropical Diseases (NITD), Chromos, Singapore.|Novartis Institute for Tropical Diseases (NITD), Chromos, Singapore.', 'Singapore|Singapore|Singapore|Singapore', 0, 'Algorithms|Computational Biology|Drug Design|Drug Industry|Drug Resistance, Microbial|Drug Resistance, Multiple|Mycobacterium tuberculosis|Pharmaceutical Preparations|Pharmacogenetics|Software|Tuberculosis', 'Journal Article', '10.1371/journal.pcbi.0020061', '16789813', 'We have developed a software program that weights and integrates specific properties on the genes in a pathogen so that they may be ranked as drug targets. We applied this software to produce three prioritized drug target lists for Mycobacterium tuberculosis, the causative agent of tuberculosis, a disease for which a new drug is desperately needed. Each list is based on an individual criterion. The first list prioritizes metabolic drug targets by the uniqueness of their roles in the M. tuberculosis metabolome (metabolic chokepoints) and their similarity to known druggable protein classes (i.e., classes whose activity has previously been shown to be modulated by binding a small molecule). The second list prioritizes targets that would specifically impair M. tuberculosis, by weighting heavily those that are closely conserved within the Actinobacteria class but lack close homology to the host and gut flora. M. tuberculosis can survive asymptomatically in its host for many years by adapting to a dormant state referred to as persistence. The final list aims to prioritize potential targets involved in maintaining persistence in M. tuberculosis. The rankings of current, candidate, and proposed drug targets are highlighted with respect to these lists. Some features were found to be more accurate than others in prioritizing studied targets. It can also be shown that targets can be prioritized by using evolutionary programming to optimize the weights of each desired property. We demonstrate this approach in prioritizing persistence targets.'),
(83465, 2006, 'plos', 'Integrated assessment and prediction of transcription factor binding', 'Beyer, Andreas|Workman, Christopher|Hollunder, Jens|Radke, Dörte|Möller, Ulrich|Wilhelm, Thomas|Ideker, Trey', 'Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de|Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de|Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de|Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de|Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de|Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de|Department of Bioengineering, University of California San Diego, La Jolla, California, USA. beyer@fli-leibniz.de', 'United States|United States|United States|United States|United States|United States|United States', 71, 'Algorithms|Base Sequence|Binding Sites|Chromatin Immunoprecipitation|Computer Simulation|Models, Chemical|Models, Genetic|Molecular Sequence Data|Protein Binding|Sequence Alignment|Sequence Analysis, DNA|Systems Integration|Transcription Factors|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020070', '16789814', 'Systematic chromatin immunoprecipitation (chIP-chip) experiments have become a central technique for mapping transcriptional interactions in model organisms and humans. However, measurement of chromatin binding does not necessarily imply regulation, and binding may be difficult to detect if it is condition or cofactor dependent. To address these challenges, we present an approach for reliably assigning transcription factors (TFs) to target genes that integrates many lines of direct and indirect evidence into a single probabilistic model. Using this approach, we analyze publicly available chIP-chip binding profiles measured for yeast TFs in standard conditions, showing that our model interprets these data with significantly higher accuracy than previous methods. Pooling the high-confidence interactions reveals a large network containing 363 significant sets of factors (TF modules) that cooperate to regulate common target genes. In addition, the method predicts 980 novel binding interactions with high confidence that are likely to occur in so-far untested conditions. Indeed, using new chIP-chip experiments we show that predicted interactions for the factors Rpn4p and Pdr1p are observed only after treatment of cells with methyl-methanesulfonate, a DNA-damaging agent. We outline the first approach for consistently integrating all available evidences for TF-target interactions and we comprehensively identify the resulting TF module hierarchy. Prioritizing experimental conditions for each factor will be especially important as increasing numbers of chIP-chip assays are performed in complex organisms such as humans, for which standard conditions are ill defined.'),
(83466, 2006, 'plos', 'Parametric alignment of Drosophila genomes', 'Dewey, Colin N|Huggins, Peter M|Woods, Kevin|Sturmfels, Bernd|Pachter, Lior', 'Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California, USA.|Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California, USA.|Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California, USA.|Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California, USA.|Department of Electrical Engineering and Computer Sciences, University of California Berkeley, Berkeley, California, USA.', 'United States|United States|United States|United States|United States', 30, 'Algorithms|Animals|Base Sequence|Chromosome Mapping|Conserved Sequence|Drosophila|Genome, Insect|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid', 'Journal Article', '10.1371/journal.pcbi.0020073', '16789815', 'The classic algorithms of Needleman-Wunsch and Smith-Waterman find a maximum a posteriori probability alignment for a pair hidden Markov model (PHMM). To process large genomes that have undergone complex genome rearrangements, almost all existing whole genome alignment methods apply fast heuristics to divide genomes into small pieces that are suitable for Needleman-Wunsch alignment. In these alignment methods, it is standard practice to fix the parameters and to produce a single alignment for subsequent analysis by biologists. As the number of alignment programs applied on a whole genome scale continues to increase, so does the disagreement in their results. The alignments produced by different programs vary greatly, especially in non-coding regions of eukaryotic genomes where the biologically correct alignment is hard to find. Parametric alignment is one possible remedy. This methodology resolves the issue of robustness to changes in parameters by finding all optimal alignments for all possible parameters in a PHMM. Our main result is the construction of a whole genome parametric alignment of Drosophila melanogaster and Drosophila pseudoobscura. This alignment draws on existing heuristics for dividing whole genomes into small pieces for alignment, and it relies on advances we have made in computing convex polytopes that allow us to parametrically align non-coding regions using biologically realistic models. We demonstrate the utility of our parametric alignment for biological inference by showing that cis-regulatory elements are more conserved between Drosophila melanogaster and Drosophila pseudoobscura than previously thought. We also show how whole genome parametric alignment can be used to quantitatively assess the dependence of branch length estimates on alignment parameters.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83467, 2006, 'plos', 'On modeling HIV and T cells in vivo: assessing causal estimators in vaccine trials', 'Wick, W David|Gilbert, Peter B|Self, Steven G', 'Statistical Center for HIV and AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. wick@scharp.org|Statistical Center for HIV and AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. wick@scharp.org|Statistical Center for HIV and AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. wick@scharp.org', 'United States|United States|United States', 7, 'AIDS Vaccines|Clinical Trials as Topic|Computer Simulation|Data Interpretation, Statistical|Drug Design|HIV|HIV Infections|Humans|Kinetics|Models, Immunological|Models, Statistical|Risk Assessment|Risk Factors|Stochastic Processes|T-Lymphocytes|Vaccination|Viral Load', 'Journal Article', '10.1371/journal.pcbi.0020064', '16789816', 'The first efficacy trials--named STEP--of a T cell vaccine against HIV/AIDS began in 2004. The unprecedented structure of these trials raised new modeling and statistical challenges. Is it plausible that memory T cells, as opposed to antibodies, can actually prevent infection? If they fail at prevention, to what extent can they ameliorate disease? And how do we estimate efficacy in a vaccine trial with two primary endpoints, one traditional, one entirely novel (viral load after infection), and where the latter may be influenced by selection bias due to the former? In preparation for the STEP trials, biostatisticians developed novel techniques for estimating a causal effect of a vaccine on viral load, while accounting for post-randomization selection bias. But these techniques have not been tested in biologically plausible scenarios. We introduce new stochastic models of T cell and HIV kinetics, making use of new estimates of the rate that cytotoxic T lymphocytes--CTLs, the so-called killer T cells--can kill HIV-infected cells. Based on these models, we make the surprising discovery that it is not entirely implausible that HIV-specific CTLs might prevent infection--as the designers explicitly acknowledged when they chose the endpoints of the STEP trials. By simulating thousands of trials, we demonstrate that the new statistical methods can correctly identify an efficacious vaccine, while protecting against a false conclusion that the vaccine exacerbates disease. In addition to uncovering a surprising immunological scenario, our results illustrate the utility of mechanistic modeling in biostatistics.'),
(83468, 2006, 'plos', 'Assessing the accuracy of ancestral protein reconstruction methods', 'Williams, Paul D|Pollock, David D|Blackburne, Benjamin P|Goldstein, Richard A', 'Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.|Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.|Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.|Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.', 'United States|United States|United States|United States', 116, 'Algorithms|Conserved Sequence|Evolution, Molecular|Genetic Variation|Proteins|Reproducibility of Results|Sensitivity and Specificity|Sequence Alignment|Sequence Analysis, Protein|Sequence Homology, Amino Acid', 'Journal Article', '10.1371/journal.pcbi.0020069', '16789817', 'The phylogenetic inference of ancestral protein sequences is a powerful technique for the study of molecular evolution, but any conclusions drawn from such studies are only as good as the accuracy of the reconstruction method. Every inference method leads to errors in the ancestral protein sequence, resulting in potentially misleading estimates of the ancestral proteins properties. To assess the accuracy of ancestral protein reconstruction methods, we performed computational population evolution simulations featuring near-neutral evolution under purifying selection, speciation, and divergence using an off-lattice protein model where fitness depends on the ability to be stable in a specified target structure. We were thus able to compare the thermodynamic properties of the true ancestral sequences with the properties of ancestral sequences inferred by maximum parsimony, maximum likelihood, and Bayesian methods. Surprisingly, we found that methods such as maximum parsimony and maximum likelihood that reconstruct a best guess amino acid at each position overestimate thermostability, while a Bayesian method that sometimes chooses less-probable residues from the posterior probability distribution does not. Maximum likelihood and maximum parsimony apparently tend to eliminate variants at a position that are slightly detrimental to structural stability simply because such detrimental variants are less frequent. Other properties of ancestral proteins might be similarly overestimated. This suggests that ancestral reconstruction studies require greater care to come to credible conclusions regarding functional evolution. Inferred functional patterns that mimic reconstruction bias should be reevaluated.'),
(83469, 2006, 'plos', 'A community resource benchmarking predictions of peptide binding to MHC-I molecules', 'Peters, Bjoern|Bui, Huynh-Hoa|Frankild, Sune|Nielson, Morten|Lundegaard, Claus|Kostem, Emrah|Basch, Derek|Lamberth, Kasper|Harndahl, Mikkel|Fleri, Ward|Wilson, Stephen S|Sidney, John|Lund, Ole|Buus, Soren|Sette, Alessandro', 'La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org|La Jolla Institute for Allergy and Immunology, San Diego, California, USA. bpeters@liai.org', 'United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States|United States', 227, 'Animals|Databases, Factual|HLA Antigens|Histocompatibility Antigens Class I|Humans|Inhibitory Concentration 50|Macaca|Mice|Neural Networks (Computer)|Pan troglodytes|Peptides|ROC Curve|Software', 'Journal Article', '10.1371/journal.pcbi.0020065', '16789818', 'Recognition of peptides bound to major histocompatibility complex (MHC) class I molecules by T lymphocytes is an essential part of immune surveillance. Each MHC allele has a characteristic peptide binding preference, which can be captured in prediction algorithms, allowing for the rapid scan of entire pathogen proteomes for peptide likely to bind MHC. Here we make public a large set of 48,828 quantitative peptide-binding affinity measurements relating to 48 different mouse, human, macaque, and chimpanzee MHC class I alleles. We use this data to establish a set of benchmark predictions with one neural network method and two matrix-based prediction methods extensively utilized in our groups. In general, the neural network outperforms the matrix-based predictions mainly due to its ability to generalize even on a small amount of data. We also retrieved predictions from tools publicly available on the internet. While differences in the data used to generate these predictions hamper direct comparisons, we do conclude that tools based on combinatorial peptide libraries perform remarkably well. The transparent prediction evaluation on this dataset provides tool developers with a benchmark for comparison of newly developed prediction methods. In addition, to generate and evaluate our own prediction methods, we have established an easily extensible web-based prediction framework that allows automated side-by-side comparisons of prediction methods implemented by experts. This is an advance over the current practice of tool developers having to generate reference predictions themselves, which can lead to underestimating the performance of prediction methods they are not as familiar with as their own. The overall goal of this effort is to provide a transparent prediction evaluation allowing bioinformaticians to identify promising features of prediction methods and providing guidance to immunologists regarding the reliability of prediction tools.'),
(83470, 2006, 'plos', 'Inference of disease-related molecular logic from systems-based microarray analysis', 'Varadan, Vinay|Anastassiou, Dimitris', 'Department of Electrical Engineering and Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, New York, USA.|Department of Electrical Engineering and Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, New York, USA.', 'United States|United States', 27, 'Algorithms|Biomarkers, Tumor|Computer Simulation|Diagnosis, Computer-Assisted|Gene Expression Profiling|Humans|Logistic Models|Male|Models, Biological|Neoplasm Proteins|Oligonucleotide Array Sequence Analysis|Prostatic Neoplasms|Systems Theory', 'Journal Article', '10.1371/journal.pcbi.0020068', '16789819', 'Computational analysis of gene expression data from microarrays has been useful for medical diagnosis and prognosis. The ability to analyze such data at the level of biological modules, rather than individual genes, has been recognized as important for improving our understanding of disease-related pathways. It has proved difficult, however, to infer pathways from microarray data by deriving modules of multiple synergistically interrelated genes, rather than individual genes. Here we propose a systems-based approach called Entropy Minimization and Boolean Parsimony (EMBP) that identifies, directly from gene expression data, modules of genes that are jointly associated with disease. Furthermore, the technique provides insight into the underlying biomolecular logic by inferring a logic function connecting the joint expression levels in a gene module with the outcome of disease. Coupled with biological knowledge, this information can be useful for identifying disease-related pathways, suggesting potential therapeutic approaches for interfering with the functions of such pathways. We present an example providing such gene modules associated with prostate cancer from publicly available gene expression data, and we successfully validate the results on additional independently derived data. Our results indicate a link between prostate cancer and cellular damage from oxidative stress combined with inhibition of apoptotic mechanisms normally triggered by such damage.'),
(83471, 2006, 'plos', 'Adaptation to different human populations by HIV-1 revealed by codon-based analyses', 'Pond, Sergei L Kosakovsky|Frost, Simon D W|Grossman, Zehava|Gravenor, Michael B|Richman, Douglas D|Brown, Andrew J Leigh', 'Department of Pathology, University of California San Diego, La Jolla, California, USA.|Department of Pathology, University of California San Diego, La Jolla, California, USA.|Department of Pathology, University of California San Diego, La Jolla, California, USA.|Department of Pathology, University of California San Diego, La Jolla, California, USA.|Department of Pathology, University of California San Diego, La Jolla, California, USA.|Department of Pathology, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States|United States|United States|United States', 175, 'Adaptation, Physiological|Biological Evolution|Codon|Genetic Predisposition to Disease|Genetic Variation|Genetics, Population|HIV Infections|HIV-1|Humans|Selection, Genetic|Sequence Analysis, DNA', 'Journal Article', '10.1371/journal.pcbi.0020062', '16789820', 'Several codon-based methods are available for detecting adaptive evolution in protein-coding sequences, but to date none specifically identify sites that are selected differentially in two populations, although such comparisons between populations have been historically useful in identifying the action of natural selection. We have developed two fixed effects maximum likelihood methods: one for identifying codon positions showing selection patterns that persist in a population and another for detecting whether selection is operating differentially on individual codons of a gene sampled from two different populations. Applying these methods to two HIV populations infecting genetically distinct human hosts, we have found that few of the positively selected amino acid sites persist in the population, the other changes are detected only at the tips of the phylogenetic tree and appear deleterious in the long term. Additionally, we have identified seven amino acid sites in protease and reverse transcriptase that are selected differentially in the two samples, demonstrating specific population-level adaptation of HIV to human populations.'),
(83472, 2006, 'plos', 'Molecular simulations of cotranslational protein folding: fragment stabilities, folding cooperativity, and trapping in the ribosome', 'Elcock, Adrian H', 'Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA. adrian-elcock@uiowa.edu', 'United States', 0, 'Binding Sites|Computer Simulation|Kinetics|Models, Chemical|Models, Molecular|Motion|Peptide Fragments|Protein Binding|Protein Conformation|Protein Folding|Protein Modification, Translational|Proteins|Ribosomes', 'Journal Article', '10.1371/journal.pcbi.0020098.eor', '16789821', 'Although molecular simulation methods have yielded valuable insights into mechanistic aspects of protein refolding in vitro, they have up to now not been used to model the folding of proteins as they are actually synthesized by the ribosome. To address this issue, we report here simulation studies of three model proteins: chymotrypsin inhibitor 2 (CI2), barnase, and Semliki forest virus protein (SFVP), and directly compare their folding during ribosome-mediated synthesis with their refolding from random, denatured conformations. To calibrate the methodology, simulations are first compared with in vitro data on the folding stabilities of N-terminal fragments of CI2 and barnase, the simulations reproduce the fact that both the stability and thermal folding cooperativity increase as fragments increase in length. Coupled simulations of synthesis and folding for the same two proteins are then described, showing that both fold essentially post-translationally, with mechanisms effectively identical to those for refolding. In both cases, confinement of the nascent polypeptide chain within the ribosome tunnel does not appear to promote significant formation of native structure during synthesis, there are however clear indications that the formation of structure within the nascent chain is sensitive to location within the ribosome tunnel, being subject to both gain and loss as the chain lengthens. Interestingly, simulations in which CI2 is artificially stabilized show a pronounced tendency to become trapped within the tunnel in partially folded conformations: non-cooperative folding, therefore, appears in the simulations to exert a detrimental effect on the rate at which fully folded conformations are formed. Finally, simulations of the two-domain protease module of SFVP, which experimentally folds cotranslationally, indicate that for multi-domain proteins, ribosome-mediated folding may follow different pathways from those taken during refolding. Taken together, these studies provide a first step toward developing more realistic methods for simulating protein folding as it occurs in vivo.'),
(83473, 2006, 'plos', 'Moving forward moving backward: directional sorting of chemotactic cells due to size and adhesion differences', 'Käfer, Jos|Hogeweg, Paulien|Marée, Athanasius F M', 'Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, Netherlands.|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, Netherlands.|Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, Netherlands.', 'Netherlands|Netherlands|Netherlands', 28, 'Animals|Anisotropy|Cell Adhesion|Cell Movement|Chemotaxis|Computational Biology|Cyclic AMP|Dictyostelium|Models, Biological|Monte Carlo Method', 'Journal Article', '10.1371/journal.pcbi.0020056', '16789822', 'Differential movement of individual cells within tissues is an important yet poorly understood process in biological development. Here we present a computational study of cell sorting caused by a combination of cell adhesion and chemotaxis, where we assume that all cells respond equally to the chemotactic signal. To capture in our model mesoscopic properties of biological cells, such as their size and deformability, we use the Cellular Potts Model, a multiscale, cell-based Monte Carlo model. We demonstrate a rich array of cell-sorting phenomena, which depend on a combination of mescoscopic cell properties and tissue level constraints. Under the conditions studied, cell sorting is a fast process, which scales linearly with tissue size. We demonstrate the occurrence of absolute negative mobility, which means that cells may move in the direction opposite to the applied force (here chemotaxis). Moreover, during the sorting, cells may even reverse the direction of motion. Another interesting phenomenon is minority sorting, where the direction of movement does not depend on cell type, but on the frequency of the cell type in the tissue. A special case is the cAMP-wave-driven chemotaxis of Dictyostelium cells, which generates pressure waves that guide the sorting. The mechanisms we describe can easily be overlooked in studies of differential cell movement, hence certain experimental observations may be misinterpreted.'),
(83474, 2006, 'plos', 'Intronic alternative splicing regulators identified by comparative genomics in nematodes', 'Kabat, Jennifer L|Barberan-Soler, Sergio|McKenna, Paul|Clawson, Hiram|Farrer, Tracy|Zahler, Alan M', 'Department of Molecular, Cell, and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Molecular, Cell, and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Molecular, Cell, and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Molecular, Cell, and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Molecular, Cell, and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, California, USA.|Department of Molecular, Cell, and Developmental Biology and Center for Molecular Biology of RNA, University of California Santa Cruz, Santa Cruz, California, USA.', 'United States|United States|United States|United States|United States|United States', 52, 'Alternative Splicing|Animals|Base Sequence|Caenorhabditis|Caenorhabditis elegans|Computational Biology|Conserved Sequence|Evolution, Molecular|Genomics|Humans|Introns|Molecular Sequence Data', 'Comparative Study', '10.1371/journal.pcbi.0020086', '16839192', 'Many alternative splicing events are regulated by pentameric and hexameric intronic sequences that serve as binding sites for splicing regulatory factors. We hypothesized that intronic elements that regulate alternative splicing are under selective pressure for evolutionary conservation. Using a Wobble Aware Bulk Aligner genomic alignment of Caenorhabditis elegans and Caenorhabditis briggsae, we identified 147 alternatively spliced cassette exons that exhibit short regions of high nucleotide conservation in the introns flanking the alternative exon. In vivo experiments on the alternatively spliced let-2 gene confirm that these conserved regions can be important for alternative splicing regulation. Conserved intronic element sequences were collected into a dataset and the occurrence of each pentamer and hexamer motif was counted. We compared the frequency of pentamers and hexamers in the conserved intronic elements to a dataset of all C. elegans intron sequences in order to identify short intronic motifs that are more likely to be associated with alternative splicing. High-scoring motifs were examined for upstream or downstream preferences in introns surrounding alternative exons. Many of the high-scoring nematode pentamer and hexamer motifs correspond to known mammalian splicing regulatory sequences, such as (T)GCATG, indicating that the mechanism of alternative splicing regulation is well conserved in metazoans. A comparison of the analysis of the conserved intronic elements, and analysis of the entire introns flanking these same exons, reveals that focusing on intronic conservation can increase the sensitivity of detecting putative splicing regulatory motifs. This approach also identified novel sequences whose role in splicing is under investigation and has allowed us to take a step forward in defining a catalog of splicing regulatory elements for an organism. In vivo experiments confirm that one novel high-scoring sequence from our analysis, (T)CTATC, is important for alternative splicing regulation of the unc-52 gene.'),
(83475, 2006, 'plos', 'Single-molecule dynamics reveals cooperative binding-folding in protein recognition', 'Wang, Jin|Lu, Qiang|Lu, H Peter', 'State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu|State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, Peoples Republic of China. jin.wang.1@stonybrook.edu', 'China|China|China', 48, 'Computational Biology|DNA Mutational Analysis|Humans|Models, Theoretical|Protein Binding|Protein Conformation|Protein Folding|Protein Structure, Tertiary|Proteins|Thermodynamics|cdc42 GTP-Binding Protein', 'Journal Article', '10.1371/journal.pcbi.0020078', '16839193', 'The study of associations between two biomolecules is the key to understanding molecular function and recognition. Molecular function is often thought to be determined by underlying structures. Here, combining a single-molecule study of protein binding with an energy-landscape-inspired microscopic model, we found strong evidence that biomolecular recognition is determined by flexibilities in addition to structures. Our model is based on coarse-grained molecular dynamics on the residue level with the energy function biased toward the native binding structure (the Go model). With our model, the underlying free-energy landscape of the binding can be explored. There are two distinct conformational states at the free-energy minimum, one with partial folding of CBD itself and significant interface binding of CBD to Cdc42, and the other with native folding of CBD itself and native interface binding of CBD to Cdc42. This shows that the binding process proceeds with a significant interface binding of CBD with Cdc42 first, without a complete folding of CBD itself, and that binding and folding are then coupled to reach the native binding state. The single-molecule experimental finding of dynamic fluctuations among the loosely and closely bound conformational states can be identified with the theoretical, calculated free-energy minimum and explained quantitatively in the model as a result of binding associated with large conformational changes. The theoretical predictions identified certain key residues for binding that were consistent with mutational experiments. The combined study identified fundamental mechanisms and provided insights about designing and further exploring biomolecular recognition with large conformational changes.'),
(83476, 2006, 'plos', 'Wiggle-predicting functionally flexible regions from primary sequence', 'Gu, Jenny|Gribskov, Michael|Bourne, Philip E', 'Department of Pharmacology and Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA. jgu@sdsc.edu|Department of Pharmacology and Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA. jgu@sdsc.edu|Department of Pharmacology and Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA. jgu@sdsc.edu', 'United States|United States|United States', 23, 'Algorithms|Amino Acid Sequence|Animals|Computational Biology|Humans|Markov Chains|Models, Biological|Models, Statistical|Molecular Sequence Data|Normal Distribution|Proteins|Proteomics|Sequence Analysis, Protein|Sequence Homology, Amino Acid|Software', 'Journal Article', '10.1371/journal.pcbi.0020090', '16839194', 'The Wiggle series are support vector machine-based predictors that identify regions of functional flexibility using only protein sequence information. Functionally flexible regions are defined as regions that can adopt different conformational states and are assumed to be necessary for bioactivity. Many advances have been made in understanding the relationship between protein sequence and structure. This work contributes to those efforts by making strides to understand the relationship between protein sequence and flexibility. A coarse-grained protein dynamic modeling approach was used to generate the dataset required for support vector machine training. We define our regions of interest based on the participation of residues in correlated large-scale fluctuations. Even with this structure-based approach to computationally define regions of functional flexibility, predictors successfully extract sequence-flexibility relationships that have been experimentally confirmed to be functionally important. Thus, a sequence-based tool to identify flexible regions important for protein function has been created. The ability to identify functional flexibility using a sequence based approach complements structure-based definitions and will be especially useful for the large majority of proteins with unknown structures. The methodology offers promise to identify structural genomics targets amenable to crystallization and the possibility to engineer more flexible or rigid regions within proteins to modify their bioactivity.'),
(83477, 2006, 'plos', 'Identification of genome-scale metabolic network models using experimentally measured flux profiles', 'Herrgård, Markus J|Fong, Stephen S|Palsson, Bernhard Ø', 'Department of Bioengineering, University of California San Diego, La Jolla, California, USA.|Department of Bioengineering, University of California San Diego, La Jolla, California, USA.|Department of Bioengineering, University of California San Diego, La Jolla, California, USA.', 'United States|United States|United States', 89, 'Computational Biology|Computer Simulation|Escherichia coli|Genetic Engineering|Genome, Bacterial|Models, Biological|Models, Genetic|Mutation|Phenotype|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.0020072', '16839195', 'Genome-scale metabolic network models can be reconstructed for well-characterized organisms using genomic annotation and literature information. However, there are many instances in which model predictions of metabolic fluxes are not entirely consistent with experimental data, indicating that the reactions in the model do not match the active reactions in the in vivo system. We introduce a method for determining the active reactions in a genome-scale metabolic network based on a limited number of experimentally measured fluxes. This method, called optimal metabolic network identification (OMNI), allows efficient identification of the set of reactions that results in the best agreement between in silico predicted and experimentally measured flux distributions. We applied the method to intracellular flux data for evolved Escherichia coli mutant strains with lower than predicted growth rates in order to identify reactions that act as flux bottlenecks in these strains. The expression of the genes corresponding to these bottleneck reactions was often found to be downregulated in the evolved strains relative to the wild-type strain. We also demonstrate the ability of the OMNI method to diagnose problems in E. coli strains engineered for metabolite overproduction that have not reached their predicted production potential. The OMNI method applied to flux data for evolved strains can be used to provide insights into mechanisms that limit the ability of microbial strains to evolve towards their predicted optimal growth phenotypes. When applied to industrial production strains, the OMNI method can also be used to suggest metabolic engineering strategies to improve byproduct secretion. In addition to these applications, the method should prove to be useful in general for reconstructing metabolic networks of ill-characterized microbial organisms based on limited amounts of experimental data.'),
(83478, 2006, 'plos', 'Systematic analysis of head-to-head gene organization: evolutionary conservation and potential biological relevance', 'Li, Yuan-Yuan|Yu, Hui|Guo, Zong-Ming|Guo, Ting-Qing|Tu, Kang|Li, Yi-Xue', 'Shanghai Center for Bioinformation Technology, Shanghai, Peoples Republic of China.|Shanghai Center for Bioinformation Technology, Shanghai, Peoples Republic of China.|Shanghai Center for Bioinformation Technology, Shanghai, Peoples Republic of China.|Shanghai Center for Bioinformation Technology, Shanghai, Peoples Republic of China.|Shanghai Center for Bioinformation Technology, Shanghai, Peoples Republic of China.|Shanghai Center for Bioinformation Technology, Shanghai, Peoples Republic of China.', 'China|China|China|China|China|China', 4, 'Animals|Chickens|Chromosome Mapping|Computational Biology|Databases, Genetic|Evolution, Molecular|Genetic Linkage|Genome|Humans|Mice|Models, Biological|Open Reading Frames|Phylogeny|Rats|Species Specificity|Systems Biology|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020074', '16839196', 'Several head-to-head (or bidirectional) gene pairs have been studied in individual experiments, but genome-wide analysis of this gene organization, especially in terms of transcriptional correlation and functional association, is still insufficient. We conducted a systematic investigation of head-to-head gene organization focusing on structural features, evolutionary conservation, expression correlation and functional association. Of the present 1,262, 1,071, and 491 head-to-head pairs identified in human, mouse, and rat genomes, respectively, pairs with 1- to 400-base pair distance between transcription start sites form the majority (62.36%, 64.15%, and 55.19% for human, mouse, and rat,respectively) of each dataset, and the largest group is always the one with a transcription start site distance of 101 to 200 base pairs. The phylogenetic analysis among Fugu, chicken, and human indicates a negative selection on the separation of head-to-head genes across vertebrate evolution, and thus the ancestral existence of this gene organization. The expression analysis shows that most of the human head-to-head genes are significantly correlated,and the correlation could be positive, negative, or alternative depending on the experimental conditions. Finally, head to-head genes statistically tend to perform similar functions, and gene pairs associated with the significant cofunctions seem to have stronger expression correlations. The findings indicate that the head-to-head gene organization is ancient and conserved, which subjects functionally related genes to correlated transcriptional regulation and thus provides an exquisite mechanism of transcriptional regulation based on gene organization. These results have significantly expanded the knowledge about head-to-head gene organization. Supplementary materials for this study are available at http://www.scbit.org/h2h.'),
(83479, 2006, 'plos', 'Evolutionary and physiological importance of hub proteins', 'Batada, Nizar N|Hurst, Laurence D|Tyers, Mike', 'Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada. nizar.batada@gmail.com|Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada. nizar.batada@gmail.com|Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada. nizar.batada@gmail.com', 'Canada|Canada|Canada', 190, 'Biological Evolution|Cluster Analysis|Computational Biology|Databases, Genetic|Evolution, Molecular|Gene Expression Regulation|Models, Statistical|Protein Interaction Mapping|RNA, Messenger|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.0020088', '16839197', 'It has been claimed that proteins with more interaction partners (hubs) are both physiologically more important (i.e., less dispensable) and, owing to an assumed high density of binding sites, slow evolving. Not all analyses, however, support these results, probably because of biased and less-than reliable global protein interaction data. Here we provide the first examination of these issues using a comprehensive literature-curated dataset of well-substantiated protein interactions in Saccharomyces cerevisiae. Whereas use of less reliable yeast two-hybrid data alone can reject the possibility that local connectivity correlates with measures of dispensability, in higher quality datasets a relatively robust correlation is observed. In contrast, local connectivity does not correlate with the rate of protein evolution even in reliable datasets. This perhaps surprising lack of correlation with evolutionary rate appears in part to arise from the fact that hub proteins do not have a higher density of residues associated with binding. However, hub proteins do have at least one other set of unusual features, namely rapid turnover and regulation, as manifest in high mRNA decay rates and a large number of phosphorylation sites. This, we suggest, is an adaptation to minimize unwanted activation of pathways that might be mediated by adventitious binding to hubs, were they to actively persist longer than required at any given time point. We conclude that hub proteins are more important for cellular growth rate and under tight regulation but are not slow evolving.'),
(83480, 2006, 'plos', 'Emergence of protein fold families through rational design', 'Ding, Feng|Dokholyan, Nikolay V', 'Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.', 'United States|United States', 9, 'Computational Biology|Computers|Entropy|Escherichia coli|Evolution, Molecular|Models, Molecular|Molecular Conformation|Protein Conformation|Protein Folding|Protein Structure, Tertiary|Proteins|Software|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0020085', '16839198', 'Diverse proteins with similar structures are grouped into families of homologs and analogs, if their sequence similarity is higher or lower, respectively, than 20%-30%. It was suggested that protein homologs and analogs originate from a common ancestor and diverge in their distinct evolutionary time scales, emerging as a consequence of the physical properties of the protein sequence space. Although a number of studies have determined key signatures of protein family organization, the sequence-structure factors that differentiate the two evolution-related protein families remain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologous families, lead to distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs. We propose that such differentiation results in the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa, to computationally design protein sequences that correspond to the same fold family. We find that analogous proteins emerge when a backbone structure deviates only 1-2 angstroms root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to approximately 25%-30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences, thereby validating our computational design methodology.'),
(83481, 2006, 'plos', 'Noise-induced Min phenotypes in E coli', 'Fange, David|Elf, Johan', 'Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.|Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, Uppsala, Sweden.', 'Sweden|Sweden', 143, 'Adenosine Triphosphatases|Cell Cycle Proteins|Cell Nucleus|Cell Size|Diffusion|Escherichia coli|Escherichia coli Proteins|Membrane Proteins|Models, Biological|Mutation|Phenotype', 'Journal Article', '10.1371/journal.pcbi.0020080', '16846247', 'The spatiotemporal oscillations of the Escherichia coli proteins MinD and MinE direct cell division to the region between the chromosomes. Several quantitative models of the Min system have been suggested before, but no one of them accounts for the behavior of all documented mutant phenotypes. We analyzed the stochastic reaction-diffusion kinetics of the Min proteins for several E. coli mutants and compared the results to the corresponding deterministic mean-field description. We found that wild-type (wt) and filamentous (ftsZ-) cells are well characterized by the mean-field model, but that a stochastic model is necessary to account for several of the characteristics of the spherical (rodA-) and phospathedylethanolamide-deficient (PE-) phenotypes. For spherical cells, the mean-field model is bistable, and the system can get trapped in a non-oscillatory state. However, when the intrinsic noise is considered, only the experimentally observed oscillatory behavior remains. The stochastic model also reproduces the change in oscillation directions observed in the spherical phenotype and the occasional gliding of the MinD region along the inner membrane. For the PE- mutant, the stochastic model explains the appearance of randomly localized and dense MinD clusters as a nucleation phenomenon, in which the stochastic kinetics at low copy number causes local discharges of the high MinD(ATP) to MinD(ADP) potential. We find that a simple five-reaction model of the Min system can explain all documented Min phenotypes, if stochastic kinetics and three-dimensional diffusion are accounted for. Our results emphasize that local copy number fluctuation may result in phenotypic differences although the total number of molecules of the relevant species is high.'),
(83482, 2006, 'plos', 'Functional classification using phylogenomic inference', 'Brown, Duncan|Sjölander, Kimmen', 'University of California Berkeley, Berkeley, California, USA.|University of California Berkeley, Berkeley, California, USA.', 'United States|United States', 0, 'Animals|Databases, Genetic|Genome|Genomics|Humans|Phylogeny|Proteins|Reproducibility of Results|Research Design', 'Journal Article', '10.1371/journal.pcbi.0020077', '16846248', '-'),
(83483, 2006, 'plos', 'Identification and analysis of genes and pseudogenes within duplicated regions in the human and mouse genomes', 'Suyama, Mikita|Harrington, Eoghan|Bork, Peer|Torrents, David', 'European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.|European Molecular Biology Laboratory, Heidelberg, Germany.', 'Germany|Germany|Germany|Germany', 0, 'Animals|Gene Dosage|Gene Duplication|Gene Silencing|Genes, Duplicate|Genome|Humans|Mice|Open Reading Frames|Pseudogenes', 'Journal Article', '10.1371/journal.pcbi.0020076', '16846249', 'The identification and classification of genes and pseudogenes in duplicated regions still constitutes a challenge for standard automated genome annotation procedures. Using an integrated homology and orthology analysis independent of current gene annotation, we have identified 9,484 and 9,017 gene duplicates in human and mouse, respectively. On the basis of the integrity of their coding regions, we have classified them into functional and inactive duplicates, allowing us to define the first consistent and comprehensive collection of 1,811 human and 1,581 mouse unprocessed pseudogenes. Furthermore, of the total of 14,172 human and mouse duplicates predicted to be functional genes, as many as 420 are not included in current reference gene databases and therefore correspond to likely novel mammalian genes. Some of these correspond to partial duplicates with less than half of the length of the original source genes, yet they are conserved and syntenic among different mammalian lineages. The genes and unprocessed pseudogenes obtained here will enable further studies on the mechanisms involved in gene duplication as well as of the fate of duplicated genes.'),
(83484, 2006, 'plos', 'Immunoinformatics comes of age', 'Korber, Bette|LaBute, Montiago|Yusim, Karina', 'Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. btk@lanl.gov|Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. btk@lanl.gov|Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA. btk@lanl.gov', 'Mexico|Mexico|Mexico', 0, 'Amino Acid Sequence|Animals|Computational Biology|Databases, Factual|Epitopes, B-Lymphocyte|Epitopes, T-Lymphocyte|Humans|Immunity', 'Journal Article', '10.1371/journal.pcbi.0020071', '16846250', 'With the burgeoning immunological data in the scientific literature, scientists must increasingly rely on Internet resources to inform and enhance their work. Here we provide a brief overview of the adaptive immune response and summaries of immunoinformatics resources, emphasizing those with Web interfaces. These resources include searchable databases of epitopes and immune-related molecules, and analysis tools for T cell and B cell epitope prediction, vaccine design, and protein structure comparisons. There is an agreeable synergy between the growing collections in immune-related databases and the growing sophistication of analysis software, the databases provide the foundation for developing predictive computational tools, which in turn enable more rapid identification of immune responses to populate the databases. Collectively, these resources contribute to improved understanding of immune responses and escape, and evolution of pathogens under immune pressure. The public health implications are vast, including designing vaccines, understanding autoimmune diseases, and defining the correlates of immune protection.'),
(83485, 2006, 'plos', 'Toward a census of bacteria in soil', 'Schloss, Patrick D|Handelsman, Jo', 'Department of Plant Pathology, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Department of Plant Pathology, University of Wisconsin-Madison, Madison, Wisconsin, USA.', 'United States|United States', 255, 'Alaska|Bacteria|Colony Count, Microbial|Gene Library|Minnesota|Models, Statistical|RNA, Bacterial|RNA, Ribosomal, 16S|Soil Microbiology', 'Journal Article', '10.1371/journal.pcbi.0020092', '16848637', 'For more than a century, microbiologists have sought to determine the species richness of bacteria in soil, but the extreme complexity and unknown structure of soil microbial communities have obscured the answer. We developed a statistical model that makes the problem of estimating richness statistically accessible by evaluating the characteristics of samples drawn from simulated communities with parametric community distributions. We identified simulated communities with rank-abundance distributions that followed a truncated lognormal distribution whose samples resembled the structure of 16S rRNA gene sequence collections made using Alaskan and Minnesotan soils. The simulated communities constructed based on the distribution of 16S rRNA gene sequences sampled from the Alaskan and Minnesotan soils had a richness of 5,000 and 2,000 operational taxonomic units (OTUs), respectively, where an OTU represents a collection of sequences not more than 3% distant from each other. To sample each of these OTUs in the Alaskan 16S rRNA gene library at least twice, 480,000 sequences would be required, however, to estimate the richness of the simulated communities using nonparametric richness estimators would require only 18,000 sequences. Quantifying the richness of complex environments such as soil is an important step in building an ecological framework. We have shown that generating sufficient sequence data to do so requires less sequencing effort than completely sequencing a bacterial genome.'),
(83486, 2006, 'plos', 'Nonoptimal component placement, but short processing paths, due to long-distance projections in neural systems', 'Kaiser, Marcus|Hilgetag, Claus C', 'School of Computing Science, University of Newcastle, Newcastle upon Tyne, United Kingdom. M.Kaiser@ncl.ac.uk|School of Computing Science, University of Newcastle, Newcastle upon Tyne, United Kingdom. M.Kaiser@ncl.ac.uk', 'United Kingdom|United Kingdom', 0, 'Animals|Caenorhabditis elegans|Macaca|Models, Neurological|Nerve Net|Nervous System|Space Perception', 'Journal Article', '10.1371/journal.pcbi.0020095', '16848638', 'It has been suggested that neural systems across several scales of organization show optimal component placement, in which any spatial rearrangement of the components would lead to an increase of total wiring. Using extensive connectivity datasets for diverse neural networks combined with spatial coordinates for network nodes, we applied an optimization algorithm to the network layouts, in order to search for wire-saving component rearrangements. We found that optimized component rearrangements could substantially reduce total wiring length in all tested neural networks. Specifically, total wiring among 95 primate (Macaque) cortical areas could be decreased by 32%, and wiring of neuronal networks in the nematode Caenorhabditis elegans could be reduced by 48% on the global level, and by 49% for neurons within frontal ganglia. Wiring length reductions were possible due to the existence of long-distance projections in neural networks. We explored the role of these projections by comparing the original networks with minimally rewired networks of the same size, which possessed only the shortest possible connections. In the minimally rewired networks, the number of processing steps along the shortest paths between components was significantly increased compared to the original networks. Additional benchmark comparisons also indicated that neural networks are more similar to network layouts that minimize the length of processing paths, rather than wiring length. These findings suggest that neural systems are not exclusively optimized for minimal global wiring, but for a variety of factors including the minimization of processing steps.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83487, 2006, 'plos', 'Complex parameter landscape for a complex neuron model', 'Achard, Pablo|De Schutter, Erik', 'Theoretical Neurobiology, University of Antwerp, Belgium.|Theoretical Neurobiology, University of Antwerp, Belgium.', 'Belgium|Belgium', 157, 'Algorithms|Cell Line|Computational Biology|Humans|Models, Neurological|Neurons|Purkinje Cells|Synapses', 'Journal Article', '10.1371/journal.pcbi.0020094', '16848639', 'The electrical activity of a neuron is strongly dependent on the ionic channels present in its membrane. Modifying the maximal conductances from these channels can have a dramatic impact on neuron behavior. But the effect of such modifications can also be cancelled out by compensatory mechanisms among different channels. We used an evolution strategy with a fitness function based on phase-plane analysis to obtain 20 very different computational models of the cerebellar Purkinje cell. All these models produced very similar outputs to current injections, including tiny details of the complex firing pattern. These models were not completely isolated in the parameter space, but neither did they belong to a large continuum of good models that would exist if weak compensations between channels were sufficient. The parameter landscape of good models can best be described as a set of loosely connected hyperplanes. Our method is efficient in finding good models in this complex landscape. Unraveling the landscape is an important step towards the understanding of functional homeostasis of neurons.'),
(83488, 2006, 'plos', 'Protein-protein interactions more conserved within species than across species', 'Mika, Sven|Rost, Burkhard', 'Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. mika@rostlab.org|Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA. mika@rostlab.org', 'United States|United States', 0, 'Animals|Binding Sites|Caenorhabditis elegans|Conserved Sequence|Drosophila melanogaster|Evolution, Molecular|Humans|Models, Biological|Protein Binding|Proteins|Saccharomyces cerevisiae|Species Specificity|Structural Homology, Protein', 'Comparative Study', '10.1371/journal.pcbi.0020079', '16854211', 'Experimental high-throughput studies of protein-protein interactions are beginning to provide enough data for comprehensive computational studies. Today, about ten large data sets, each with thousands of interacting pairs, coarsely sample the interactions in fly, human, worm, and yeast. Another about 55,000 pairs of interacting proteins have been identified by more careful, detailed biochemical experiments. Most interactions are experimentally observed in prokaryotes and simple eukaryotes, very few interactions are observed in higher eukaryotes such as mammals. It is commonly assumed that pathways in mammals can be inferred through homology to model organisms, e.g. the experimental observation that two yeast proteins interact is transferred to infer that the two corresponding proteins in human also interact. Two pairs for which the interaction is conserved are often described as interologs. The goal of this investigation was a large-scale comprehensive analysis of such inferences, i.e. of the evolutionary conservation of interologs. Here, we introduced a novel score for measuring the overlap between protein-protein interaction data sets. This measure appeared to reflect the overall quality of the data and was the basis for our two surprising results from our large-scale analysis. Firstly, homology-based inferences of physical protein-protein interactions appeared far less successful than expected. In fact, such inferences were accurate only for extremely high levels of sequence similarity. Secondly, and most surprisingly, the identification of interacting partners through sequence similarity was significantly more reliable for protein pairs within the same organism than for pairs between species. Our analysis underlined that the discrepancies between different datasets are large, even when using the same type of experiment on the same organism. This reality considerably constrains the power of homology-based transfer of interactions. In particular, the experimental probing of interactions in distant model organisms has to be undertaken with some caution. More comprehensive images of protein-protein networks will require the combination of many high-throughput methods, including in silico inferences and predictions. http://www.rostlab.org/results/2006/ppi_homology/'),
(83489, 2006, 'plos', 'Extracting gene networks for low-dose radiation using graph theoretical algorithms', 'Voy, Brynn H|Scharff, Jon A|Perkins, Andy D|Saxton, Arnold M|Borate, Bhavesh|Chesler, Elissa J|Branstetter, Lisa K|Langston, Michael A', 'Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov|Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. voybh@ornl.gov', 'United States|United States|United States|United States|United States|United States|United States|United States', 75, 'Algorithms|Animals|Cell Line|Computational Biology|Computer Simulation|Dose-Response Relationship, Radiation|Gene Expression Regulation|Humans|Mice|Oligonucleotide Array Sequence Analysis|Proteins|Radiation Dosage|Radiation, Ionizing', 'Journal Article', '10.1371/journal.pcbi.0020089', '16854212', 'Genes with common functions often exhibit correlated expression levels, which can be used to identify sets of interacting genes from microarray data. Microarrays typically measure expression across genomic space, creating a massive matrix of co-expression that must be mined to extract only the most relevant gene interactions. We describe a graph theoretical approach to extracting co-expressed sets of genes, based on the computation of cliques. Unlike the results of traditional clustering algorithms, cliques are not disjoint and allow genes to be assigned to multiple sets of interacting partners, consistent with biological reality. A graph is created by thresholding the correlation matrix to include only the correlations most likely to signify functional relationships. Cliques computed from the graph correspond to sets of genes for which significant edges are present between all members of the set, representing potential members of common or interacting pathways. Clique membership can be used to infer function about poorly annotated genes, based on the known functions of better-annotated genes with which they share clique membership (i.e., guilt-by-association). We illustrate our method by applying it to microarray data collected from the spleens of mice exposed to low-dose ionizing radiation. Differential analysis is used to identify sets of genes whose interactions are impacted by radiation exposure. The correlation graph is also queried independently of clique to extract edges that are impacted by radiation. We present several examples of multiple gene interactions that are altered by radiation exposure and thus represent potential molecular pathways that mediate the radiation response.'),
(83490, 2006, 'plos', 'Key role of local regulation in chemosensing revealed by a new molecular interaction-based modeling method', 'Meier-Schellersheim, Martin|Xu, Xuehua|Angermann, Bastian|Kunkel, Eric J|Jin, Tian|Germain, Ronald N', 'Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov|Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov|Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov|Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov|Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov|Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov', 'United States|United States|United States|United States|United States|United States', 98, 'Animals|Cell Line|Cell Membrane|Computer Simulation|Cyclic AMP|Dictyostelium|Models, Biological|PTEN Phosphohydrolase|Phosphatidylinositol 3-Kinases|Phosphatidylinositol Phosphates|Protein Binding|Protein Transport|Protozoan Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0020082', '16854213', 'The signaling network underlying eukaryotic chemosensing is a complex combination of receptor-mediated transmembrane signals, lipid modifications, protein translocations, and differential activation/deactivation of membrane-bound and cytosolic components. As such, it provides particularly interesting challenges for a combined computational and experimental analysis. We developed a novel detailed molecular signaling model that, when used to simulate the response to the attractant cyclic adenosine monophosphate (cAMP), made nontrivial predictions about Dictyostelium chemosensing. These predictions, including the unexpected existence of spatially asymmetrical, multiphasic, cyclic adenosine monophosphate-induced PTEN translocation and phosphatidylinositol-(3,4,5)P3 generation, were experimentally verified by quantitative single-cell microscopy leading us to propose significant modifications to the current standard model for chemoattractant-induced biochemical polarization in this organism. Key to this successful modeling effort was the use of Simmune, a new software package that supports the facile development and testing of detailed computational representations of cellular behavior. An intuitive interface allows user definition of complex signaling networks based on the definition of specific molecular binding site interactions and the subcellular localization of molecules. It automatically translates such inputs into spatially resolved simulations and dynamic graphical representations of the resulting signaling network that can be explored in a manner that closely parallels wet lab experimental procedures. These features of Simmune were critical to the model development and analysis presented here and are likely to be useful in the computational investigation of many aspects of cell biology.'),
(83491, 2006, 'plos', 'On the estimation of intron evolution', 'Csurös, Miklós', 'Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov', 'United States', 8, 'Animals|Computer Simulation|Conserved Sequence|Eukaryotic Cells|Evolution, Molecular|Humans|Introns|Likelihood Functions|Models, Genetic|Models, Statistical|Sequence Alignment|Sequence Analysis, DNA|Spliceosomes', 'Comment', '10.1371/journal.pcbi.0020084', '16863393', '-'),
(83492, 2006, 'plos', 'Circadian rhythmicity by autocatalysis', 'Mehra, Arun|Hong, Christian I|Shi, Mi|Loros, Jennifer J|Dunlap, Jay C|Ruoff, Peter', 'Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, USA.|Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, USA.|Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, USA.|Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, USA.|Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, USA.|Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire, USA.', 'United States|United States|United States|United States|United States|United States', 57, 'Bacterial Proteins|Biological Clocks|Catalysis|Circadian Rhythm|Circadian Rhythm Signaling Peptides and Proteins|Computer Simulation|Cyanobacteria|Feedback|Kinetics|Models, Biological|Periodicity|Phosphorylation|Signal Transduction|Temperature', 'Journal Article', '10.1371/journal.pcbi.0020096', '16863394', 'The temperature compensated in vitro oscillation of cyanobacterial KaiC phosphorylation, the first example of a thermodynamically closed system showing circadian rhythmicity, only involves the three Kai proteins (KaiA, KaiB, and KaiC) and ATP. In this paper, we describe a model in which the KaiA- and KaiB-assisted autocatalytic phosphorylation and dephosphorylation of KaiC are the source for circadian rhythmicity. This model, based upon autocatalysis instead of transcription-translation negative feedback, shows temperature-compensated circadian limit-cycle oscillations with KaiC phosphorylation profiles and has period lengths and rate constant values that are consistent with experimental observations.'),
(83493, 2006, 'plos', 'From functional genomics to functional immunomics: new challenges, old problems, big rewards', 'Braga-Neto, Ulisses M|Marques, Ernesto T A', 'Experimental Therapy Laboratory, Aggeu Magalhães Research Center - CPqAM/FIOCRUZ, Recife, Brazil. ub@ieee.org|Experimental Therapy Laboratory, Aggeu Magalhães Research Center - CPqAM/FIOCRUZ, Recife, Brazil. ub@ieee.org', 'Brazil|Brazil', 0, 'Biotechnology|Epitope Mapping|Forecasting|Genomics|Microarray Analysis|Proteome', 'Journal Article', '10.1371/journal.pcbi.0020081', '16863395', 'The development of DNA microarray technology a decade ago led to the establishment of functional genomics as one of the most active and successful scientific disciplines today. With the ongoing development of immunomic microarray technology-a spatially addressable, large-scale technology for measurement of specific immunological response-the new challenge of functional immunomics is emerging, which bears similarities to but is also significantly different from functional genomics. Immunonic data has been successfully used to identify biological markers involved in autoimmune diseases, allergies, viral infections such as human immunodeficiency virus (HIV), influenza, diabetes, and responses to cancer vaccines. This review intends to provide a coherent vision of this nascent scientific field, and speculate on future research directions. We discuss at some length issues such as epitope prediction, immunomic microarray technology and its applications, and computation and statistical challenges related to functional immunomics. Based on the recent discovery of regulation mechanisms in T cell responses, we envision the use of immunomic microarrays as a tool for advances in systems biology of cellular immune responses, by means of immunomic regulatory network models.'),
(83494, 2006, 'plos', 'Module-based analysis of robustness tradeoffs in the heat shock response system', 'Kurata, Hiroyuki|El-Samad, Hana|Iwasaki, Rei|Ohtake, Hisao|Doyle, John C|Grigorova, Irina|Gross, Carol A|Khammash, Mustafa', 'Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp|Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, Japan. kurata@bio.kyutech.ac.jp', 'Japan|Japan|Japan|Japan|Japan|Japan|Japan|Japan', 78, 'Computer Simulation|Escherichia coli|Escherichia coli Proteins|Feedback|Gene Expression Regulation, Bacterial|Heat-Shock Proteins|Heat-Shock Response|Models, Biological|Oxidative Stress|Signal Transduction|Systems Biology', 'Journal Article', '10.1371/journal.pcbi.0020059', '16863396', 'Biological systems have evolved complex regulatory mechanisms, even in situations where much simpler designs seem to be sufficient for generating nominal functionality. Using module-based analysis coupled with rigorous mathematical comparisons, we propose that in analogy to control engineering architectures, the complexity of cellular systems and the presence of hierarchical modular structures can be attributed to the necessity of achieving robustness. We employ the Escherichia coli heat shock response system, a strongly conserved cellular mechanism, as an example to explore the design principles of such modular architectures. In the heat shock response system, the sigma-factor sigma32 is a central regulator that integrates multiple feedforward and feedback modules. Each of these modules provides a different type of robustness with its inherent tradeoffs in terms of transient response and efficiency. We demonstrate how the overall architecture of the system balances such tradeoffs. An extensive mathematical exploration nevertheless points to the existence of an array of alternative strategies for the existing heat shock response that could exhibit similar behavior. We therefore deduce that the evolutionary constraints facing the system might have steered its architecture toward one of many robustly functional solutions.'),
(83495, 2006, 'plos', 'Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes', 'Haynes, Chad|Oldfield, Christopher J|Ji, Fei|Klitgord, Niels|Cusick, Michael E|Radivojac, Predrag|Uversky, Vladimir N|Vidal, Marc|Iakoucheva, Lilia M', 'Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.|Laboratory of Statistical Genetics, The Rockefeller University, New York, New York, USA.', 'United States|United States|United States|United States|United States|United States|United States|United States|United States', 426, 'Amino Acids|Animals|Caenorhabditis elegans|Caenorhabditis elegans Proteins|Carrier Proteins|Computational Biology|Drosophila Proteins|Drosophila melanogaster|ELAV Proteins|ELAV-Like Protein 2|Humans|Ligases|Models, Molecular|Protein Binding|Protein Structure, Tertiary|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins', 'Journal Article', '10.1371/journal.pcbi.0020100', '16884331', 'Recent proteome-wide screening approaches have provided a wealth of information about interacting proteins in various organisms. To test for a potential association between protein connectivity and the amount of predicted structural disorder, the disorder propensities of proteins with various numbers of interacting partners from four eukaryotic organisms (Caenorhabditis elegans, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens) were investigated. The results of PONDR VL-XT disorder analysis show that for all four studied organisms, hub proteins, defined here as those that interact with > or = 10 partners, are significantly more disordered than end proteins, defined here as those that interact with just one partner. The proportion of predicted disordered residues, the average disorder score, and the number of predicted disordered regions of various lengths were higher overall in hubs than in ends. A binary classification of hubs and ends into ordered and disordered subclasses using the consensus prediction method showed a significant enrichment of wholly disordered proteins and a significant depletion of wholly ordered proteins in hubs relative to ends in worm, fly, and human. The functional annotation of yeast hubs and ends using GO categories and the correlation of these annotations with disorder predictions demonstrate that proteins with regulation, transcription, and development annotations are enriched in disorder, whereas proteins with catalytic activity, transport, and membrane localization annotations are depleted in disorder. The results of this study demonstrate that intrinsic structural disorder is a distinctive and common characteristic of eukaryotic hub proteins, and that disorder may serve as a determinant of protein interactivity.'),
(83496, 2006, 'plos', 'Insights into the coupling of duplication events and macroevolution from an age profile of animal transmembrane gene families', 'Ding, Guohui|Kang, Jiuhong|Liu, Qi|Shi, Tieliu|Pei, Gang|Li, Yixue', 'Bioinformatics Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Peoples Republic of China.|Bioinformatics Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Peoples Republic of China.|Bioinformatics Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Peoples Republic of China.|Bioinformatics Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Peoples Republic of China.|Bioinformatics Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Peoples Republic of China.|Bioinformatics Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, Peoples Republic of China.', 'China|China|China|China|China|China', 9, 'Animals|Biodiversity|Computational Biology|Evolution, Molecular|Gene Duplication|Humans|Membrane Proteins|Monte Carlo Method|Multigene Family|Oxidation-Reduction|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020102', '16895434', 'The evolution of new gene families subsequent to gene duplication may be coupled to the fluctuation of population and environment variables. Based upon that, we presented a systematic analysis of the animal transmembrane gene duplication events on a macroevolutionary scale by integrating the palaeontology repository. The age of duplication events was calculated by maximum likelihood method, and the age distribution was estimated by density histogram and normal kernel density estimation. We showed that the density of the duplicates displays a positive correlation with the estimates of maximum number of cell types of common ancestors, and the oxidation events played a key role in the major transitions of this density trace. Next, we focused on the Phanerozoic phase, during which more macroevolution data are available. The pulse mass extinction timepoints coincide with the local peaks of the age distribution, suggesting that the transmembrane gene duplicates fixed frequently when the environment changed dramatically. Moreover, a 61-million-year cycle is the most possible cycle in this phase by spectral analysis, which is consistent with the cycles recently detected in biodiversity. Our data thus elucidate a strong coupling of duplication events and macroevolution, furthermore, our method also provides a new way to address these questions.'),
(83497, 2006, 'plos', 'Matrix formalism to describe functional states of transcriptional regulatory systems', 'Gianchandani, Erwin P|Papin, Jason A|Price, Nathan D|Joyce, Andrew R|Palsson, Bernhard O', 'Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.|Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.', 'United States|United States|United States|United States|United States', 73, 'Computational Biology|Escherichia coli|Gene Expression Regulation|Genome|Genomics|Lac Operon|Models, Genetic|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020101', '16895435', 'Complex regulatory networks control the transcription state of a genome. These transcriptional regulatory networks (TRNs) have been mathematically described using a Boolean formalism, in which the state of a gene is represented as either transcribed or not transcribed in response to regulatory signals. The Boolean formalism results in a series of regulatory rules for the individual genes of a TRN that in turn can be used to link environmental cues to the transcription state of a genome, thereby forming a complete transcriptional regulatory system (TRS). Herein, we develop a formalism that represents such a set of regulatory rules in a matrix form. Matrix formalism allows for the systemic characterization of the properties of a TRS and facilitates the computation of the transcriptional state of the genome under any given set of environmental conditions. Additionally, it provides a means to incorporate mechanistic detail of a TRS as it becomes available. In this study, the regulatory network matrix, R, for a prototypic TRS is characterized and the fundamental subspaces of this matrix are described. We illustrate how the matrix representation of a TRS coupled with its environment (R*) allows for a sampling of all possible expression states of a given network, and furthermore, how the fundamental subspaces of the matrix provide a way to study key TRS features and may assist in experimental design.'),
(83498, 2006, 'plos', 'An integrative method for accurate comparative genome mapping', 'Swidan, Firas|Rocha, Eduardo P C|Shmoish, Michael|Pinter, Ron Y', 'Department of Computer Science, Technion, Israel Institute of Technology, Haifa, Israel. Swidanf@janelia.hhmi.org|Department of Computer Science, Technion, Israel Institute of Technology, Haifa, Israel. Swidanf@janelia.hhmi.org|Department of Computer Science, Technion, Israel Institute of Technology, Haifa, Israel. Swidanf@janelia.hhmi.org|Department of Computer Science, Technion, Israel Institute of Technology, Haifa, Israel. Swidanf@janelia.hhmi.org', 'Israel|Israel|Israel|Israel', 18, 'Algorithms|Base Sequence|Chromosome Mapping|Evolution, Molecular|Molecular Sequence Data|Sequence Alignment|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid|Software|Systems Integration', 'Comparative Study', '10.1371/journal.pcbi.0020075', '16933978', 'We present MAGIC, an integrative and accurate method for comparative genome mapping. Our method consists of two phases: preprocessing for identifying maximal similar segments, and mapping for clustering and classifying these segments. MAGICs main novelty lies in its biologically intuitive clustering approach, which aims towards both calculating reorder-free segments and identifying orthologous segments. In the process, MAGIC efficiently handles ambiguities resulting from duplications that occurred before the speciation of the considered organisms from their most recent common ancestor. We demonstrate both MAGICs robustness and scalability: the former is asserted with respect to its initial input and with respect to its parameters values. The latter is asserted by applying MAGIC to distantly related organisms and to large genomes. We compare MAGIC to other comparative mapping methods and provide detailed analysis of the differences between them. Our improvements allow a comprehensive study of the diversity of genetic repertoires resulting from large-scale mutations, such as indels and duplications, including explicitly transposable and phagic elements. The strength of our method is demonstrated by detailed statistics computed for each type of these large-scale mutations. MAGIC enabled us to conduct a comprehensive analysis of the different forces shaping prokaryotic genomes from different clades, and to quantify the importance of novel gene content introduced by horizontal gene transfer relative to gene duplication in bacterial genome evolution. We use these results to investigate the breakpoint distribution in several prokaryotic genomes.'),
(83499, 2006, 'plos', 'The ion channel inverse problem: neuroinformatics meets biophysics', 'Cannon, Robert C|DAlessandro, Giampaolo', 'Department of Psychology Center for Memory and Brain, Boston, Massachusetts, USA. robert@textensor.com|Department of Psychology Center for Memory and Brain, Boston, Massachusetts, USA. robert@textensor.com', 'United States|United States', 27, 'Biophysics|Cell Physiological Phenomena|Computational Biology|Computer Simulation|Ion Channel Gating|Ion Channels|Models, Biological|Models, Chemical|Neurosciences', 'Journal Article', '10.1371/journal.pcbi.0020091', '16933979', 'Ion channels are the building blocks of the information processing capability of neurons: any realistic computational model of a neuron must include reliable and effective ion channel components. Sophisticated statistical and computational tools have been developed to study the ion channel structure-function relationship, but this work is rarely incorporated into the models used for single neurons or small networks. The disjunction is partly a matter of convention. Structure-function studies typically use a single Markov model for the whole channel whereas until recently whole-cell modeling software has focused on serial, independent, two-state subunits that can be represented by the Hodgkin-Huxley equations. More fundamentally, there is a difference in purpose that prevents models being easily reused. Biophysical models are typically developed to study one particular aspect of channel gating in detail, whereas neural modelers require broad coverage of the entire range of channel behavior that is often best achieved with approximate representations that omit structural features that cannot be adequately constrained. To bridge the gap so that more recent channel data can be used in neural models requires new computational infrastructure for bringing together diverse sources of data to arrive at best-fit models for whole-cell modeling. We review the current state of channel modeling and explore the developments needed for its conclusions to be integrated into whole-cell modeling.'),
(83500, 2006, 'plos', 'Transient resetting: a novel mechanism for synchrony and its biological examples', 'Li, Chunguang|Chen, Luonan|Aihara, Kazuyuki', 'ERATO Aihara Complexity Modelling Project, Komaba Open Laboratory, University of Tokyo, Tokyo, Japan. cgli@uestc.edu.cn|ERATO Aihara Complexity Modelling Project, Komaba Open Laboratory, University of Tokyo, Tokyo, Japan. cgli@uestc.edu.cn|ERATO Aihara Complexity Modelling Project, Komaba Open Laboratory, University of Tokyo, Tokyo, Japan. cgli@uestc.edu.cn', 'Japan|Japan|Japan', 34, 'Action Potentials|Algorithms|Biological Clocks|Circadian Rhythm|Computer Simulation|Kinetics|Models, Biological|Nerve Net|Neurons|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020103', '16933980', 'The study of synchronization in biological systems is essential for the understanding of the rhythmic phenomena of living organisms at both molecular and cellular levels. In this paper, by using simple dynamical systems theory, we present a novel mechanism, named transient resetting, for the synchronization of uncoupled biological oscillators with stimuli. This mechanism not only can unify and extend many existing results on (deterministic and stochastic) stimulus-induced synchrony, but also may actually play an important role in biological rhythms. We argue that transient resetting is a possible mechanism for the synchronization in many biological organisms, which might also be further used in the medical therapy of rhythmic disorders. Examples of the synchronization of neural and circadian oscillators as well as a chaotic neuron model are presented to verify our hypothesis.'),
(83501, 2006, 'plos', 'Conservation of expression and sequence of metabolic genes is reflected by activity across metabolic states', 'Bilu, Yonatan|Shlomi, Tomer|Barkai, Naama|Ruppin, Eytan', 'Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. yonatan.bilu@weizmann.ac.il|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. yonatan.bilu@weizmann.ac.il|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. yonatan.bilu@weizmann.ac.il|Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. yonatan.bilu@weizmann.ac.il', 'Israel|Israel|Israel|Israel', 31, 'Cell Proliferation|Computer Simulation|Gene Expression Regulation, Fungal|Models, Biological|Protein Interaction Mapping|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0020106', '16933982', 'Variation in gene expression levels on a genomic scale has been detected among different strains, among closely related species, and within populations of genetically identical cells. What are the driving forces that lead to expression divergence in some genes and conserved expression in others? Here we employ flux balance analysis to address this question for metabolic genes. We consider the genome-scale metabolic model of Saccharomyces cerevisiae, and its entire space of optimal and near-optimal flux distributions. We show that this space reveals underlying evolutionary constraints on expression regulation, as well as on the conservation of the underlying gene sequences. Genes that have a high range of optimal flux levels tend to display divergent expression levels among different yeast strains and species. This suggests that gene regulation has diverged in those parts of the metabolic network that are less constrained. In addition, we show that genes that are active in a large fraction of the space of optimal solutions tend to have conserved sequences. This supports the possibility that there is less selective pressure to maintain genes that are relevant for only a small number of metabolic states.'),
(83502, 2006, 'plos', 'Modeling somatic evolution in tumorigenesis', 'Spencer, Sabrina L|Gerety, Ryan A|Pienta, Kenneth J|Forrest, Stephanie', 'Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. spencers@mit.edu|Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. spencers@mit.edu|Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. spencers@mit.edu|Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. spencers@mit.edu', 'United States|United States|United States|United States', 78, 'Cell Transformation, Neoplastic|Computer Simulation|Evolution, Molecular|Humans|Models, Genetic|Neoplasm Proteins|Neoplasms|Neovascularization, Pathologic', 'Journal Article', '10.1371/journal.pcbi.0020108', '16933983', 'Tumorigenesis in humans is thought to be a multistep process where certain mutations confer a selective advantage, allowing lineages derived from the mutated cell to outcompete other cells. Although molecular cell biology has substantially advanced cancer research, our understanding of the evolutionary dynamics that govern tumorigenesis is limited. This paper analyzes the computational implications of cancer progression presented by Hanahan and Weinberg in The Hallmarks of Cancer. We model the complexities of tumor progression as a small set of underlying rules that govern the transformation of normal cells to tumor cells. The rules are implemented in a stochastic multistep model. The model predicts that (i) early-onset cancers proceed through a different sequence of mutation acquisition than late-onset cancers, (ii) tumor heterogeneity varies with acquisition of genetic instability, mutation pathway, and selective pressures during tumorigenesis, (iii) there exists an optimal initial telomere length which lowers cancer incidence and raises time of cancer onset, and (iv) the ability to initiate angiogenesis is an important stage-setting mutation, which is often exploited by other cells. The model offers insight into how the sequence of acquired mutations affects the timing and cellular makeup of the resulting tumor and how the cellular-level population dynamics drive neoplastic evolution.'),
(83503, 2006, 'plos', 'High epitope expression levels increase competition between T cells', 'Scherer, Almut|Salathé, Marcel|Bonhoeffer, Sebastian', 'Theoretical Biology, Institute of Integrative Biology, Swiss Federal Institute of Technology, Zurich, Switzerland.|Theoretical Biology, Institute of Integrative Biology, Swiss Federal Institute of Technology, Zurich, Switzerland.|Theoretical Biology, Institute of Integrative Biology, Swiss Federal Institute of Technology, Zurich, Switzerland.', 'Switzerland|Switzerland|Switzerland', 19, 'Animals|Antigen Presentation|Cell Communication|Computer Simulation|Epitopes, T-Lymphocyte|Gene Expression|Gene Expression Regulation|Histocompatibility Antigens Class II|Humans|Models, Immunological|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.0020109', '16933984', 'Both theoretical predictions and experimental findings suggest that T cell populations can compete with each other. There is some debate on whether T cells compete for aspecific stimuli, such as access to the surface on antigen-presenting cells (APCs) or for specific stimuli, such as their cognate epitope ligand. We have developed an individual-based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell competition is mainly for specific or aspecific stimuli. Under low epitope expression, competition is mainly for the specific epitope stimuli, and, hence, different epitope-specific T cell populations coexist readily. However, if epitope expression levels are high, aspecific competition becomes more important. Such between-specificity competition can lead to competitive exclusion between different epitope-specific T cell populations. Our model allows us to delineate the circumstances that facilitate coexistence of T cells of different epitope specificity. Understanding mechanisms of T cell coexistence has important practical implications for immune therapies that require a broad immune response.'),
(83504, 2006, 'plos', 'Expansion of protein domain repeats', 'Björklund, Asa K|Ekman, Diana|Elofsson, Arne', 'Stockholm Bioinformatics Center, Center for Biomembrane Research, Stockholm University, Stockholm, Sweden.|Stockholm Bioinformatics Center, Center for Biomembrane Research, Stockholm University, Stockholm, Sweden.|Stockholm Bioinformatics Center, Center for Biomembrane Research, Stockholm University, Stockholm, Sweden.', 'Sweden|Sweden|Sweden', 166, 'Animals|Base Sequence|Conserved Sequence|Evolution, Molecular|Humans|Molecular Sequence Data|Protein Structure, Tertiary|Proteins|Repetitive Sequences, Nucleic Acid|Sequence Analysis', 'Journal Article', '10.1371/journal.pcbi.0020114', '16933986', 'Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e.g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.'),
(83505, 2006, 'plos', 'Evidence of influence of genomic DNA sequence on human X chromosome inactivation', 'Wang, Zhong|Willard, Huntington F|Mukherjee, Sayan|Furey, Terrence S', 'Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.|Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America.', 'United States|United States|United States|United States', 73, 'Base Sequence|Chromosomes, Human, X|Computational Biology|Genome, Human|Humans|Probability|Selection, Genetic|Transcription, Genetic|X Chromosome Inactivation', 'Journal Article', '10.1371/journal.pcbi.0020113', '16948528', 'A significant number of human X-linked genes escape X chromosome inactivation and are thus expressed from both the active and inactive X chromosomes. The basis for escape from inactivation and the potential role of the X chromosome primary DNA sequence in determining a genes X inactivation status is unclear. Using a combination of the X chromosome sequence and a comprehensive X inactivation profile of more than 600 genes, two independent yet complementary approaches were used to systematically investigate the relationship between X inactivation and DNA sequence features. First, statistical analyses revealed that a number of repeat features, including long interspersed nuclear element (LINE) and mammalian-wide interspersed repeat repetitive elements, are significantly enriched in regions surrounding transcription start sites of genes that are subject to inactivation, while Alu repetitive elements and short motifs containing ACG/CGT are significantly enriched in those that escape inactivation. Second, linear support vector machine classifiers constructed using primary DNA sequence features were used to correctly predict the X inactivation status for >80% of all X-linked genes. We further identified a small set of features that are important for accurate classification, among which LINE-1 and LINE-2 content show the greatest individual discriminatory power. Finally, as few as 12 features can be used for accurate support vector machine classification. Taken together, these results suggest that features of the underlying primary DNA sequence of the human X chromosome may influence the spreading and/or maintenance of X inactivation.'),
(83506, 2006, 'plos', 'Striking similarities in the genomic distribution of tandemly arrayed genes in Arabidopsis and rice', 'Rizzon, Carene|Ponger, Loic|Gaut, Brandon S', 'Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California, United States of America.|Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California, United States of America.|Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California, United States of America.', 'United States|United States|United States', 172, 'Arabidopsis|Chromosomes, Plant|Computational Biology|Computer Simulation|Genes, Duplicate|Genes, Plant|Genome, Plant|Genomics|Oryza|Recombination, Genetic|Sensitivity and Specificity', 'Comparative Study', '10.1371/journal.pcbi.0020115', '16948529', 'In Arabidopsis, tandemly arrayed genes (TAGs) comprise >10% of the genes in the genome. These duplicated genes represent a rich template for genetic innovation, but little is known of the evolutionary forces governing their generation and maintenance. Here we compare the organization and evolution of TAGs between Arabidopsis and rice, two plant genomes that diverged ~150 million years ago. TAGs from the two genomes are similar in a number of respects, including the proportion of genes that are tandemly arrayed, the number of genes within an array, the number of tandem arrays, and the dearth of TAGs relative to single copy genes in centromeric regions. Analysis of recombination rates along rice chromosomes confirms a positive correlation between the occurrence of TAGs and recombination rate, as found in Arabidopsis. TAGs are also biased functionally relative to duplicated, nontandemly arrayed genes. In both genomes, TAGs are enriched for genes that encode membrane proteins and function in abiotic and biotic stress but underrepresented for genes involved in transcription and DNA or RNA binding functions. We speculate that these observations reflect an evolutionary trend in which successful tandem duplication involves genes either at the end of biochemical pathways or in flexible steps in a pathway, for which fluctuation in copy number is unlikely to affect downstream genes. Despite differences in the age distribution of tandem arrays, the striking similarities between rice and Arabidopsis indicate similar mechanisms of TAG generation and maintenance.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83507, 2006, 'plos', 'Model-based design of growth-attenuated viruses', 'Lim, Kwang-Il|Lang, Tobias|Lam, Vy|Yin, John', 'Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.|Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|Cell Line|Computational Biology|Cricetinae|Genome, Viral|Mice|Models, Biological|Nucleocapsid|Promoter Regions, Genetic|Protein Biosynthesis|RNA, Messenger|Vaccines, Attenuated|Vesicular stomatitis Indiana virus|Viral Proteins|Viral Vaccines|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.0020116', '16948530', 'Live-virus vaccines activate both humoral and cell-mediated immunity, require only a single boosting, and generally provide longer immune protection than killed or subunit vaccines. However, growth of live-virus vaccines must be attenuated to minimize their potential pathogenic effects, and mechanisms of attenuation by conventional serial-transfer viral adaptation are not well-understood. New methods of attenuation based on rational engineering of viral genomes may offer a potentially greater control if one can link defined genetic modifications to changes in virus growth. To begin to establish such links between genotype and growth phenotype, we developed a computer model for the intracellular growth of vesicular stomatitis virus (VSV), a well-studied, nonsegmented, negative-stranded RNA virus. Our model incorporated established regulatory mechanisms of VSV while integrating key wild-type infection steps: hijacking of host resources, transcription, translation, and replication, followed by assembly and release of progeny VSV particles. Generalization of the wild-type model to allow for genome rearrangements matched the experimentally observed attenuation ranking for recombinant VSV strains that altered the genome position of their nucleocapsid gene. Finally, our simulations captured previously reported experimental results showing how altering the positions of other VSV genes has the potential to attenuate the VSV growth while overexpressing the immunogenic VSV surface glycoprotein. Such models will facilitate the engineering of new live-virus vaccines by linking genomic manipulations to controlled changes in virus gene-expression and growth.'),
(83508, 2006, 'plos', 'Scientific software development is not an oxymoron', 'Baxter, Susan M|Day, Steven W|Fetrow, Jacquelyn S|Reisinger, Stephanie J', 'National Center for Genome Resources, Santa Fe, New Mexico, United States of America. smb@ncgr.org|National Center for Genome Resources, Santa Fe, New Mexico, United States of America. smb@ncgr.org|National Center for Genome Resources, Santa Fe, New Mexico, United States of America. smb@ncgr.org|National Center for Genome Resources, Santa Fe, New Mexico, United States of America. smb@ncgr.org', 'Mexico|Mexico|Mexico|Mexico', 0, 'Research|Software Design', 'Journal Article', '10.1371/journal.pcbi.0020087', '16965174', '-'),
(83509, 2006, 'plos', 'Oscillatory regulation of Hes1: Discrete stochastic delay modelling and simulation', 'Barrio, Manuel|Burrage, Kevin|Leier, André|Tian, Tianhai', 'Departamento de Informática, Universidad de Valladolid, Valladolid, Spain. kb@maths.uq.edu.au|Departamento de Informática, Universidad de Valladolid, Valladolid, Spain. kb@maths.uq.edu.au|Departamento de Informática, Universidad de Valladolid, Valladolid, Spain. kb@maths.uq.edu.au|Departamento de Informática, Universidad de Valladolid, Valladolid, Spain. kb@maths.uq.edu.au', 'Spain|Spain|Spain|Spain', 0, 'Computational Biology|Computer Simulation|Gene Expression Regulation|Homeodomain Proteins|Models, Biological|Molecular Sequence Data|RNA, Messenger|Sensitivity and Specificity|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0020117', '16965175', 'Discrete stochastic simulations are a powerful tool for understanding the dynamics of chemical kinetics when there are small-to-moderate numbers of certain molecular species. In this paper we introduce delays into the stochastic simulation algorithm, thus mimicking delays associated with transcription and translation. We then show that this process may well explain more faithfully than continuous deterministic models the observed sustained oscillations in expression levels of hes1 mRNA and Hes1 protein.'),
(83510, 2006, 'plos', 'Imitating manual curation of text-mined facts in biomedicine', 'Rodriguez-Esteban, Raul|Iossifov, Ivan|Rzhetsky, Andrey', 'Department of Electrical Engineering, Columbia University, New York, New York, United States of America.|Department of Electrical Engineering, Columbia University, New York, New York, United States of America.|Department of Electrical Engineering, Columbia University, New York, New York, United States of America.', 'United States|United States|United States', 21, 'Abstracting and Indexing as Topic|Algorithms|Artificial Intelligence|Automation|Biomedical Research|Cocaine|Computational Biology|Computer Simulation|Sensitivity and Specificity', 'Journal Article', '10.1371/journal.pcbi.0020118', '16965176', 'Text-mining algorithms make mistakes in extracting facts from natural-language texts. In biomedical applications, which rely on use of text-mined data, it is critical to assess the quality (the probability that the message is correctly extracted) of individual facts--to resolve data conflicts and inconsistencies. Using a large set of almost 100,000 manually produced evaluations (most facts were independently reviewed more than once, producing independent evaluations), we implemented and tested a collection of algorithms that mimic human evaluation of facts provided by an automated information-extraction system. The performance of our best automated classifiers closely approached that of our human evaluators (ROC score close to 0.95). Our hypothesis is that, were we to use a larger number of human experts to evaluate any given sentence, we could implement an artificial-intelligence curator that would perform the classification job at least as accurately as an average individual human evaluator. We illustrated our analysis by visualizing the predicted accuracy of the text-mined relations involving the term cocaine.'),
(83511, 2006, 'plos', 'Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation', 'Lindskog, Maria|Kim, MyungSook|Wikström, Martin A|Blackwell, Kim T|Kotaleski, Jeanette Hellgren', 'School of Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden.|School of Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden.|School of Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden.|School of Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden.|School of Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden.', 'Sweden|Sweden|Sweden|Sweden|Sweden', 78, 'Calcium|Computational Biology|Computer Simulation|Cyclic AMP-Dependent Protein Kinases|Dopamine|Dopamine and cAMP-Regulated Phosphoprotein 32|Models, Biological|Phosphorylation|Phosphothreonine|Protein Binding|Second Messenger Systems', 'Journal Article', '10.1371/journal.pcbi.0020119', '16965177', 'Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.'),
(83512, 2006, 'plos', 'Modeling of oxygen transport and cellular energetics explains observations on in vivo cardiac energy metabolism', 'Beard, Daniel A', 'Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America. dbeard@mcw.edu', 'United States', 0, 'Adenosine Triphosphate|Biological Transport|Computational Biology|Computer Simulation|Cytosol|Energy Metabolism|Mitochondria|Models, Biological|Myocardium|Myoglobin|Oxygen|Phosphates', 'Journal Article', '10.1371/journal.pcbi.0020107', '16978045', 'Observations on the relationship between cardiac work rate and the levels of energy metabolites adenosine triphosphate (ATP), adenosine diphosphate (ADP), and phosphocreatine (CrP) have not been satisfactorily explained by theoretical models of cardiac energy metabolism. Specifically, the in vivo stability of ATP, ADP, and CrP levels in response to changes in work and respiratory rate has eluded explanation. Here a previously developed model of mitochondrial oxidative phosphorylation, which was developed based on data obtained from isolated cardiac mitochondria, is integrated with a spatially distributed model of oxygen transport in the myocardium to analyze data obtained from several laboratories over the past two decades. The model includes the components of the respiratory chain, the F0F1-ATPase, adenine nucleotide translocase, and the mitochondrial phosphate transporter at the mitochondrial level, adenylate kinase, creatine kinase, and ATP consumption in the cytoplasm, and oxygen transport between capillaries, interstitial fluid, and cardiomyocytes. The integrated model is able to reproduce experimental observations on ATP, ADP, CrP, and inorganic phosphate levels in canine hearts over a range of workload and during coronary hypoperfusion and predicts that cytoplasmic inorganic phosphate level is a key regulator of the rate of mitochondrial respiration at workloads for which the rate of cardiac oxygen consumption is less than or equal to approximately 12 mumol per minute per gram of tissue. At work rates corresponding to oxygen consumption higher than 12 mumol min(-1) g(-1), model predictions deviate from the experimental data, indicating that at high work rates, additional regulatory mechanisms that are not currently incorporated into the model may be important. Nevertheless, the integrated model explains metabolite levels observed at low to moderate workloads and the changes in metabolite levels and tissue oxygenation observed during graded hypoperfusion. These findings suggest that the observed stability of energy metabolites emerges as a property of a properly constructed model of cardiac substrate transport and mitochondrial metabolism. In addition, the validated model provides quantitative predictions of changes in phosphate metabolites during cardiac ischemia.'),
(83513, 2006, 'plos', 'Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability', 'Legewie, Stefan|Blüthgen, Nils|Herzel, Hanspeter', 'Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de|Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de', 'Germany|Germany|Germany', 156, 'Apoptosis|Caspase Inhibitors|Caspases|Computational Biology|Computer Simulation|Enzyme Activation|Feedback, Physiological|Inhibitor of Apoptosis Proteins|Kinetics|Mitochondria|Models, Biological|Molecular Sequence Data|Signal Transduction|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020120', '16978046', 'The intrinsic, or mitochondrial, pathway of caspase activation is essential for apoptosis induction by various stimuli including cytotoxic stress. It depends on the cellular context, whether cytochrome c released from mitochondria induces caspase activation gradually or in an all-or-none fashion, and whether caspase activation irreversibly commits cells to apoptosis. By analyzing a quantitative kinetic model, we show that inhibition of caspase-3 (Casp3) and Casp9 by inhibitors of apoptosis (IAPs) results in an implicit positive feedback, since cleaved Casp3 augments its own activation by sequestering IAPs away from Casp9. We demonstrate that this positive feedback brings about bistability (i.e., all-or-none behaviour), and that it cooperates with Casp3-mediated feedback cleavage of Casp9 to generate irreversibility in caspase activation. Our calculations also unravel how cell-specific protein expression brings about the observed qualitative differences in caspase activation (gradual versus all-or-none and reversible versus irreversible). Finally, known regulators of the pathway are shown to efficiently shift the apoptotic threshold stimulus, suggesting that the bistable caspase cascade computes multiple inputs into an all-or-none caspase output. As cellular inhibitory proteins (e.g., IAPs) frequently inhibit consecutive intermediates in cellular signaling cascades (e.g., Casp3 and Casp9), the feedback mechanism described in this paper is likely to be a widespread principle on how cells achieve ultrasensitivity, bistability, and irreversibility.'),
(83514, 2006, 'plos', 'Intricate knots in proteins: Function and evolution', 'Virnau, Peter|Mirny, Leonid A|Kardar, Mehran', 'Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. virnau@mit.edu|Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. virnau@mit.edu|Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. virnau@mit.edu', 'United States|United States|United States', 219, 'Bacterial Proteins|Computational Biology|Cysteine Endopeptidases|Databases, Genetic|Evolution, Molecular|Humans|Models, Molecular|Protein Binding|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.0020122', '16978047', 'Our investigation of knotted structures in the Protein Data Bank reveals the most complicated knot discovered to date. We suggest that the occurrence of this knot in a human ubiquitin hydrolase might be related to the role of the enzyme in protein degradation. While knots are usually preserved among homologues, we also identify an exception in a transcarbamylase. This allows us to exemplify the function of knots in proteins and to suggest how they may have been created.'),
(83515, 2006, 'plos', 'Transcriptional dynamics of the embryonic stem cell switch', 'Chickarmane, Vijay|Troein, Carl|Nuber, Ulrike A|Sauro, Herbert M|Peterson, Carsten', 'Keck Graduate Institute, Claremont, California, United States of America.|Keck Graduate Institute, Claremont, California, United States of America.|Keck Graduate Institute, Claremont, California, United States of America.|Keck Graduate Institute, Claremont, California, United States of America.|Keck Graduate Institute, Claremont, California, United States of America.', 'United States|United States|United States|United States|United States', 185, 'Animals|Computational Biology|Computer Simulation|Embryonic Stem Cells|Gene Regulatory Networks|High Mobility Group Proteins|Homeodomain Proteins|Humans|Models, Biological|Octamer Transcription Factor-3|Phylogeny|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020123', '16978048', 'Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched on/off by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is on, the self-renewal genes are on and the differentiation genes are off. The opposite holds when the switch is off. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains on even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG.'),
(83516, 2006, 'plos', 'Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy', 'Mac Gabhann, Feilim|Ji, James W|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|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. feilim@jhu.edu', 'United States|United States|United States', 0, 'Cell- and Tissue-Based Therapy|Computational Biology|Computer Simulation|Heparan Sulfate Proteoglycans|Kinetics|Models, Biological|Muscle, Skeletal|Neovascularization, Physiologic|Protein Binding|Protein Transport|Receptors, Vascular Endothelial Growth Factor|Sensitivity and Specificity|Up-Regulation|Vascular Endothelial Growth Factor A', 'Journal Article', '10.1371/journal.pcbi.0020127', '17002494', 'Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers, binding to the extracellular matrix, binding to and activation of endothelial cell surface VEGF receptors, and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 mum) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 mum) is sufficient for cellular sensing, the tip cell of a vessel sprout is approximately 50 mum long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches.'),
(83517, 2006, 'plos', 'Sampling realistic protein conformations using local structural bias', 'Hamelryck, Thomas|Kent, John T|Krogh, Anders', 'Bioinformatics Center, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark. thamelry@binf.ku.dk|Bioinformatics Center, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark. thamelry@binf.ku.dk|Bioinformatics Center, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark. thamelry@binf.ku.dk', 'Denmark|Denmark|Denmark', 67, 'Amino Acid Sequence|Computational Biology|Computer Simulation|Models, Molecular|Probability|Protein Structure, Secondary|Protein Structure, Tertiary|Proteins', 'Journal Article', '10.1371/journal.pcbi.0020131', '17002495', 'The prediction of protein structure from sequence remains a major unsolved problem in biology. The most successful protein structure prediction methods make use of a divide-and-conquer strategy to attack the problem: a conformational sampling method generates plausible candidate structures, which are subsequently accepted or rejected using an energy function. Conceptually, this often corresponds to separating local structural bias from the long-range interactions that stabilize the compact, native state. However, sampling protein conformations that are compatible with the local structural bias encoded in a given protein sequence is a long-standing open problem, especially in continuous space. We describe an elegant and mathematically rigorous method to do this, and show that it readily generates native-like protein conformations simply by enforcing compactness. Our results have far-reaching implications for protein structure prediction, determination, simulation, and design.'),
(83518, 2006, 'plos', 'Ten simple rules for reviewers', 'Bourne, Philip E|Korngreen, Alon', 'Bioinformatics Center, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark. thamelry@binf.ku.dk|Bioinformatics Center, Institute of Molecular Biology and Physiology, University of Copenhagen, Copenhagen, Denmark. thamelry@binf.ku.dk', 'Denmark|Denmark', 22, 'Authorship|Conflict of Interest|Peer Review, Research|Time Factors', 'Editorial', '10.1371/journal.pcbi.0020110', '17009861', '-'),
(83519, 2006, 'plos', 'The many faces of protein-protein interactions: A compendium of interface geometry', 'Kim, Wan Kyu|Henschel, Andreas|Winter, Christof|Schroeder, Michael', 'Bioinformatics Group, Biotechnological Centre, Technische Universität Dresden, Dresden, Germany.|Bioinformatics Group, Biotechnological Centre, Technische Universität Dresden, Dresden, Germany.|Bioinformatics Group, Biotechnological Centre, Technische Universität Dresden, Dresden, Germany.|Bioinformatics Group, Biotechnological Centre, Technische Universität Dresden, Dresden, Germany.', 'Germany|Germany|Germany|Germany', 89, 'Amino Acid Sequence|Binding Sites|Computational Biology|Databases, Genetic|Dimerization|Gene Fusion|Models, Molecular|Molecular Sequence Data|Protein Binding|Protein Structure, Quaternary|Proteins|Sequence Alignment|Structural Homology, Protein', 'Journal Article', '10.1371/journal.pcbi.0020124', '17009862', 'A systematic classification of protein-protein interfaces is a valuable resource for understanding the principles of molecular recognition and for modelling protein complexes. Here, we present a classification of domain interfaces according to their geometry. Our new algorithm uses a hybrid approach of both sequential and structural features. The accuracy is evaluated on a hand-curated dataset of 416 interfaces. Our hybrid procedure achieves 83% precision and 95% recall, which improves the earlier sequence-based method by 5% on both terms. We classify virtually all domain interfaces of known structure, which results in nearly 6,000 distinct types of interfaces. In 40% of the cases, the interacting domain families associate in multiple orientations, suggesting that all the possible binding orientations need to be explored for modelling multidomain proteins and protein complexes. In general, hub proteins are shown to use distinct surface regions (multiple faces) for interactions with different partners. Our classification provides a convenient framework to query genuine gene fusion, which conserves binding orientation in both fused and separate forms. The result suggests that the binding orientations are not conserved in at least one-third of the gene fusion cases detected by a conventional sequence similarity search. We show that any evolutionary analysis on interfaces can be skewed by multiple binding orientations and multiple interaction partners. The taxonomic distribution of interface types suggests that ancient interfaces common to the three major kingdoms of life are enriched by symmetric homodimers. The classification results are online at http://www.scoppi.org.'),
(83520, 2006, 'plos', 'Can transgenic maize affect soil microbial communities?', 'Mulder, Christian|Wouterse, Marja|Raubuch, Markus|Roelofs, Willem|Rutgers, Michiel', 'Laboratory for Ecological Risk Assessment, National Institute for Public Health and the Environment, Bilthoven, Netherlands. christian.mulder@rivm.nl|Laboratory for Ecological Risk Assessment, National Institute for Public Health and the Environment, Bilthoven, Netherlands. christian.mulder@rivm.nl|Laboratory for Ecological Risk Assessment, National Institute for Public Health and the Environment, Bilthoven, Netherlands. christian.mulder@rivm.nl|Laboratory for Ecological Risk Assessment, National Institute for Public Health and the Environment, Bilthoven, Netherlands. christian.mulder@rivm.nl|Laboratory for Ecological Risk Assessment, National Institute for Public Health and the Environment, Bilthoven, Netherlands. christian.mulder@rivm.nl', 'Netherlands|Netherlands|Netherlands|Netherlands|Netherlands', 0, 'Carbon|Plants, Genetically Modified|Soil Microbiology|Zea mays', 'Journal Article', '10.1371/journal.pcbi.0020128', '17009863', 'The aim of the experiment was to determine if temporal variations of belowground activity reflect the influence of the Cry1Ab protein from transgenic maize on soil bacteria and, hence, on a regulatory change of the microbial community (ability to metabolize sources belonging to different chemical guilds) and/or a change in numerical abundance of their cells. Litter placement is known for its strong influence on the soil decomposer communities. The effects of the addition of crop residues on respiration and catabolic activities of the bacterial community were examined in microcosm experiments. Four cultivars of Zea mays L. of two different isolines (each one including the conventional crop and its Bacillus thuringiensis cultivar) and one control of bulk soil were included in the experimental design. The growth models suggest a dichotomy between soils amended with either conventional or transgenic maize residues. The Cry1Ab protein appeared to influence the composition of the microbial community. The highly enhanced soil respiration observed during the first 72 h after the addition of Bt-maize residues can be interpreted as being related to the presence of the transgenic crop residues. This result was confirmed by agar plate counting, as the averages of the colony-forming units of soils in conventional treatments were about one-third of those treated with transgenic straw. Furthermore, the addition of Bt-maize appeared to induce increased microbial consumption of carbohydrates in BIOLOG EcoPlates. Three weeks after the addition of maize residues to the soils, no differences between the consumption rate of specific chemical guilds by bacteria in soils amended with transgenic maize and bacteria in soils amended with conventional maize were detectable. Reaped crop residues, comparable to post-harvest maize straw (a common practice in current agriculture), rapidly influence the soil bacterial cells at a functional level. Overall, these data support the existence of short Bt-induced ecological shifts in the microbial communities of croplands soils.'),
(83521, 2006, 'plos', 'Phylogenetic reconstruction of orthology, paralogy, and conserved synteny for dog and human', 'Goodstadt, Leo|Ponting, Chris P', 'Medical Research Council Functional Genetics Unit, University of Oxford, Department of Physiology, Anatomy, and Genetics, Oxford, United Kingdom. leo.goodstadt@anat.ox.ac.uk|Medical Research Council Functional Genetics Unit, University of Oxford, Department of Physiology, Anatomy, and Genetics, Oxford, United Kingdom. leo.goodstadt@anat.ox.ac.uk', 'United Kingdom|United Kingdom', 0, 'Animals|Chromosomes, Mammalian|Computational Biology|Dogs|Female|Genome|Humans|Male|Pedigree|Phylogeny|Synteny|Transcription, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020133', '17009864', 'Accurate predictions of orthology and paralogy relationships are necessary to infer human molecular function from experiments in model organisms. Previous genome-scale approaches to predicting these relationships have been limited by their use of protein similarity and their failure to take into account multiple splicing events and gene prediction errors. We have developed PhyOP, a new phylogenetic orthology prediction pipeline based on synonymous rate estimates, which accurately predicts orthology and paralogy relationships for transcripts, genes, exons, or genomic segments between closely related genomes. We were able to identify orthologue relationships to human genes for 93% of all dog genes from Ensembl. Among 1:1 orthologues, the alignments covered a median of 97.4% of protein sequences, and 92% of orthologues shared essentially identical gene structures. PhyOP accurately recapitulated genomic maps of conserved synteny. Benchmarking against predictions from Ensembl and Inparanoid showed that PhyOP is more accurate, especially in its predictions of paralogy. Nearly half (46%) of PhyOP paralogy predictions are unique. Using PhyOP to investigate orthologues and paralogues in the human and dog genomes, we found that the human assembly contains 3-fold more gene duplications than the dog. Species-specific duplicate genes, or in-paralogues, are generally shorter and have fewer exons than 1:1 orthologues, which is consistent with selective constraints and mutation biases based on the sizes of duplicated genes. In-paralogues have experienced elevated amino acid and synonymous nucleotide substitution rates. Duplicates possess similar biological functions for either the dog or human lineages. Having accounted for 2,954 likely pseudogenes and gene fragments, and after separating 346 erroneously merged genes, we estimated that the human genome encodes a minimum of 19,700 protein-coding genes, similar to the gene count of nematode worms. PhyOP is a fast and robust approach to orthology prediction that will be applicable to whole genomes from multiple closely related species. PhyOP will be particularly useful in predicting orthology for mammalian genomes that have been incompletely sequenced, and for large families of rapidly duplicating genes.'),
(83522, 2006, 'plos', 'Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors', 'Cheng, Xiaolin|Wang, Hailong|Grant, Barry|Sine, Steven M|McCammon, J Andrew', 'Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. xcheng@mccammon.ucsd.edu|Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. xcheng@mccammon.ucsd.edu|Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. xcheng@mccammon.ucsd.edu|Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. xcheng@mccammon.ucsd.edu|Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America. xcheng@mccammon.ucsd.edu', 'United States|United States|United States|United States|United States', 0, 'Amino Acid Sequence|Animals|Arginine|Cell Membrane|Computational Biology|Computer Simulation|Conserved Sequence|Glutamic Acid|Humans|Hydrogen Bonding|Ion Channel Gating|Ligands|Models, Molecular|Molecular Sequence Data|Protein Structure, Quaternary|Protein Structure, Tertiary|Receptors, Nicotinic|Sequence Alignment|Structural Homology, Protein|Water', 'Journal Article', '10.1371/journal.pcbi.0020134', '17009865', 'The initial coupling between ligand binding and channel gating in the human alpha7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo- and ligand-bound AChBP structures shows only minor rearrangements distal from the ligand-binding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the alpha7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding.'),
(83523, 2006, 'plos', 'Simulating properties of in vitro epithelial cell morphogenesis', 'Grant, Mark R|Mostov, Keith E|Tlsty, Thea D|Hunt, C Anthony', 'University of California San Francisco/University of California Berkeley Joint Graduate Group in Bioengineering, University of California Berkeley, Berkeley, California, United States of America.|University of California San Francisco/University of California Berkeley Joint Graduate Group in Bioengineering, University of California Berkeley, Berkeley, California, United States of America.|University of California San Francisco/University of California Berkeley Joint Graduate Group in Bioengineering, University of California Berkeley, Berkeley, California, United States of America.|University of California San Francisco/University of California Berkeley Joint Graduate Group in Bioengineering, University of California Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States|United States', 54, 'Cell Shape|Computational Biology|Computer Simulation|Epithelial Cells|Models, Biological|Phenotype', 'Journal Article', '10.1371/journal.pcbi.0020129', '17029556', 'How do individual epithelial cells (ECs) organize into multicellular structures? ECs are studied in vitro to help answer that question. Characteristic growth features include stable cyst formation in embedded culture, inverted cyst formation in suspension culture, and lumen formation in overlay culture. Formation of these characteristic structures is believed to be a consequence of an intrinsic program of differentiation and de-differentiation. To help discover how such a program may function, we developed an in silico analogue in which space, events, and time are discretized. Software agents and objects represent cells and components of the environment. Cells act independently. The program governing their behavior is embedded within each in the form of axioms and an inflexible decisional process. Relationships between the axioms and recognized cell functions are specified. Interactions between cells and environment components during simulation give rise to a complex in silico phenotype characterized by context-dependent structures that mimic counterparts observed in four different in vitro culture conditions: a targeted set of in vitro phenotypic attributes was matched by in silico attributes. However, for a particular growth condition, the analogue failed to exhibit behaviors characteristic of functionally polarized ECs. We solved this problem by following an iterative refinement method that improved the first analogue and led to a second: it exhibited characteristic differentiation and growth properties in all simulated growth conditions. It is the first model to simultaneously provide a representation of nonpolarized and structurally polarized cell types, and a mechanism for their interconversion. The second analogue also uses an inflexible axiomatic program. When specific axioms are relaxed, growths strikingly characteristic of cancerous and precancerous lesions are observed. In one case, the simulated cause is aberrant matrix production. Analogue design facilitates gaining deeper insight into such phenomena by making it easy to replace low-resolution components with increasingly detailed and realistic components.'),
(83524, 2006, 'plos', 'Natural biocombinatorics in the polyketide synthase genes of the actinobacterium Streptomyces avermitilis', 'Jenke-Kodama, Holger|Börner, Thomas|Dittmann, Elke', 'Department of Molecular Ecology, Institute of Biology, Humboldt University, Berlin, Germany.|Department of Molecular Ecology, Institute of Biology, Humboldt University, Berlin, Germany.|Department of Molecular Ecology, Institute of Biology, Humboldt University, Berlin, Germany.', 'Germany|Germany|Germany', 84, 'Computational Biology|Macrolides|Molecular Structure|Multigene Family|Phylogeny|Polyketide Synthases|Recombination, Genetic|Streptomyces', 'Journal Article', '10.1371/journal.pcbi.0020132', '17029557', 'Modular polyketide synthases (PKSs) of bacteria provide an enormous reservoir of natural chemical diversity. Studying natural biocombinatorics may aid in the development of concepts for experimental design of genes for the biosynthesis of new bioactive compounds. Here we address the question of how the modularity of biosynthetic enzymes and the prevalence of multiple gene clusters in Streptomyces drive the evolution of metabolic diversity. The phylogeny of ketosynthase (KS) domains of Streptomyces PKSs revealed that the majority of modules involved in the biosynthesis of a single compound evolved by duplication of a single ancestor module. Using Streptomyces avermitilis as a model organism, we have reconstructed the evolutionary relationships of different domain types. This analysis suggests that 65% of the modules were altered by recombinational replacements that occurred within and between biosynthetic gene clusters. The natural reprogramming of the biosynthetic pathways was unambiguously confined to domains that account for the structural diversity of the polyketide products and never observed for the KS domains. We provide examples for natural acyltransferase (AT), ketoreductase (KR), and dehydratase (DH)-KR domain replacements. Potential sites of homologous recombination could be identified in interdomain regions and within domains. Our results indicate that homologous recombination facilitated by the modularity of PKS architecture is the most important mechanism underlying polyketide diversity in bacteria.'),
(83525, 2006, 'plos', 'Large-scale turnover of functional transcription factor binding sites in Drosophila', 'Moses, Alan M|Pollard, Daniel A|Nix, David A|Iyer, Venky N|Li, Xiao-Yong|Biggin, Mark D|Eisen, Michael B', 'Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.|Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.|Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.|Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.|Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.|Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.|Graduate Group in Biophysics, University of California Berkeley, Berkeley, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States', 169, 'Animals|Base Sequence|Binding Sites|Computational Biology|Conserved Sequence|DNA, Intergenic|DNA-Binding Proteins|Drosophila Proteins|Drosophila melanogaster|Evolution, Molecular|Models, Genetic|Molecular Sequence Data|Promoter Regions, Genetic|Response Elements|Selection, Genetic|Sequence Alignment|Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0020130', '17040121', 'The gain and loss of functional transcription factor binding sites has been proposed as a major source of evolutionary change in cis-regulatory DNA and gene expression. We have developed an evolutionary model to study binding-site turnover that uses multiple sequence alignments to assess the evolutionary constraint on individual binding sites, and to map gain and loss events along a phylogenetic tree. We apply this model to study the evolutionary dynamics of binding sites of the Drosophila melanogaster transcription factor Zeste, using genome-wide in vivo (ChIP-chip) binding data to identify functional Zeste binding sites, and the genome sequences of D. melanogaster, D. simulans, D. erecta, and D. yakuba to study their evolution. We estimate that more than 5% of functional Zeste binding sites in D. melanogaster were gained along the D. melanogaster lineage or lost along one of the other lineages. We find that Zeste-bound regions have a reduced rate of binding-site loss and an increased rate of binding-site gain relative to flanking sequences. Finally, we show that binding-site gains and losses are asymmetrically distributed with respect to D. melanogaster, consistent with lineage-specific acquisition and loss of Zeste-responsive regulatory elements.'),
(83526, 2006, 'plos', 'Viral and latent reservoir persistence in HIV-1-infected patients on therapy', 'Kim, Hwijin|Perelson, Alan S', 'Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.', 'Mexico|Mexico', 0, 'Cell Proliferation|Computational Biology|Computer Simulation|HIV Infections|HIV-1|Humans|Kinetics|Models, Biological|T-Lymphocytes|Virus Latency|Virus Replication', 'Journal Article', '10.1371/journal.pcbi.0020135', '17040122', 'Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation, the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the critical efficacy irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence.');
INSERT INTO `papers` (`id`, `ano`, `journal`, `titulo`, `autores`, `afiliacao`, `pais`, `citacoes`, `palavra_chave`, `categorias`, `doi`, `pubmed`, `abstract`) VALUES
(83527, 2006, 'plos', 'Quantitative analyses of circadian gene expression in mammalian cell cultures', 'Izumo, Mariko|Sato, Takashi R|Straume, Martin|Johnson, Carl Hirschie', 'Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America.', 'United States|United States|United States|United States', 0, 'Animals|CLOCK Proteins|Cell Line|Circadian Rhythm|Colforsin|Dexamethasone|Gene Expression Profiling|Genes, Reporter|Kinetics|Promoter Regions, Genetic|Rats|Trans-Activators', 'Journal Article', '10.1371/journal.pcbi.0020136', '17040123', 'The central circadian pacemaker is located in the hypothalamus of mammals, but essentially the same oscillating system operates in peripheral tissues and even in immortalized cell lines. Using luciferase reporters that allow automated monitoring of circadian gene expression in mammalian fibroblasts, we report the collection and analysis of precise rhythmic data from these cells. We use these methods to analyze signaling pathways of peripheral tissues by studying the responses of Rat-1 fibroblasts to ten different compounds. To quantify these rhythms, which show significant variation and large non-stationarities (damping and baseline drifting), we developed a new fast Fourier transform-nonlinear least squares analysis procedure that specifically optimizes the quantification of amplitude for circadian rhythm data. This enhanced analysis method successfully distinguishes among the ten signaling compounds for their rhythm-inducing properties. We pursued detailed analyses of the responses to two of these compounds that induced the highest amplitude rhythms in fibroblasts, forskolin (an activator of adenylyl cyclase), and dexamethasone (an agonist of glucocorticoid receptors). Our quantitative analyses clearly indicate that the synchronization mechanisms by the cAMP and glucocorticoid pathways are different, implying that actions of different genes stimulated by these pathways lead to distinctive programs of circadian synchronization.'),
(83528, 2006, 'plos', 'The role of compensatory mutations in the emergence of drug resistance', 'Handel, Andreas|Regoes, Roland R|Antia, Rustom', 'Department of Biology, Emory University, Atlanta, Georgia, United States of America. ahandel@emory.edu|Department of Biology, Emory University, Atlanta, Georgia, United States of America. ahandel@emory.edu|Department of Biology, Emory University, Atlanta, Georgia, United States of America. ahandel@emory.edu', 'Georgia|Georgia|Georgia', 76, 'Computational Biology|Drug Resistance|Models, Biological|Mutation|Probability|Stochastic Processes|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020137', '17040124', 'Pathogens that evolve resistance to drugs usually have reduced fitness. However, mutations that largely compensate for this reduction in fitness often arise. We investigate how these compensatory mutations affect population-wide resistance emergence as a function of drug treatment. Using a model of gonorrhea transmission dynamics, we obtain generally applicable, qualitative results that show how compensatory mutations lead to more likely and faster resistance emergence. We further show that resistance emergence depends on the level of drug use in a strongly nonlinear fashion. We also discuss what data need to be obtained to allow future quantitative predictions of resistance emergence.'),
(83529, 2006, 'plos', 'The transcriptional regulator CBP has defined spatial associations within interphase nuclei', 'McManus, Kirk J|Stephens, David A|Adams, Niall M|Islam, Suhail A|Freemont, Paul S|Hendzel, Michael J', 'Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.|Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.|Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.|Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.|Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.|Department of Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada', 0, 'Acetylation|Animals|CREB-Binding Protein|Cell Compartmentation|Cell Cycle Proteins|Cell Line|Cell Nucleus|Chromatin|Histone Acetyltransferases|Histones|Interphase|Mice|Muntjacs|Protein Transport|Transcription Factors|Transcription, Genetic|p300-CBP Transcription Factors', 'Journal Article', '10.1371/journal.pcbi.0020139', '17054391', 'It is becoming increasingly clear that nuclear macromolecules and macromolecular complexes are compartmentalized through binding interactions into an apparent three-dimensionally ordered structure. This ordering, however, does not appear to be deterministic to the extent that chromatin and nonchromatin structures maintain a strict 3-D arrangement. Rather, spatial ordering within the cell nucleus appears to conform to stochastic rather than deterministic spatial relationships. The stochastic nature of organization becomes particularly problematic when any attempt is made to describe the spatial relationship between proteins involved in the regulation of the genome. The CREB-binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume. Markers for euchromatic sequences have similar patterns. Surprisingly, in most cases, the predicted one-to-one relationship between transcription factor and chromatin sequence is not observed. Consequently, to understand whether spatial relationships that are not coincident are nonrandom and potentially biologically important, it is necessary to develop statistical approaches. In this study, we report on the development of such an approach and apply it to understanding the role of CBP in mediating chromatin modification and transcriptional regulation. We have used nearest-neighbor distance measurements and probability analyses to study the spatial relationship between CBP and other nuclear subcompartments enriched in transcription factors, chromatin, and splicing factors. Our results demonstrate that CBP has an order of spatial association with other nuclear subcompartments. We observe closer associations between CBP and RNA polymerase II-enriched foci and SC35 speckles than nascent RNA or specific acetylated histones. Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12. This study demonstrates that complex relationships not described by colocalization exist in the interphase nucleus and can be characterized and quantified. The subnuclear distribution of CBP is difficult to reconcile with a model where chromatin organization is the sole determinant of the nuclear organization of proteins that regulate transcription but is consistent with a close link between spatial associations and nuclear functions.'),
(83530, 2006, 'plos', 'Cooperation prevails when individuals adjust their social ties', 'Santos, Francisco C|Pacheco, Jorge M|Lenaerts, Tom', 'Computer and Decision Engineering Department, Institut de Recherches Interdisciplinaires et de Développements en Intelligence Artificielle, Université Libre de Bruxelles, Brussels, Belgium.|Computer and Decision Engineering Department, Institut de Recherches Interdisciplinaires et de Développements en Intelligence Artificielle, Université Libre de Bruxelles, Brussels, Belgium.|Computer and Decision Engineering Department, Institut de Recherches Interdisciplinaires et de Développements en Intelligence Artificielle, Université Libre de Bruxelles, Brussels, Belgium.', 'Belgium|Belgium|Belgium', 364, 'Biological Evolution|Computer Simulation|Cooperative Behavior|Game Theory|Humans|Models, Biological|Selection, Genetic|Social Behavior', 'Journal Article', '10.1371/journal.pcbi.0020140', '17054392', 'Conventional evolutionary game theory predicts that natural selection favours the selfish and strong even though cooperative interactions thrive at all levels of organization in living systems. Recent investigations demonstrated that a limiting factor for the evolution of cooperative interactions is the way in which they are organized, cooperators becoming evolutionarily competitive whenever individuals are constrained to interact with few others along the edges of networks with low average connectivity. Despite this insight, the conundrum of cooperation remains since recent empirical data shows that real networks exhibit typically high average connectivity and associated single-to-broad-scale heterogeneity. Here, a computational model is constructed in which individuals are able to self-organize both their strategy and their social ties throughout evolution, based exclusively on their self-interest. We show that the entangled evolution of individual strategy and network structure constitutes a key mechanism for the sustainability of cooperation in social networks. For a given average connectivity of the population, there is a critical value for the ratio W between the time scales associated with the evolution of strategy and of structure above which cooperators wipe out defectors. Moreover, the emerging social networks exhibit an overall heterogeneity that accounts very well for the diversity of patterns recently found in acquired data on social networks. Finally, heterogeneity is found to become maximal when W reaches its critical value. These results show that simple topological dynamics reflecting the individual capacity for self-organization of social ties can produce realistic networks of high average connectivity with associated single-to-broad-scale heterogeneity. On the other hand, they show that cooperation cannot evolve as a result of social viscosity alone in heterogeneous networks with high average connectivity, requiring the additional mechanism of topological co-evolution to ensure the survival of cooperative behaviour.'),
(83531, 2006, 'plos', 'From bad to good: Fitness reversals and the ascent of deleterious mutations', 'Cowperthwaite, Matthew C|Bull, J J|Meyers, Lauren Ancel', 'The Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America. mattccowp@mac.com|The Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America. mattccowp@mac.com|The Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America. mattccowp@mac.com', 'United States|United States|United States', 28, 'Adaptation, Biological|Computer Simulation|Evolution, Molecular|Genotype|Models, Genetic|Mutation|Probability|Selection, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020141', '17054393', 'Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10(-5) of all mutations).'),
(83532, 2006, 'plos', 'A biocurator perspective: annotation at the Research Collaboratory for Structural Bioinformatics Protein Data Bank', 'Burkhardt, Kyle|Schneider, Bohdan|Ory, Jeramia', 'National Center for Biotechnology Information, United States of America. kyle@rcsb.rutgers.edu|National Center for Biotechnology Information, United States of America. kyle@rcsb.rutgers.edu|National Center for Biotechnology Information, United States of America. kyle@rcsb.rutgers.edu', 'United States|United States|United States', 0, 'Abstracting and Indexing as Topic|Amino Acid Sequence|Computational Biology|Cooperative Behavior|Database Management Systems|Databases, Protein|Documentation|Molecular Sequence Data|Proteins|Research|Structure-Activity Relationship', 'Journal Article', '10.1371/journal.pcbi.0020099', '17069453', '-'),
(83533, 2006, 'plos', 'The biocurator: connecting and enhancing scientific data', 'Salimi, Nima|Vita, Randi', 'National Center for Biotechnology Information, United States of America.|National Center for Biotechnology Information, United States of America.', 'United States|United States', 0, 'Abstracting and Indexing as Topic|Amino Acid Sequence|Database Management Systems|Databases, Protein|Documentation|Epitope Mapping|Epitopes|Information Storage and Retrieval|Molecular Sequence Data|Science', 'Journal Article', '10.1371/journal.pcbi.0020125', '17069454', '-'),
(83534, 2006, 'plos', 'Mapping information flow in sensorimotor networks', 'Lungarella, Max|Sporns, Olaf', 'Department of Mechano-Informatics, The University of Tokyo, Tokyo, Japan. maxl@isi.imi.i.u-tokyo.ac.jp|Department of Mechano-Informatics, The University of Tokyo, Tokyo, Japan. maxl@isi.imi.i.u-tokyo.ac.jp', 'Japan|Japan', 0, 'Biomimetics|Humans|Information Storage and Retrieval|Motor Cortex|Movement|Nerve Net|Robotics|Sensation|Somatosensory Cortex', 'Journal Article', '10.1371/journal.pcbi.0020144', '17069456', 'Biological organisms continuously select and sample information used by their neural structures for perception and action, and for creating coherent cognitive states guiding their autonomous behavior. Information processing, however, is not solely an internal function of the nervous system. Here we show, instead, how sensorimotor interaction and body morphology can induce statistical regularities and information structure in sensory inputs and within the neural control architecture, and how the flow of information between sensors, neural units, and effectors is actively shaped by the interaction with the environment. We analyze sensory and motor data collected from real and simulated robots and reveal the presence of information structure and directed information flow induced by dynamically coupled sensorimotor activity, including effects of motor outputs on sensory inputs. We find that information structure and information flow in sensorimotor networks (a) is spatially and temporally specific, (b) can be affected by learning, and (c) can be affected by changes in body morphology. Our results suggest a fundamental link between physical embeddedness and information, highlighting the effects of embodied interactions on internal (neural) information processing, and illuminating the role of various system components on the generation of behavior.'),
(83535, 2006, 'plos', 'Ab initio modeling of the herpesvirus VP26 core domain assessed by CryoEM density', 'Baker, Matthew L|Jiang, Wen|Wedemeyer, William J|Rixon, Frazer J|Baker, David|Chiu, Wah', 'National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.', 'United States|United States|United States|United States|United States|United States', 0, 'Absorptiometry, Photon|Amino Acid Sequence|Capsid Proteins|Computer Simulation|Cryoelectron Microscopy|Crystallography|Models, Chemical|Models, Molecular|Molecular Sequence Data|Protein Conformation|Protein Structure, Tertiary', 'Journal Article', '10.1371/journal.pcbi.0020146', '17069457', 'Efforts in structural biology have targeted the systematic determination of all protein structures through experimental determination or modeling. In recent years, 3-D electron cryomicroscopy (cryoEM) has assumed an increasingly important role in determining the structures of these large macromolecular assemblies to intermediate resolutions (6-10 A). While these structures provide a snapshot of the assembly and its components in well-defined functional states, the resolution limits the ability to build accurate structural models. In contrast, sequence-based modeling techniques are capable of producing relatively robust structural models for isolated proteins or domains. In this work, we developed and applied a hybrid modeling approach, utilizing cryoEM density and ab initio modeling to produce a structural model for the core domain of a herpesvirus structural protein, VP26. Specifically, this method, first tested on simulated data, utilizes the cryoEM density map as a geometrical constraint in identifying the most native-like models from a gallery of models generated by ab initio modeling. The resulting model for the core domain of VP26, based on the 8.5-A resolution herpes simplex virus type 1 (HSV-1) capsid cryoEM structure and mutational data, exhibited a novel fold. Additionally, the core domain of VP26 appeared to have a complementary interface to the known upper-domain structure of VP5, its cognate binding partner. While this new model provides for a better understanding of the assembly and interactions of VP26 in HSV-1, the approach itself may have broader applications in modeling the components of large macromolecular assemblies.'),
(83536, 2006, 'plos', 'The evolution of two-component systems in bacteria reveals different strategies for niche adaptation', 'Alm, Eric|Huang, Katherine|Arkin, Adam', 'The Virtual Institute for Microbial Stress and Survival, Berkeley, California, United States of America.|The Virtual Institute for Microbial Stress and Survival, Berkeley, California, United States of America.|The Virtual Institute for Microbial Stress and Survival, Berkeley, California, United States of America.', 'United States|United States|United States', 115, 'Adaptation, Physiological|Bacteria|Computational Biology|Evolution, Molecular|Genome, Bacterial|Genomics|Histidine Kinase|Operon|Protein Kinases|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0020143', '17083272', 'Two-component systems including histidine protein kinases represent the primary signal transduction paradigm in prokaryotic organisms. To understand how these systems adapt to allow organisms to detect niche-specific signals, we analyzed the phylogenetic distribution of nearly 5,000 histidine protein kinases from 207 sequenced prokaryotic genomes. We found that many genomes carry a large repertoire of recently evolved signaling genes, which may reflect selective pressure to adapt to new environmental conditions. Both lineage-specific gene family expansion and horizontal gene transfer play major roles in the introduction of new histidine kinases into genomes, however, there are differences in how these two evolutionary forces act. Genes imported via horizontal transfer are more likely to retain their original functionality as inferred from a similar complement of signaling domains, while gene family expansion accompanied by domain shuffling appears to be a major source of novel genetic diversity. Family expansion is the dominant source of new histidine kinase genes in the genomes most enriched in signaling proteins, and detailed analysis reveals that divergence in domain structure and changes in expression patterns are hallmarks of recent expansions. Finally, while these two modes of gene acquisition are widespread across bacterial taxa, there are clear species-specific preferences for which mode is used.'),
(83537, 2006, 'plos', 'The evolution of word composition in metazoan promoter sequence', 'Bush, Eliot C|Lahn, Bruce T', 'Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America. bush@uchicago.edu|Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America. bush@uchicago.edu', 'United States|United States', 8, 'Amino Acids|Animals|Base Sequence|Computational Biology|Evolution, Molecular|Humans|Promoter Regions, Genetic', 'Journal Article', '10.1371/journal.pcbi.0020150', '17083273', 'The field of molecular evolution provides many examples of the principle that molecular differences between species contain information about evolutionary history. One surprising case can be found in the frequency of short words in DNA: more closely related species have more similar word compositions. Interest in this has often focused on its utility in deducing phylogenetic relationships. However, it is also of interest because of the opportunity it provides for studying the evolution of genome function. Word-frequency differences between species change too slowly to be purely the result of random mutational drift. Rather, their slow pattern of change reflects the direct or indirect action of purifying selection and the presence of functional constraints. Many such constraints are likely to exist, and an important challenge is to distinguish them. Here we develop a method to do so by isolating the effects acting at different word sizes. We apply our method to 2-, 4-, and 8-base-pair (bp) words across several classes of noncoding sequence. Our major result is that similarities in 8-bp word frequencies scale with evolutionary time for regions immediately upstream of genes. This association is present although weaker in intronic sequence, but cannot be detected in intergenic sequence using our method. In contrast, 2-bp and 4-bp word frequencies scale with time in all classes of noncoding sequence. These results suggest that different genomic processes are involved at different word sizes. The pattern in 2-bp and 4-bp words may be due to evolutionary changes in processes such as DNA replication and repair, as has been suggested before. The pattern in 8-bp words may reflect evolutionary changes in gene-regulatory machinery, such as changes in the frequencies of transcription-factor binding sites, or in the affinity of transcription factors for particular sequences.'),
(83538, 2006, 'plos', 'A curvature-mediated mechanism for localization of lipids to bacterial poles', 'Huang, Kerwyn Casey|Mukhopadhyay, Ranjan|Wingreen, Ned S', 'Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. kchuang@princeton.edu|Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. kchuang@princeton.edu|Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America. kchuang@princeton.edu', 'Jersey|Jersey|Jersey', 0, 'Bacillus subtilis|Cell Membrane|Computer Simulation|Escherichia coli|Lipid Bilayers|Lipid Metabolism|Membrane Fluidity|Models, Biological|Molecular Sequence Data', 'Journal Article', '10.1371/journal.pcbi.0020151', '17096591', 'Subcellular protein localization is a universal feature of eukaryotic cells, and the ubiquity of protein localization in prokaryotic species is now acquiring greater appreciation. Though some targeting anchors are known, the origin of polar and division-site localization remains mysterious for a large fraction of bacterial proteins. Ultimately, the molecular components responsible for such symmetry breaking must employ a high degree of self-organization. Here we propose a novel physical mechanism, based on the two-dimensional curvature of the membrane, for spontaneous lipid targeting to the poles and division site of rod-shaped bacterial cells. If one of the membrane components has a large intrinsic curvature, the geometrical constraint of the plasma membrane by the more rigid bacterial cell wall naturally leads to lipid microphase separation. We find that the resulting clusters of high-curvature lipids are large enough to spontaneously and stably localize to the two cell poles. Recent evidence of localization of the phospholipid cardiolipin to the poles of bacterial cells suggests that polar targeting of some proteins may rely on the membranes differential lipid content. More generally, aggregates of lipids, proteins, or lipid-protein complexes may localize in response to features of cell geometry incapable of localizing individual molecules.'),
(83539, 2006, 'plos', 'Humans can adopt optimal discounting strategy under real-time constraints', 'Schweighofer, N|Shishida, K|Han, C E|Okamoto, Y|Tanaka, S C|Yamawaki, S|Doya, K', 'Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu|Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu|Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu|Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu|Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu|Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu|Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, United States of America. schweigh@usc.edu', 'United States|United States|United States|United States|United States|United States|United States', 60, 'Adaptation, Physiological|Choice Behavior|Computer Simulation|Computer Systems|Decision Making|Game Theory|Humans|Models, Biological|Reward|Task Performance and Analysis|Time Factors', 'Journal Article', '10.1371/journal.pcbi.0020152', '17096592', 'Critical to our many daily choices between larger delayed rewards, and smaller more immediate rewards, are the shape and the steepness of the function that discounts rewards with time. Although research in artificial intelligence favors exponential discounting in uncertain environments, studies with humans and animals have consistently shown hyperbolic discounting. We investigated how humans perform in a reward decision task with temporal constraints, in which each choice affects the time remaining for later trials, and in which the delays vary at each trial. We demonstrated that most of our subjects adopted exponential discounting in this experiment. Further, we confirmed analytically that exponential discounting, with a decay rate comparable to that used by our subjects, maximized the total reward gain in our task. Our results suggest that the particular shape and steepness of temporal discounting is determined by the task that the subject is facing, and question the notion of hyperbolic reward discounting as a universal principle.'),
(83540, 2006, 'plos', 'Structural modeling of protein interactions by analogy: application to PSD-95', 'Korkin, Dmitry|Davis, Fred P|Alber, Frank|Luong, Tinh|Shen, Min-Yi|Lucic, Vladan|Kennedy, Mary B|Sali, Andrej', 'Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.|Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.', 'United States|United States|United States|United States|United States|United States|United States|Un', 0, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Dimerization|Disks Large Homolog 4 Protein|Guanylate Kinases|Intracellular Signaling Peptides and Proteins|Membrane Proteins|Models, Chemical|Models, Molecular|Molecular Sequence Data|Multiprotein Complexes|Protein Binding|Protein Conformation|Protein Interaction Mapping|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0020153', '17096593', 'We describe comparative patch analysis for modeling the structures of multidomain proteins and protein complexes, and apply it to the PSD-95 protein. Comparative patch analysis is a hybrid of comparative modeling based on a template complex and protein docking, with a greater applicability than comparative modeling and a higher accuracy than docking. It relies on structurally defined interactions of each of the complex components, or their homologs, with any other protein, irrespective of its fold. For each component, its known binding modes with other proteins of any fold are collected and expanded by the known binding modes of its homologs. These modes are then used to restrain conventional molecular docking, resulting in a set of binary domain complexes that are subsequently ranked by geometric complementarity and a statistical potential. The method is evaluated by predicting 20 binary complexes of known structure. It is able to correctly identify the binding mode in 70% of the benchmark complexes compared with 30% for protein docking. We applied comparative patch analysis to model the complex of the third PSD-95, DLG, and ZO-1 (PDZ) domain and the SH3-GK domains in the PSD-95 protein, whose structure is unknown. In the first predicted configuration of the domains, PDZ interacts with SH3, leaving both the GMP-binding site of guanylate kinase (GK) and the C-terminus binding cleft of PDZ accessible, while in the second configuration PDZ interacts with GK, burying both binding sites. We suggest that the two alternate configurations correspond to the different functional forms of PSD-95 and provide a possible structural description for the experimentally observed cooperative folding transitions in PSD-95 and its homologs. More generally, we expect that comparative patch analysis will provide useful spatial restraints for the structural characterization of an increasing number of binary and higher-order protein complexes.'),
(83541, 2006, 'plos', 'Geometrically repatterned immunological synapses uncover formation mechanisms', 'Figge, Marc Thilo|Meyer-Hermann, Michael', 'Institute for Theoretical Physics, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. figge@fias.uni-frankfurt.de|Institute for Theoretical Physics, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. figge@fias.uni-frankfurt.de', 'Germany|Germany', 20, 'Antigen-Presenting Cells|Cell Adhesion|Cell Communication|Computer Simulation|Major Histocompatibility Complex|Models, Immunological|Synapses|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.0020171', '17096594', 'The interaction of T cells and antigen-presenting cells is central to adaptive immunity and involves the formation of immunological synapses in many cases. The surface molecules of the cells form a characteristic spatial pattern whose formation mechanisms and function are largely unknown. We perform computer simulations of recent experiments on geometrically repatterned immunological synapses and explain the emerging structure as well as the formation dynamics. Only the combination of in vitro experiments and computer simulations has the potential to pinpoint the kind of interactions involved. The presented simulations make clear predictions for the structure of the immunological synapse and elucidate the role of a self-organizing attraction between complexes of T cell receptor and peptide-MHC molecule, versus a centrally directed motion of these complexes.'),
(83542, 2006, 'plos', 'Funneled landscape leads to robustness of cell networks: yeast cell cycle', 'Wang, Jin|Huang, Bo|Xia, Xuefeng|Sun, Zhirong', 'Department of Chemistry and Department of Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America. jin.wang.1@stonybrook.edu|Department of Chemistry and Department of Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America. jin.wang.1@stonybrook.edu|Department of Chemistry and Department of Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America. jin.wang.1@stonybrook.edu|Department of Chemistry and Department of Physics, State University of New York at Stony Brook, Stony Brook, New York, United States of America. jin.wang.1@stonybrook.edu', 'United States|United States|United States|United States', 38, 'Cell Cycle|Computer Simulation|Energy Metabolism|Models, Biological|Saccharomyces cerevisiae|Saccharomyces cerevisiae Proteins|Signal Transduction', 'Journal Article', '10.1371/journal.pcbi.0020147', '17112311', 'We uncovered the underlying energy landscape for a cellular network. We discovered that the energy landscape of the yeast cell-cycle network is funneled towards the global minimum (G0/G1 phase) from the experimentally measured or inferred inherent chemical reaction rates. The funneled landscape is quite robust against random perturbations. This naturally explains robustness from a physical point of view. The ratio of slope versus roughness of the landscape becomes a quantitative measure of robustness of the network. The funneled landscape can be seen as a possible realization of the Darwinian principle of natural selection at the cellular network level. It provides an optimal criterion for network connections and design. Our approach is general and can be applied to other cellular networks.'),
(83543, 2006, 'plos', 'Optimal noise filtering in the chemotactic response of Escherichia coli', 'Andrews, Burton W|Yi, Tau-Mu|Iglesias, Pablo A', 'Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.|Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.', 'United States|United States|United States', 0, 'Chemotaxis|Computer Simulation|Escherichia coli|Escherichia coli Proteins|Models, Biological|Models, Statistical|Stochastic Processes', 'Journal Article', '10.1371/journal.pcbi.0020154', '17112312', 'Information-carrying signals in the real world are often obscured by noise. A challenge for any system is to filter the signal from the corrupting noise. This task is particularly acute for the signal transduction network that mediates bacterial chemotaxis, because the signals are subtle, the noise arising from stochastic fluctuations is substantial, and the system is effectively acting as a differentiator which amplifies noise. Here, we investigated the filtering properties of this biological system. Through simulation, we first show that the cutoff frequency has a dramatic effect on the chemotactic efficiency of the cell. Then, using a mathematical model to describe the signal, noise, and system, we formulated and solved an optimal filtering problem to determine the cutoff frequency that bests separates the low-frequency signal from the high-frequency noise. There was good agreement between the theory, simulations, and published experimental data. Finally, we propose that an elegant implementation of the optimal filter in combination with a differentiator can be achieved via an integral control system. This paper furnishes a simple quantitative framework for interpreting many of the key notions about bacterial chemotaxis, and, more generally, it highlights the constraints on biological systems imposed by noise.'),
(83544, 2006, 'plos', '3D complex: a structural classification of protein complexes', 'Levy, Emmanuel D|Pereira-Leal, Jose B|Chothia, Cyrus|Teichmann, Sarah A', 'Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. elevy@mrc-lmb.cam.ac.uk|Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. elevy@mrc-lmb.cam.ac.uk|Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. elevy@mrc-lmb.cam.ac.uk|Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. elevy@mrc-lmb.cam.ac.uk', 'United Kingdom|United Kingdom|United Kingdom|United Kingdom', 0, 'Amino Acid Sequence|Binding Sites|Computer Simulation|Databases, Protein|Models, Chemical|Models, Molecular|Molecular Sequence Data|Multiprotein Complexes|Protein Binding|Protein Conformation|Protein Interaction Mapping|Proteins|Sequence Analysis, Protein', 'Journal Article', '10.1371/journal.pcbi.0020155', '17112313', 'Most of the proteins in a cell assemble into complexes to carry out their function. It is therefore crucial to understand the physicochemical properties as well as the evolution of interactions between proteins. The Protein Data Bank represents an important source of information for such studies, because more than half of the structures are homo- or heteromeric protein complexes. Here we propose the first hierarchical classification of whole protein complexes of known 3-D structure, based on representing their fundamental structural features as a graph. This classification provides the first overview of all the complexes in the Protein Data Bank and allows nonredundant sets to be derived at different levels of detail. This reveals that between one-half and two-thirds of known structures are multimeric, depending on the level of redundancy accepted. We also analyse the structures in terms of the topological arrangement of their subunits and find that they form a small number of arrangements compared with all theoretically possible ones. This is because most complexes contain four subunits or less, and the large majority are homomeric. In addition, there is a strong tendency for symmetry in complexes, even for heteromeric complexes. Finally, through comparison of Biological Units in the Protein Data Bank with the Protein Quaternary Structure database, we identified many possible errors in quaternary structure assignments. Our classification, available as a database and Web server at http://www.3Dcomplex.org, will be a starting point for future work aimed at understanding the structure and evolution of protein complexes.'),
(83545, 2006, 'plos', 'An integrative genomic approach to uncover molecular mechanisms of prokaryotic traits', 'Liu, Yang|Li, Jianrong|Sam, Lee|Goh, Chern-Sing|Gerstein, Mark|Lussier, Yves A', 'Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States|United States|United States|United States|United States', 25, 'Algorithms|Base Sequence|Chromosome Mapping|Conserved Sequence|Evolution, Molecular|Genome, Bacterial|Molecular Sequence Data|Phenotype|Quantitative Trait Loci|Sequence Alignment|Sequence Analysis, DNA|Sequence Homology, Nucleic Acid|Systems Integration', 'Journal Article', '10.1371/journal.pcbi.0020159', '17112314', 'With mounting availability of genomic and phenotypic databases, data integration and mining become increasingly challenging. While efforts have been put forward to analyze prokaryotic phenotypes, current computational technologies either lack high throughput capacity for genomic scale analysis, or are limited in their capability to integrate and mine data across different scales of biology. Consequently, simultaneous analysis of associations among genomes, phenotypes, and gene functions is prohibited. Here, we developed a high throughput computational approach, and demonstrated for the first time the feasibility of integrating large quantities of prokaryotic phenotypes along with genomic datasets for mining across multiple scales of biology (protein domains, pathways, molecular functions, and cellular processes). Applying this method over 59 fully sequenced prokaryotic species, we identified genetic basis and molecular mechanisms underlying the phenotypes in bacteria. We identified 3,711 significant correlations between 1,499 distinct Pfam and 63 phenotypes, with 2,650 correlations and 1,061 anti-correlations. Manual evaluation of a random sample of these significant correlations showed a minimal precision of 30% (95% confidence interval: 20%-42%, n = 50). We stratified the most significant 478 predictions and subjected 100 to manual evaluation, of which 60 were corroborated in the literature. We furthermore unveiled 10 significant correlations between phenotypes and KEGG pathways, eight of which were corroborated in the evaluation, and 309 significant correlations between phenotypes and 166 GO concepts evaluated using a random sample (minimal precision = 72%, 95% confidence interval: 60%-80%, n = 50). Additionally, we conducted a novel large-scale phenomic visualization analysis to provide insight into the modular nature of common molecular mechanisms spanning multiple biological scales and reused by related phenotypes (metaphenotypes). We propose that this method elucidates which classes of molecular mechanisms are associated with phenotypes or metaphenotypes and holds promise in facilitating a computable systems biology approach to genomic and biomedical research.'),
(83546, 2006, 'plos', 'Ten simple rules for selecting a postdoctoral position', 'Bourne, Philip E|Friedberg, Iddo', 'Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.|Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.', 'United States|United States', 0, 'Algorithms|Biological Science Disciplines|Career Choice|Education, Professional|Job Application|Research Personnel|United States', 'Editorial', '10.1371/journal.pcbi.0020121', '17121457', '-'),
(83547, 2006, 'plos', 'Meta-analysis of differentiating mouse embryonic stem cell gene expression kinetics reveals early change of a small gene set', 'Glover, Clive H|Marin, Michael|Eaves, Connie J|Helgason, Cheryl D|Piret, James M|Bryan, Jennifer', 'Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.|Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.', 'Canada|Canada|Canada|Canada|Canada|Canada', 36, 'Adaptation, Physiological|Animals|Cell Differentiation|Embryonic Stem Cells|Gene Expression Regulation, Developmental|Kinetics|Mice|Proteome', 'Journal Article', '10.1371/journal.pcbi.0020158', '17121458', 'Stem cell differentiation involves critical changes in gene expression. Identification of these should provide endpoints useful for optimizing stem cell propagation as well as potential clues about mechanisms governing stem cell maintenance. Here we describe the results of a new meta-analysis methodology applied to multiple gene expression datasets from three mouse embryonic stem cell (ESC) lines obtained at specific time points during the course of their differentiation into various lineages. We developed methods to identify genes with expression changes that correlated with the altered frequency of functionally defined, undifferentiated ESC in culture. In each dataset, we computed a novel statistical confidence measure for every gene which captured the certainty that a particular gene exhibited an expression pattern of interest within that dataset. This permitted a joint analysis of the datasets, despite the different experimental designs. Using a ranking scheme that favored genes exhibiting patterns of interest, we focused on the top 88 genes whose expression was consistently changed when ESC were induced to differentiate. Seven of these (103728_at, 8430410A17Rik, Klf2, Nr0b1, Sox2, Tcl1, and Zfp42) showed a rapid decrease in expression concurrent with a decrease in frequency of undifferentiated cells and remained predictive when evaluated in additional maintenance and differentiating protocols. Through a novel meta-analysis, this study identifies a small set of genes whose expression is useful for identifying changes in stem cell frequencies in cultures of mouse ESC. The methods and findings have broader applicability to understanding the regulation of self-renewal of other stem cell types.'),
(83548, 2006, 'plos', 'Robustness and fragility in immunosenescence', 'Stromberg, Sean P|Carlson, Jean', 'Physics Department, University of California Santa Barbara, Santa Barbara, California, United States of America. stromberg@physics.ucsb.edu|Physics Department, University of California Santa Barbara, Santa Barbara, California, United States of America. stromberg@physics.ucsb.edu', 'United States|United States', 0, 'Adaptation, Physiological|Aging|Animals|Cellular Senescence|Computer Simulation|Humans|Immunity, Innate|Infection|Models, Immunological|T-Lymphocytes', 'Journal Article', '10.1371/journal.pcbi.0020160', '17121459', 'We construct a model to study tradeoffs associated with aging in the adaptive immune system, focusing on cumulative effects of replacing naive cells with memory cells. Binding affinities are characterized by a stochastic shape space model. System loss arising from an individual infection is associated with disease severity, as measured by the total antigen population over the course of an infection. We monitor evolution of cell populations on the shape space over a string of infections, and find that the distribution of losses becomes increasingly heavy-tailed with time. Initially this lowers the average loss: the memory cell population becomes tuned to the history of past exposures, reducing the loss of the system when subjected to a second, similar infection. This is accompanied by a corresponding increase in vulnerability to novel infections, which ultimately causes the expected loss to increase due to overspecialization, leading to increasing fragility with age (i.e., immunosenescence). In our model, immunosenescence is not the result of a performance degradation of some specific lymphocyte, but rather a natural consequence of the built-in mechanisms for system adaptation. This robust, yet fragile behavior is a key signature of Highly Optimized Tolerance.');
