MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'PLoS Computational Biology' source. Thu, 09 Feb 2012 14:32:14 +0100 http://www.medworm.com/index.php?rid=5656243&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FTkspxSzz2Rw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002357 by Pranidhi Sood, Robert J. Johnston, Edo Kussell The photoreceptors of the Drosophila compound eye are a classical model for studying cell fate specification. Photoreceptors (PRs) are organized in bundles of eight cells with two major types – inner PRs involved in color vision and outer PRs involved in motion detection. In wild type flies, most PRs express a single type of Rhodopsin (Rh): inner PRs express either Rh3, Rh4, Rh5 or Rh6 and outer PRs express Rh1. In outer PRs, the K50 homeodomain protein Dve is a key repressor that acts to ensure exclusive Rh expression. Loss of Dve results in de-repression of Rhodopsins in outer PRs, and leads to a wide distribution of expression levels. To quantify these effects, we introduce an automated image analysis method to measure Rhodopsin l... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656243 Thu, 02 Feb 2012 05:00:00 +0100 5656243 http://www.medworm.com/index.php?rid=5656242&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FaKm5Dr63nnM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002356 by István Miklós, Zoltán Zádori HD amino acid duplex has been found in the active center of many different enzymes. The dyad plays remarkably different roles in their catalytic processes that usually involve metal coordination. An HD motif is positioned directly on the amyloid beta fragment (Aβ) and on the carboxy-terminal region of the extracellular domain (CAED) of the human amyloid precursor protein (APP) and a taxonomically well defined group of APP orthologues (APPOs). In human Aβ HD is part of a presumed, RGD-like integrin-binding motif RHD; however, neither RHD nor RXD demonstrates reasonable conservation in APPOs. The sequences of CAEDs and the position of the HD are not particularly conserved either, yet we show with a novel statistical method using evolutionary modelin... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656242 Thu, 02 Feb 2012 05:00:00 +0100 5656242 http://www.medworm.com/index.php?rid=5656241&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FzcciM9JQn14%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002376 by Xueyang Feng, You Xu, Yixin Chen, Yinjie J. Tang Shewanella oneidensis MR-1 sequentially utilizes lactate and its waste products (pyruvate and acetate) during batch culture. To decipher MR-1 metabolism, we integrated genome-scale flux balance analysis (FBA) into a multiple-substrate Monod model to perform the dynamic flux balance analysis (dFBA). The dFBA employed a static optimization approach (SOA) by dividing the batch time into small intervals (i.e., ∼400 mini-FBAs), then the Monod model provided time-dependent inflow/outflow fluxes to constrain the mini-FBAs to profile the pseudo-steady-state fluxes in each time interval. The mini-FBAs used a dual-objective function (a weighted combination of “maximizing growth rate” and “minimizing overall flux”) to capture trade-of... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656241 Thu, 02 Feb 2012 05:00:00 +0100 5656241 http://www.medworm.com/index.php?rid=5656240&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FVIeYWbA9zNs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002374 by Kaustubh Supekar, Vinod Menon Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI) to investigate the maturation of control processes underlying problem solving skills in 7–9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI), ventrolateral prefrontal cortex and anterior... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656240 Thu, 02 Feb 2012 05:00:00 +0100 5656240 http://www.medworm.com/index.php?rid=5656239&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FO5ZgMRlWg6c%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002360 by Steven J. Lade, Thilo Gross Critical transitions are sudden, often irreversible, changes that can occur in a large variety of complex systems; signals that warn of critical transitions are therefore highly desirable. We propose a new method for early warning signals that integrates multiple sources of information and data about the system through the framework of a generalized model. We demonstrate our proposed approach through several examples, including a previously published fisheries model. We regard our method as complementary to existing early warning signals, taking an approach of intermediate complexity between model-free approaches and fully parameterized simulations. One potential advantage of our approach is that, under appropriate conditions, it may reduce the amount of... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656239 Thu, 02 Feb 2012 05:00:00 +0100 5656239 http://www.medworm.com/index.php?rid=5656238&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FyWzHES6_0UE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002365 by Ekaterina Kotelnikova, Maria A. Shkrob, Mikhail A. Pyatnitskiy, Alessandra Ferlini, Nikolai Daraselia Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for drug and biomarkers discovery using comprehensive analysis of multiple expression profiling datasets. The new method relies on aggregation of individual profiling experiments combined with leave-one-dataset-out validation approach. Aggregated datasets were studied using Sub-Network Enrichment Analysis algorithm (SNEA) to find consistent statistically significant key... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656238 Thu, 02 Feb 2012 05:00:00 +0100 5656238 http://www.medworm.com/index.php?rid=5656237&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FcfrggR65pjw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002364 by Nadav Rappoport, Michal Linial The infection cycle of viruses creates many opportunities for the exchange of genetic material with the host. Many viruses integrate their sequences into the genome of their host for replication. These processes may lead to the virus acquisition of host sequences. Such sequences are prone to accumulation of mutations and deletions. However, in rare instances, sequences acquired from a host become beneficial for the virus. We searched for unexpected sequence similarity among the 900,000 viral proteins and all proteins from cellular organisms. Here, we focus on viruses that infect metazoa. The high-conservation analysis yielded 187 instances of highly similar viral-host sequences. Only a small number of them represent viruses that hijacked host sequence... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656237 Thu, 02 Feb 2012 05:00:00 +0100 5656237 http://www.medworm.com/index.php?rid=5656236&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FjSVvWqkSgMo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002363 by Ali R. Zomorrodi, Costas D. Maranas Microorganisms rarely live isolated in their natural environments but rather function in consolidated and socializing communities. Despite the growing availability of high-throughput sequencing and metagenomic data, we still know very little about the metabolic contributions of individual microbial players within an ecological niche and the extent and directionality of interactions among them. This calls for development of efficient modeling frameworks to shed light on less understood aspects of metabolism in microbial communities. Here, we introduce OptCom, a comprehensive flux balance analysis framework for microbial communities, which relies on a multi-level and multi-objective optimization formulation to properly describe trade-offs between i... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656236 Thu, 02 Feb 2012 05:00:00 +0100 5656236 http://www.medworm.com/index.php?rid=5656235&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FWxAYFKK4xlk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002355 by Yu Wu, Yao Lu, Weiqiang Chen, Jianping Fu, Rong Fan Tumor cells do not develop in isolation, but co-evolve with stromal cells and tumor-associated immune cells in a tumor microenvironment mediated by an array of soluble factors, forming a complex intercellular signaling network. Herein, we report an unbiased, generic model to integrate prior biochemical data and the constructed brain tumor microenvironment in silico as characterized by an intercellular signaling network comprising 5 types of cells, 15 cytokines, and 69 signaling pathways. The results show that glioma develops through three distinct phases: pre-tumor, rapid expansion, and saturation. We designed a microglia depletion therapy and observed significant benefit for virtual patients treated at the early stages but striki... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656235 Thu, 02 Feb 2012 05:00:00 +0100 5656235 http://www.medworm.com/index.php?rid=5656234&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F_oH1uBGFz0w%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002342 by Camille Morvan, Laurence T. Maloney Researchers have conjectured that eye movements during visual search are selected to minimize the number of saccades. The optimal Bayesian eye movement strategy minimizing saccades does not simply direct the eye to whichever location is judged most likely to contain the target but makes use of the entire retina as an information gathering device during each fixation. Here we show that human observers do not minimize the expected number of saccades in planning saccades in a simple visual search task composed of three tokens. In this task, the optimal eye movement strategy varied, depending on the spacing between tokens (in the first experiment) or the size of tokens (in the second experiment), and changed abruptly once the separation or size surpa... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5656234 Thu, 02 Feb 2012 05:00:00 +0100 5656234 http://www.medworm.com/index.php?rid=5635242&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FUoRxARd1pp4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002334 by Yotam Luz, Maoz Shamir It has been suggested that excitatory and inhibitory inputs to cortical cells are balanced, and that this balance is important for the highly irregular firing observed in the cortex. There are two hypotheses as to the origin of this balance. One assumes that it results from a stable solution of the recurrent neuronal dynamics. This model can account for a balance of steady state excitation and inhibition without fine tuning of parameters, but not for transient inputs. The second hypothesis suggests that the feed forward excitatory and inhibitory inputs to a postsynaptic cell are already balanced. This latter hypothesis thus does account for the balance of transient inputs. However, it remains unclear what mechanism underlies the fine tuning required for balan... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635242 Thu, 26 Jan 2012 05:00:00 +0100 5635242 http://www.medworm.com/index.php?rid=5635241&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fm5i5GA2Dgnw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002331 We present the first demonstration that Turing pattern formation can arise in a new family of oscillator-driven gene network topologies, specifically when a second feedback loop is introduced which quenches oscillations and incorporates a diffusible molecule. We provide an analysis of the system that predicts the range of kinetic parameters over which patterning should emerge and demonstrate the system's viability using stochastic simulations of a field of cells using realistic parameters. The primary goal of this paper is to provide a circuit architecture which can be implemented with relative ease by practitioners and which could serve as a model system for pattern generation in synthetic multicellular systems. Given the wide range of oscillatory circuits in natural systems, our system s... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635241 Thu, 26 Jan 2012 05:00:00 +0100 5635241 http://www.medworm.com/index.php?rid=5635240&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FkmbBFlFdI4s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002311 by Ioannis Vlachos, Ad Aertsen, Arvind Kumar It is a common and good practice in experimental sciences to assess the statistical significance of measured outcomes. For this, the probability of obtaining the actual results is estimated under the assumption of an appropriately chosen null-hypothesis. If this probability is smaller than some threshold, the results are deemed statistically significant and the researchers are content in having revealed, within their own experimental domain, a “surprising” anomaly, possibly indicative of a hitherto hidden fragment of the underlying “ground-truth”. What is often neglected, though, is the actual importance of these experimental outcomes for understanding the system under investigation. We illustrate this point by giving practical and ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635240 Thu, 26 Jan 2012 05:00:00 +0100 5635240 http://www.medworm.com/index.php?rid=5635239&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FY8w2FzWzoEs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002387 by Rosemary Dickin, Chris James Hall, Laura K. Taylor, Andrew M. Collings, Ruth Nussinov, Philip E. Bourne (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635239 Thu, 26 Jan 2012 05:00:00 +0100 5635239 http://www.medworm.com/index.php?rid=5635238&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FOetAFhl27jw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002350 by Xinan Yang, Kelly Regan, Yong Huang, Qingbei Zhang, Jianrong Li, Tanguy Y. Seiwert, Ezra E. W. Cohen, H. Rosie Xing, Yves A. Lussier Gene expression signatures that are predictive of therapeutic response or prognosis are increasingly useful in clinical care; however, mechanistic (and intuitive) interpretation of expression arrays remains an unmet challenge. Additionally, there is surprisingly little gene overlap among distinct clinically validated expression signatures. These “causality challenges” hinder the adoption of signatures as compared to functionally well-characterized single gene biomarkers. To increase the utility of multi-gene signatures in survival studies, we developed a novel approach to generate “personal mechanism signatures” of molecular pathways and funct... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635238 Thu, 26 Jan 2012 05:00:00 +0100 5635238 http://www.medworm.com/index.php?rid=5635237&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FAKOu6_iVYVM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002338 by Patrick D. McMullen, Erin Z. Aprison, Peter B. Winter, Luis A. N. Amaral, Richard I. Morimoto, Ilya Ruvinsky A major goal of systems biology is to understand how organism-level behavior arises from a myriad of molecular interactions. Often this involves complex sets of rules describing interactions among a large number of components. As an alternative, we have developed a simple, macro-level model to describe how chronic temperature stress affects reproduction in C. elegans. Our approach uses fundamental engineering principles, together with a limited set of experimentally derived facts, and provides quantitatively accurate predictions of performance under a range of physiologically relevant conditions. We generated detailed time-resolved experimental data to evaluate the ability o... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635237 Thu, 26 Jan 2012 05:00:00 +0100 5635237 http://www.medworm.com/index.php?rid=5635236&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FpqAz3V92B1c%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002296 by William Stafford Noble, Michael J. MacCoss High-throughput proteomics experiments involving tandem mass spectrometry produce large volumes of complex data that require sophisticated computational analyses. As such, the field offers many challenges for computational biologists. In this article, we briefly introduce some of the core computational and statistical problems in the field and then describe a variety of outstanding problems that readers of PLoS Computational Biology might be able to help solve. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5635236 Thu, 26 Jan 2012 05:00:00 +0100 5635236 http://www.medworm.com/index.php?rid=5616850&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fpcdw4L6npSI%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002361 by Navneet Rai, Rajat Anand, Krishna Ramkumar, Varun Sreenivasan, Sugat Dabholkar, K. V. Venkatesh, Mukund Thattai Quorum-sensing systems mediate chemical communication between bacterial cells, coordinating cell-density-dependent processes like biofilm formation and virulence-factor expression. In the proteobacterial LuxI/LuxR quorum sensing paradigm, a signaling molecule generated by an enzyme (LuxI) diffuses between cells and allosterically stimulates a transcriptional regulator (LuxR) to activate its cognate promoter (pR). By expressing either LuxI or LuxR in positive feedback from pR, these versatile systems can generate smooth (monostable) or abrupt (bistable) density-dependent responses to suit the ecological context. Here we combine theory and experiment to demonstrate that the... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616850 Thu, 19 Jan 2012 05:00:00 +0100 5616850 http://www.medworm.com/index.php?rid=5616849&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F7KxEIbaNHAg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002352 by Fiona Achcar, Eduard J. Kerkhoven, The SilicoTryp Consortium, Barbara M. Bakker, Michael P. Barrett, Rainer Breitling Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616849 Thu, 19 Jan 2012 05:00:00 +0100 5616849 http://www.medworm.com/index.php?rid=5616848&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FdHuIPG7RseA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002346 In this study, we ask whether the brain generalizes in an optimal way. Specifically, we used Bayesian learning theory and fMRI to test whether neuronal responses reflect context-sensitive changes in ambiguity or uncertainty about experience-dependent beliefs. We found that the hippocampus expresses clear ambiguity-dependent responses that are associated with an augmented rate of learning. These findings suggest candidate neuronal systems that may be involved in aberrations of generalization, such as over-confidence. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616848 Thu, 19 Jan 2012 05:00:00 +0100 5616848 http://www.medworm.com/index.php?rid=5616847&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FBIsFNoWQ2XQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002349 by J. Naudé, J. T. Paz, H. Berry, B. Delord Intrinsic plasticity (IP) is a ubiquitous activity-dependent process regulating neuronal excitability and a cellular correlate of behavioral learning and neuronal homeostasis. Because IP is induced rapidly and maintained long-term, it likely represents a major determinant of adaptive collective neuronal dynamics. However, assessing the exact impact of IP has remained elusive. Indeed, it is extremely difficult disentangling the complex non-linear interaction between IP effects, by which conductance changes alter neuronal activity, and IP rules, whereby activity modifies conductance via signaling pathways. Moreover, the two major IP effects on firing rate, threshold and gain modulation, remain unknown in their very mechanisms. Here, using ext... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616847 Thu, 19 Jan 2012 05:00:00 +0100 5616847 http://www.medworm.com/index.php?rid=5616846&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FwIx81Ru6yms%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002354 by Michael N. Economo, John A. White Computational studies as well as in vivo and in vitro results have shown that many cortical neurons fire in a highly irregular manner and at low average firing rates. These patterns seem to persist even when highly rhythmic signals are recorded by local field potential electrodes or other methods that quantify the summed behavior of a local population. Models of the 30–80 Hz gamma rhythm in which network oscillations arise through ‘stochastic synchrony’ capture the variability observed in the spike output of single cells while preserving network-level organization. We extend upon these results by constructing model networks constrained by experimental measurements and using them to probe the effect of biophysical parameters on network-level a... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616846 Thu, 19 Jan 2012 05:00:00 +0100 5616846 http://www.medworm.com/index.php?rid=5616845&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FXUvAIBSnLaw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002316 by Caterina A. M. La Porta, Stefano Zapperi, James P. Sethna Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616845 Thu, 19 Jan 2012 05:00:00 +0100 5616845 http://www.medworm.com/index.php?rid=5616844&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FFKcaCkWQsuo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002359 We present the first mechanistic mathematical model of polymerase inhibition by NAs that takes into account the reversibility of polymerase inhibition. Analytical solutions for the model point out the cellular- and kinetic aspects of inhibition. Our model correctly predicts for HIV-1 that resistance against nucleoside analog reverse transcriptase inhibitors (NRTIs) can be conferred by decreasing their incorporation rate, increasing their excision rate, or decreasing their affinity for the polymerase enzyme. For all analyzed NRTIs and their combinations, model-predicted macroscopic parameters (efficacy, fitness and toxicity) were consistent with observations. NRTI efficacy was found to greatly vary between distinct target cells. Surprisingly, target cells with low dNTP/NTP levels may not co... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5616844 Thu, 19 Jan 2012 05:00:00 +0100 5616844 http://www.medworm.com/index.php?rid=5592799&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FqORtiznAM50%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002341 We report such coupling for SH3, PDZ, SH2 and WW domains, where residue phosphorylation within or next to the motif is implied to be associated with switching on or off domain binding. For domains that require motif phosphorylation for binding, such as SH2 domains, we found coupled phosphorylation events other than the ones required for domain binding. Furthermore, we show that phosphorylation might function as a double switch, concurrently enabling interaction of the motif with one domain and disabling interaction with another domain. Evolutionary analysis shows that co-evolution of the motif and the proximal residues capable of phosphorylation predominates over other evolutionary scenarios, in which the motif appeared before the potentially phosphorylated residue, or vice versa. Our find... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592799 Thu, 12 Jan 2012 05:00:00 +0100 5592799 http://www.medworm.com/index.php?rid=5592798&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F7vKHUaQwJGw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002348 by Ken Takiyama, Masato Okada Many redundancies play functional roles in motor control and motor learning. For example, kinematic and muscle redundancies contribute to stabilizing posture and impedance control, respectively. Another redundancy is the number of neurons themselves; there are overwhelmingly more neurons than muscles, and many combinations of neural activation can generate identical muscle activity. The functional roles of this neuronal redundancy remains unknown. Analysis of a redundant neural network model makes it possible to investigate these functional roles while varying the number of model neurons and holding constant the number of output units. Our analysis reveals that learning speed reaches its maximum value if and only if the model includes sufficient neuronal ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592798 Thu, 12 Jan 2012 05:00:00 +0100 5592798 http://www.medworm.com/index.php?rid=5592797&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F5d2WgC1NzxA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002345 by Juilee Thakar, Ashutosh K. Pathak, Lisa Murphy, Réka Albert, Isabella M. Cattadori Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune resp... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592797 Thu, 12 Jan 2012 05:00:00 +0100 5592797 http://www.medworm.com/index.php?rid=5592796&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fs5oTU00WUYg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002351 by Iain H. Moal, Paul A. Bates The prediction of protein-protein kinetic rate constants provides a fundamental test of our understanding of molecular recognition, and will play an important role in the modeling of complex biological systems. In this paper, a feature selection and regression algorithm is applied to mine a large set of molecular descriptors and construct simple models for association and dissociation rate constants using empirical data. Using separate test data for validation, the predicted rate constants can be combined to calculate binding affinity with accuracy matching that of state of the art empirical free energy functions. The models show that the rate of association is linearly related to the proportion of unbound proteins in the bound conformational ensemble re... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592796 Thu, 12 Jan 2012 05:00:00 +0100 5592796 http://www.medworm.com/index.php?rid=5592795&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F9jfZS4je784%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002344 by Kyung H. Kim, Herbert M. Sauro Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592795 Thu, 12 Jan 2012 05:00:00 +0100 5592795 http://www.medworm.com/index.php?rid=5592794&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FXP5xG5n7TP8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002333 We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between seque... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592794 Thu, 12 Jan 2012 05:00:00 +0100 5592794 http://www.medworm.com/index.php?rid=5592793&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FTb-H4QSdDKM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002286 by Michael Seifert, André Gohr, Marc Strickert, Ivo Grosse Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592793 Thu, 12 Jan 2012 05:00:00 +0100 5592793 http://www.medworm.com/index.php?rid=5592792&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FoSqfPDRCFT8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002299 by Artturi Koivuniemi, Timo Vuorela, Petri T. Kovanen, Ilpo Vattulainen, Marja T. Hyvönen Cholesteryl ester transfer protein (CETP) transports cholesteryl esters, triglycerides, and phospholipids between different lipoprotein fractions in blood plasma. The inhibition of CETP has been shown to be a sound strategy to prevent and treat the development of coronary heart disease. We employed molecular dynamics simulations to unravel the mechanisms associated with the CETP-mediated lipid exchange. To this end we used both atomistic and coarse-grained models whose results were consistent with each other. We found CETP to bind to the surface of high density lipoprotein (HDL) -like lipid droplets through its charged and tryptophan residues. Upon binding, CETP rapidly (in about 10 ns) induced ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592792 Thu, 12 Jan 2012 05:00:00 +0100 5592792 http://www.medworm.com/index.php?rid=5592791&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fg_qDXwG703s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002353 by Weihong Zhang, Debabani Ganguly, Jianhan Chen To understand the interplay of residual structures and conformational fluctuations in the interaction of intrinsically disordered proteins (IDPs), we first combined implicit solvent and replica exchange sampling to calculate atomistic disordered ensembles of the nuclear co-activator binding domain (NCBD) of transcription coactivator CBP and the activation domain of the p160 steroid receptor coactivator ACTR. The calculated ensembles are in quantitative agreement with NMR-derived residue helicity and recapitulate the experimental observation that, while free ACTR largely lacks residual secondary structures, free NCBD is a molten globule with a helical content similar to that in the folded complex. Detailed conformational analysis reveals... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592791 Thu, 12 Jan 2012 05:00:00 +0100 5592791 http://www.medworm.com/index.php?rid=5592790&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FOYeQdaF5miw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002335 We present a large-scale study that compares the sequences and best energy conformations in 69 protein-core redesigns using a rigid-rotamer model versus a continuous-rotamer model. We show that in nearly all of our redesigns the sequence found by the continuous-rotamer model is different and has a lower energy than the one found by the rigid-rotamer model. Moreover, the sequences found by the continuous-rotamer model are more similar to the native sequences. We then show that the seemingly easy solution of sampling more rigid rotamers within the continuous region is not a practical alternative to a continuous-rotamer model: at computationally feasible resolutions, using more rigid rotamers was never better than a continuous-rotamer model and almost always resulted in higher energies. Final... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5592790 Thu, 12 Jan 2012 05:00:00 +0100 5592790 http://www.medworm.com/index.php?rid=5568639&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FOEc0uqvgkc4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002329 by Benjamin Pfeuty, Jean-Francois Bodart, Ralf Blossey, Marc Lefranc Maturation of vertebrate oocytes into haploid gametes relies on two consecutive meioses without intervening DNA replication. The temporal sequence of cellular transitions driving eggs from G2 arrest to meiosis I (MI) and then to meiosis II (MII) is controlled by the interplay between cyclin-dependent and mitogen-activated protein kinases. In this paper, we propose a dynamical model of the molecular network that orchestrates maturation of Xenopus laevis oocytes. Our model reproduces the core features of maturation progression, including the characteristic non-monotonous time course of cyclin-Cdks, and unveils the network design principles underlying a precise sequence of meiotic decisions, as captured by bifurcation a... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568639 Thu, 05 Jan 2012 05:00:00 +0100 5568639 http://www.medworm.com/index.php?rid=5568638&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F57v0zmS_lws%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002339 by Bambang S. Adiwijaya, Tara L. Kieffer, Joshua Henshaw, Karen Eisenhauer, Holly Kimko, John J. Alam, Robert S. Kauffman, Varun Garg We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-expe... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568638 Thu, 05 Jan 2012 05:00:00 +0100 5568638 http://www.medworm.com/index.php?rid=5568637&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fvk9GHi09vz0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002312 by Christian Meisel, Alexander Storch, Susanne Hallmeyer-Elgner, Ed Bullmore, Thilo Gross Critical dynamics are assumed to be an attractive mode for normal brain functioning as information processing and computational capabilities are found to be optimal in the critical state. Recent experimental observations of neuronal activity patterns following power-law distributions, a hallmark of systems at a critical state, have led to the hypothesis that human brain dynamics could be poised at a phase transition between ordered and disordered activity. A so far unresolved question concerns the medical significance of critical brain activity and how it relates to pathological conditions. Using data from invasive electroencephalogram recordings from humans we show that during epileptic seizure ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568637 Thu, 05 Jan 2012 05:00:00 +0100 5568637 http://www.medworm.com/index.php?rid=5568636&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FMQPZxl92esY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002330 by Nicoló Fusi, Oliver Stegle, Neil D. Lawrence Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic re... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568636 Thu, 05 Jan 2012 05:00:00 +0100 5568636 http://www.medworm.com/index.php?rid=5568635&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FPQGIcgJLIpc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002336 by Bart Baddeley, Paul Graham, Philip Husbands, Andrew Philippides In this paper we propose a model of visually guided route navigation in ants that captures the known properties of real behaviour whilst retaining mechanistic simplicity and thus biological plausibility. For an ant, the coupling of movement and viewing direction means that a familiar view specifies a familiar direction of movement. Since the views experienced along a habitual route will be more familiar, route navigation can be re-cast as a search for familiar views. This search can be performed with a simple scanning routine, a behaviour that ants have been observed to perform. We test this proposed route navigation strategy in simulation, by learning a series of routes through visually cluttered environments consisti... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568635 Thu, 05 Jan 2012 05:00:00 +0100 5568635 http://www.medworm.com/index.php?rid=5568634&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FZEOgCaFI4Qs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002337 by Yu-Kang Cheng, Rameen Beroukhim, Ross L. Levine, Ingo K. Mellinghoff, Eric C. Holland, Franziska Michor Human cancer is caused by the accumulation of genetic alterations in cells. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and thus represent promising targets for therapeutic intervention. We have previously described a computational approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to determine the temporal sequence of genetic alterations during tumorigenesis from cross-sectional genomic data of tumors at their fully transformed stage. Since alterations within a set of genes belonging to a particular signaling pathway may have similar or equivalent effects, we applied a pathway-... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568634 Thu, 05 Jan 2012 05:00:00 +0100 5568634 http://www.medworm.com/index.php?rid=5568633&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F3A5Mv3qnqys%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002328 by João A. N. Filipe, Richard C. Cobb, Ross K. Meentemeyer, Christopher A. Lee, Yana S. Valachovic, Alex R. Cook, David M. Rizzo, Christopher A. Gilligan Exotic pathogens and pests threaten ecosystem service, biodiversity, and crop security globally. If an invasive agent can disperse asymptomatically over long distances, multiple spatial and temporal scales interplay, making identification of effective strategies to regulate, monitor, and control disease extremely difficult. The management of outbreaks is also challenged by limited data on the actual area infested and the dynamics of spatial spread, due to financial, technological, or social constraints. We examine principles of landscape epidemiology important in designing policy to prevent or slow invasion by such organisms, and us... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568633 Thu, 05 Jan 2012 05:00:00 +0100 5568633 http://www.medworm.com/index.php?rid=5568632&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FL7-Ox-K_ReE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002327 by Karl J. Friston, Tamara Shiner, Thomas FitzGerald, Joseph M. Galea, Rick Adams, Harriet Brown, Raymond J. Dolan, Rosalyn Moran, Klaas Enno Stephan, Sven Bestmann The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using sim... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568632 Thu, 05 Jan 2012 05:00:00 +0100 5568632 http://www.medworm.com/index.php?rid=5568631&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FasWU0CvxhOE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002308 by Richard P. Mann, Andrea Perna, Daniel Strömbom, Roman Garnett, James E. Herbert-Read, David J. T. Sumpter, Ashley J. W. Ward Inference of interaction rules of animals moving in groups usually relies on an analysis of large scale system behaviour. Models are tuned through repeated simulation until they match the observed behaviour. More recent work has used the fine scale motions of animals to validate and fit the rules of interaction of animals in groups. Here, we use a Bayesian methodology to compare a variety of models to the collective motion of glass prawns (Paratya australiensis). We show that these exhibit a stereotypical ‘phase transition’, whereby an increase in density leads to the onset of collective motion in one direction. We fit models to this data, which range fr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568631 Thu, 05 Jan 2012 05:00:00 +0100 5568631 http://www.medworm.com/index.php?rid=5568630&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FyGyQo4asVMk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002306 by Shuoguo Wang, Lakshmi Chandrasekaran, Fernando R. Fernandez, John A. White, Carmen C. Canavier How stable synchrony in neuronal networks is sustained in the presence of conduction delays is an open question. The Dynamic Clamp was used to measure phase resetting curves (PRCs) for entorhinal cortical cells, and then to construct networks of two such neurons. PRCs were in general Type I (all advances or all delays) or weakly type II with a small region at early phases with the opposite type of resetting. We used previously developed theoretical methods based on PRCs under the assumption of pulsatile coupling to predict the delays that synchronize these hybrid circuits. For excitatory coupling, synchrony was predicted and observed only with no delay and for delays greater than half a n... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5568630 Thu, 05 Jan 2012 05:00:00 +0100 5568630 http://www.medworm.com/index.php?rid=5556702&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fm9G5y9mLAIw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002326 by Tianyun Liu, Russ B. Altman The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding pockets, but may not recognize distant similarities where dynamics or modified interactions allow one ligand to bind apparently divergent binding pockets. In this paper, we introduce an algorithm that seeks similar microenvironments within two binding sites, and assesses overall binding site similarity by the presence of multiple shared microenvironments. The method has relatively weak geometric requirements (to allow for conformational change or dynamics in both... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556702 Thu, 29 Dec 2011 05:00:00 +0100 5556702 http://www.medworm.com/index.php?rid=5556701&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FeKzH3h2eo4M%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002321 by Edward B. Baskerville, Andy P. Dobson, Trevor Bedford, Stefano Allesina, T. Michael Anderson, Mercedes Pascual Food webs, networks of feeding relationships in an ecosystem, provide fundamental insights into mechanisms that determine ecosystem stability and persistence. A standard approach in food-web analysis, and network analysis in general, has been to identify compartments, or modules, defined by many links within compartments and few links between them. This approach can identify large habitat boundaries in the network but may fail to identify other important structures. Empirical analyses of food webs have been further limited by low-resolution data for primary producers. In this paper, we present a Bayesian computational method for identifying group structure using a flexible... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556701 Thu, 29 Dec 2011 05:00:00 +0100 5556701 http://www.medworm.com/index.php?rid=5556700&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F5okvhPbbHIk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002291 by Konrad P. Kording Experiments in systems neuroscience can be seen as consisting of three steps: (1) selecting the signals we are interested in, (2) probing the system with carefully chosen stimuli, and (3) getting data out of the brain. Here I discuss how emerging techniques in molecular biology are starting to improve these three steps. To estimate its future impact on experimental neuroscience, I will stress the analogy of ongoing progress with that of microprocessor production techniques. These techniques have allowed computers to simplify countless problems; because they are easier to use than mechanical timers, they are even built into toasters. Molecular biology may advance even faster than computer speeds and has made immense progress in understanding and designing molecules... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556700 Thu, 29 Dec 2011 05:00:00 +0100 5556700 http://www.medworm.com/index.php?rid=5556699&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F3oH8bTa8WdY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002324 by Faisal Naqib, Carole A. Farah, Christopher C. Pack, Wayne S. Sossin The sensory-motor neuron synapse of Aplysia is an excellent model system for investigating the biochemical changes underlying memory formation. In this system, training that is separated by rest periods (spaced training) leads to persistent changes in synaptic strength that depend on biochemical pathways that are different from those that occur when the training lacks rest periods (massed training). Recently, we have shown that in isolated sensory neurons, applications of serotonin, the neurotransmitter implicated in inducing these synaptic changes during memory formation, lead to desensitization of the PKC Apl II response, in a manner that depends on the method of application (spaced versus massed). Here, we devel... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556699 Thu, 29 Dec 2011 05:00:00 +0100 5556699 http://www.medworm.com/index.php?rid=5556698&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FJpNBkUPa8TQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002285 by Yuliet Mazola, Glay Chinea, Alexis Musacchio (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556698 Thu, 29 Dec 2011 05:00:00 +0100 5556698 http://www.medworm.com/index.php?rid=5556697&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FJmWyZ9aid9U%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002322 by Guillaume Guilbaud, Aurélien Rappailles, Antoine Baker, Chun-Long Chen, Alain Arneodo, Arach Goldar, Yves d'Aubenton-Carafa, Claude Thermes, Benjamin Audit, Olivier Hyrien Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains con... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556697 Thu, 29 Dec 2011 05:00:00 +0100 5556697 http://www.medworm.com/index.php?rid=5556696&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FO5AkuX3oZng%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002323 by Xing-Ming Zhao, Murat Iskar, Georg Zeller, Michael Kuhn, Vera van Noort, Peer Bork Combinatorial therapy is a promising strategy for combating complex disorders due to improved efficacy and reduced side effects. However, screening new drug combinations exhaustively is impractical considering all possible combinations between drugs. Here, we present a novel computational approach to predict drug combinations by integrating molecular and pharmacological data. Specifically, drugs are represented by a set of their properties, such as their targets or indications. By integrating several of these features, we show that feature patterns enriched in approved drug combinations are not only predictive for new drug combinations but also provide insights into mechanisms underlying combinatoria... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556696 Thu, 29 Dec 2011 05:00:00 +0100 5556696 http://www.medworm.com/index.php?rid=5556695&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F6-b1ppIy3og%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002340 by Pan-Jun Kim, Nathan D. Price The phenotype of any organism on earth is, in large part, the consequence of interplay between numerous gene products encoded in the genome, and such interplay between gene products affects the evolutionary fate of the genome itself through the resulting phenotype. In this regard, contemporary genomes can be used as molecular records that reveal associations of various genes working in their natural lifestyles. By analyzing thousands of orthologs across ∼600 bacterial species, we constructed a map of gene-gene co-occurrence across much of the sequenced biome. If genes preferentially co-occur in the same organisms, they were called herein correlogs; in the opposite case, called anti-correlogs. To quantify correlogy and anti-correlogy, we alleviated the... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556695 Thu, 29 Dec 2011 05:00:00 +0100 5556695 http://www.medworm.com/index.php?rid=5556694&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FqHm8ZSi8C4A%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002332 by Chuan Xue, Elena O. Budrene, Hans G. Othmer The enteric bacterium Proteus mirabilis, which is a pathogen that forms biofilms in vivo, can swarm over hard surfaces and form a variety of spatial patterns in colonies. Colony formation involves two distinct cell types: swarmer cells that dominate near the surface and the leading edge, and swimmer cells that prefer a less viscous medium, but the mechanisms underlying pattern formation are not understood. New experimental investigations reported here show that swimmer cells in the center of the colony stream inward toward the inoculation site and in the process form many complex patterns, including radial and spiral streams, in addition to previously-reported concentric rings. These new observations suggest that swimmers are motile and t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556694 Thu, 29 Dec 2011 05:00:00 +0100 5556694 http://www.medworm.com/index.php?rid=5556693&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FMFtiAWDH9RM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002319 In this study we analyzed data from 3,290 immuno-precipitations (IP) followed by mass spectrometry (MS) applied to human cell lines aimed at identifying CoRegs complexes. Using the semi-quantitative spectral counts, we scored binary protein-protein and domain-domain associations with several equations. Unlike previous applications, our methods scored prey-prey protein-protein interactions regardless of the baits used. We also predicted domain-domain interactions underlying predicted protein-protein interactions. The quality of predicted protein-protein and domain-domain interactions was evaluated using known binary interactions from the literature, whereas one protein-protein interaction, between STRN and CTTNBP2NL, was validated experimentally; and one domain-domain interaction, between t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5556693 Thu, 29 Dec 2011 05:00:00 +0100 5556693 http://www.medworm.com/index.php?rid=5533074&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FNariAjqnPD0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002325 by Daniel Shriner, Adebowale Adeyemo, Charles N. Rotimi For samples of admixed individuals, it is possible to test for both ancestry effects via admixture mapping and genotype effects via association mapping. Here, we describe a joint test called BMIX that combines admixture and association statistics at single markers. We first perform high-density admixture mapping using local ancestry. We then perform association mapping using stratified regression, wherein for each marker genotypes are stratified by local ancestry. In both stages, we use generalized linear models, providing the advantage that the joint test can be used with any phenotype distribution with an appropriate link function. To define the alternative densities for admixture mapping and association mapping, we describe a ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533074 Thu, 22 Dec 2011 05:00:00 +0100 5533074 http://www.medworm.com/index.php?rid=5533073&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FiOqE8QMxqvQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002320 In conclusion, Plasmodium species harbour many chromosome-internal differences in the form of protein-coding genes, some of which are potentially linked to human disease and thus promising leads for future laboratory research. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533073 Thu, 22 Dec 2011 05:00:00 +0100 5533073 http://www.medworm.com/index.php?rid=5533072&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fi3qjHA1fVlc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002300 We present a systems biology approach to efficiently evaluate a large number of possible recipes and find those that are most effective at generating iPSCs. We not only recovered several experimentally confirmed recipes but we also suggested new ones that may improve reprogramming efficiency and quality. In addition, our approach allows one to estimate the cell-state landscape, monitor the progress of reprogramming, identify important regulatory transition states, and ultimately understand the mechanisms of iPSC generation. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533072 Thu, 22 Dec 2011 05:00:00 +0100 5533072 http://www.medworm.com/index.php?rid=5533071&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FdmfhZjzQcII%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002318 by Ying Zhang, Olga Zagnitko, Irina Rodionova, Andrei Osterman, Adam Godzik Function diversification in large protein families is a major mechanism driving expansion of cellular networks, providing organisms with new metabolic capabilities and thus adding to their evolutionary success. However, our understanding of the evolutionary mechanisms of functional diversity in such families is very limited, which, among many other reasons, is due to the lack of functionally well-characterized sets of proteins. Here, using the FGGY carbohydrate kinase family as an example, we built a confidently annotated reference set (CARS) of proteins by propagating experimentally verified functional assignments to a limited number of homologous proteins that are supported by their genomic and functional co... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533071 Thu, 22 Dec 2011 05:00:00 +0100 5533071 http://www.medworm.com/index.php?rid=5533070&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F7EXunVFzc_w%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002304 In this study we show that combinatorial binding is strongly associated with co-localization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an i... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533070 Thu, 22 Dec 2011 05:00:00 +0100 5533070 http://www.medworm.com/index.php?rid=5533069&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FnJJtvE6sar4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002315 by Su-Sen Chang, Hung-Jin Huang, Calvin Yu-Chian Chen The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyrid... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533069 Thu, 22 Dec 2011 05:00:00 +0100 5533069 http://www.medworm.com/index.php?rid=5533068&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fv1tmi6Z6moo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002314 by Yang Jiao, Salvatore Torquato Understanding tumor invasion and metastasis is of crucial importance for both fundamental cancer research and clinical practice. In vitro experiments have established that the invasive growth of malignant tumors is characterized by the dendritic invasive branches composed of chains of tumor cells emanating from the primary tumor mass. The preponderance of previous tumor simulations focused on non-invasive (or proliferative) growth. The formation of the invasive cell chains and their interactions with the primary tumor mass and host microenvironment are not well understood. Here, we present a novel cellular automaton (CA) model that enables one to efficiently simulate invasive tumor growth in a heterogeneous host microenvironment. By taking into account... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533068 Thu, 22 Dec 2011 05:00:00 +0100 5533068 http://www.medworm.com/index.php?rid=5533067&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FtnW0SwgW09s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002305 by Ashok Litwin-Kumar, Anne-Marie M. Oswald, Nathaniel N. Urban, Brent Doiron Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533067 Thu, 22 Dec 2011 05:00:00 +0100 5533067 http://www.medworm.com/index.php?rid=5533066&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fvtt8Cfym05I%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002298 by Andreas Spiegler, Thomas R. Knösche, Karin Schwab, Jens Haueisen, Fatihcan M. Atay Stimulation with rhythmic light flicker (photic driving) plays an important role in the diagnosis of schizophrenia, mood disorder, migraine, and epilepsy. In particular, the adjustment of spontaneous brain rhythms to the stimulus frequency (entrainment) is used to assess the functional flexibility of the brain. We aim to gain deeper understanding of the mechanisms underlying this technique and to predict the effects of stimulus frequency and intensity. For this purpose, a modified Jansen and Rit neural mass model (NMM) of a cortical circuit is used. This mean field model has been designed to strike a balance between mathematical simplicity and biological plausibility. We reproduced the entrainment p... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5533066 Thu, 22 Dec 2011 05:00:00 +0100 5533066 http://www.medworm.com/index.php?rid=5512196&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F4nBAVqaM-0k%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002303 by Izzet B. Yildiz, Stefan J. Kiebel The neuronal system underlying learning, generation and recognition of song in birds is one of the best-studied systems in the neurosciences. Here, we use these experimental findings to derive a neurobiologically plausible, dynamic, hierarchical model of birdsong generation and transform it into a functional model of birdsong recognition. The generation model consists of neuronal rate models and includes critical anatomical components like the premotor song-control nucleus HVC (proper name), the premotor nucleus RA (robust nucleus of the arcopallium), and a model of the syringeal and respiratory organs. We use Bayesian inference of this dynamical system to derive a possible mechanism for how birds can efficiently and robustly recognize the songs of... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512196 Thu, 15 Dec 2011 05:00:00 +0100 5512196 http://www.medworm.com/index.php?rid=5512195&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FORIp6gL192c%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002310 by Zhichao Liu, Qiang Shi, Don Ding, Reagan Kelly, Hong Fang, Weida Tong Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To e... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512195 Thu, 15 Dec 2011 05:00:00 +0100 5512195 http://www.medworm.com/index.php?rid=5512194&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FV8ntNjKhnvk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002302 We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are s... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512194 Thu, 15 Dec 2011 05:00:00 +0100 5512194 http://www.medworm.com/index.php?rid=5512193&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FQwdwuxOOCM8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002279 by Mithun Biswas, Karine Voltz, Jeremy C. Smith, Jörg Langowski Histone tails play an important role in nucleosome structure and dynamics. Here we investigate the effect of truncation of histone tails H3, H4, H2A and H2B on nucleosome structure with 100 ns all-atom molecular dynamics simulations. Tail domains of H3 and H2B show propensity of -helics formation during the intact nucleosome simulation. On truncation of H4 or H2B tails no structural change occurs in histones. However, H3 or H2A tail truncation results in structural alterations in the histone core domain, and in both the cases the structural change occurs in the H2A3 domain. We also find that the contacts between the histone H2A C terminal docking domain and surrounding residues are destabilized upon H3 tail truncation. T... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512193 Thu, 15 Dec 2011 05:00:00 +0100 5512193 http://www.medworm.com/index.php?rid=5512192&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FkKQxl1kK-dw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002313 by Ismail Adeniran, Mark J. McPate, Harry J. Witchel, Jules C. Hancox, Henggui Zhang The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K+ current (IKr)-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512192 Thu, 15 Dec 2011 05:00:00 +0100 5512192 http://www.medworm.com/index.php?rid=5512191&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FVUh9H9tLm1c%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002317 by Lan K. Nguyen, Javier Muñoz-García, Helene Maccario, Aaron Ciechanover, Walter Kolch, Boris N. Kholodenko In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512191 Thu, 15 Dec 2011 05:00:00 +0100 5512191 http://www.medworm.com/index.php?rid=5512190&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FNEY1D8Tz5nE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002294 by Dejan Pecevski, Lars Buesing, Wolfgang Maass An important open problem of computational neuroscience is the generic organization of computations in networks of neurons in the brain. We show here through rigorous theoretical analysis that inherent stochastic features of spiking neurons, in combination with simple nonlinear computational operations in specific network motifs and dendritic arbors, enable networks of spiking neurons to carry out probabilistic inference through sampling in general graphical models. In particular, it enables them to carry out probabilistic inference in Bayesian networks with converging arrows (“explaining away”) and with undirected loops, that occur in many real-world tasks. Ubiquitous stochastic features of networks of spiking neurons, such as trial... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512190 Thu, 15 Dec 2011 05:00:00 +0100 5512190 http://www.medworm.com/index.php?rid=5512189&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FfuqikOFgBtA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002309 by Angela Relógio, Pal O. Westermark, Thomas Wallach, Katja Schellenberg, Achim Kramer, Hanspeter Herzel The circadian clock is accountable for the regulation of internal rhythms in most living organisms. It allows the anticipation of environmental changes during the day and a better adaptation of physiological processes. In mammals the main clock is located in the suprachiasmatic nucleus (SCN) and synchronizes secondary clocks throughout the body. Its molecular constituents form an intracellular network which dictates circadian time and regulates clock-controlled genes. These clock-controlled genes are involved in crucial biological processes including metabolism and cell cycle regulation. Its malfunction can lead to disruption of biological rhythms and cause severe damage to the or... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5512189 Thu, 15 Dec 2011 05:00:00 +0100 5512189 http://www.medworm.com/index.php?rid=5492450&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FaCLi4fzPfFM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002307 by Pranesh Padmanabhan, Narendra M. Dixit Interaction between the hepatitis C virus (HCV) envelope protein E2 and the host receptor CD81 is essential for HCV entry into target cells. The number of E2-CD81 complexes necessary for HCV entry has remained difficult to estimate experimentally. Using the recently developed cell culture systems that allow persistent HCV infection in vitro, the dependence of HCV entry and kinetics on CD81 expression has been measured. We reasoned that analysis of the latter experiments using a mathematical model of viral kinetics may yield estimates of the number of E2-CD81 complexes necessary for HCV entry. Here, we constructed a mathematical model of HCV viral kinetics in vitro, in which we accounted explicitly for the dependence of HCV entry on CD81 expres... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5492450 Thu, 08 Dec 2011 05:00:00 +0100 5492450 http://www.medworm.com/index.php?rid=5492449&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FcVW30Jjn9qU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002295 by Franck Gallier, Perrine Lallemand, Maïa Meurillon, Lars P. Jordheim, Charles Dumontet, Christian Périgaud, Corinne Lionne, Suzanne Peyrottes, Laurent Chaloin Cytosolic 5′-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5′-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymaticall... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5492449 Thu, 08 Dec 2011 05:00:00 +0100 5492449 http://www.medworm.com/index.php?rid=5492448&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FeCqcAPkq7K4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002301 by Simon Mitternacht, Igor N. Berezovsky Conformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effector ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational d... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5492448 Thu, 08 Dec 2011 05:00:00 +0100 5492448 http://www.medworm.com/index.php?rid=5492447&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Ft-WlAX1aUxo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002297 by Núria Domedel-Puig, Pau Rué, Antonio J. Pons, Jordi García-Ojalvo Living systems are capable of processing multiple sources of information simultaneously. This is true even at the cellular level, where not only coexisting signals stimulate the cell, but also the presence of fluctuating conditions is significant. When information is received by a cell signaling network via one specific input, the existence of other stimuli can provide a background activity –or chatter– that may affect signal transmission through the network and, therefore, the response of the cell. Here we study the modulation of information processing by chatter in the signaling network of a human cell, specifically, in a Boolean model of the signal transduction network of a fibroblast. We observe that the l... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5492447 Thu, 08 Dec 2011 05:00:00 +0100 5492447 http://www.medworm.com/index.php?rid=5465052&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fda_tTu1ZTpc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002276 by Matthew E. Ritchie, Mark J. Dunning, Mike L. Smith, Wei Shi, Andy G. Lynch Illumina whole-genome expression BeadArrays are a popular choice in gene profiling studies. Aside from the vendor-provided software tools for analyzing BeadArray expression data (GenomeStudio/BeadStudio), there exists a comprehensive set of open-source analysis tools in the Bioconductor project, many of which have been tailored to exploit the unique properties of this platform. In this article, we explore a number of these software packages and demonstrate how to perform a complete analysis of BeadArray data in various formats. The key steps of importing data, performing quality assessments, preprocessing, and annotation in the common setting of assessing differential expression in designed experiments will ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465052 Thu, 01 Dec 2011 05:00:00 +0100 5465052 http://www.medworm.com/index.php?rid=5465051&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FmwkXE5QotI8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002289 We present a mathematical model of within-host evolution and between-host transmission of CTL escape mutants amongst a population receiving a vaccine that elicits CTL responses to multiple epitopes. Within-host evolution at each epitope is represented by the outgrowth of escape mutants in hosts who restrict the epitope and their reversion in hosts who do not restrict the epitope. We use this model to investigate how the evolution and spread of escape mutants could affect the impact of a vaccine. We show that in the absence of escape, such a vaccine could markedly reduce the prevalence of both infection and disease in the population. However the impact of such a vaccine could be significantly abated by CTL escape mutants, especially if their selection in hosts who restrict the epitope is ra... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465051 Thu, 01 Dec 2011 05:00:00 +0100 5465051 http://www.medworm.com/index.php?rid=5465050&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fu0orxlRJsSY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002277 by Lukas Käll, Olga Vitek (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465050 Thu, 01 Dec 2011 05:00:00 +0100 5465050 http://www.medworm.com/index.php?rid=5465049&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FRX_rqT7_2CA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002269 by Christopher J. Creevey, Jean Muller, Tobias Doerks, Julie D. Thompson, Detlev Arendt, Peer Bork The identification of single copy (1-to-1) orthologs in any group of organisms is important for functional classification and phylogenetic studies. The Metazoa are no exception, but only recently has there been a wide-enough distribution of taxa with sufficiently high quality sequenced genomes to gain confidence in the wide-spread single copy status of a gene. Here, we present a phylogenetic approach for identifying overlooked single copy orthologs from multigene families and apply it to the Metazoa. Using 18 sequenced metazoan genomes of high quality we identified a robust set of 1,126 orthologous groups that have been retained in single copy since the last common ancestor of Metazo... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465049 Thu, 01 Dec 2011 05:00:00 +0100 5465049 http://www.medworm.com/index.php?rid=5465048&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F4Tt3XITHf2A%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002268 by Dieter Vanderelst, Jonas Reijniers, Uwe Firzlaff, Herbert Peremans Rhinolophidae or Horseshoe bats emit long and narrowband calls. Fluttering insect prey generates echoes in which amplitude and frequency shifts are present, i.e. glints. These glints are reliable cues about the presence of prey and also encode certain properties of the prey. In this paper, we propose that these glints, i.e. the dominant glints, are also reliable signals upon which to base prey localization. In contrast to the spectral cues used by many other bats, the localization cues in Rhinolophidae are most likely provided by self-induced amplitude modulations generated by pinnae movement. Amplitude variations in the echo not introduced by the moving pinnae can be considered as noise interfering with the localiz... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465048 Thu, 01 Dec 2011 05:00:00 +0100 5465048 http://www.medworm.com/index.php?rid=5465047&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FohhDKiIbe4w%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002290 We present analytical solutions for these equations, calculate the corresponding extinction times and compare our results to individual based stochastic simulations. Our general compartment structure can be applied to different tissues, as for example hematopoiesis, the epidermis, or colonic crypts. The solutions provide a description of the average time development of stem cell and non stem cell driven mutants and can be used to illustrate general and specific features of the dynamics of mutant cells in such hierarchically structured populations. We illustrate one possible application of this approach by discussing the origin and dynamics of PIG-A mutant clones that are found in the bloodstream of virtually every healthy adult human. From this it is apparent, that not only the occurrence ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465047 Thu, 01 Dec 2011 05:00:00 +0100 5465047 http://www.medworm.com/index.php?rid=5465046&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FhRJo8c6Ebdk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002283 by Sakuntala Chatterjee, Rava Azeredo da Silveira, Yariv Kafri Escherichia coli (E. coli) bacteria govern their trajectories by switching between running and tumbling modes as a function of the nutrient concentration they experienced in the past. At short time one observes a drift of the bacterial population, while at long time one observes accumulation in high-nutrient regions. Recent work has viewed chemotaxis as a compromise between drift toward favorable regions and accumulation in favorable regions. A number of earlier studies assume that a bacterium resets its memory at tumbles – a fact not borne out by experiment – and make use of approximate coarse-grained descriptions. Here, we revisit the problem of chemotaxis without resorting to any memory resets. We find that when bac... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465046 Thu, 01 Dec 2011 05:00:00 +0100 5465046 http://www.medworm.com/index.php?rid=5465045&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FGylajjW57SA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002293 by Maurizio De Pittà, Vladislav Volman, Hugues Berry, Eshel Ben-Jacob Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression) and/or increase (facilitation) of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465045 Thu, 01 Dec 2011 05:00:00 +0100 5465045 http://www.medworm.com/index.php?rid=5465044&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FmiePidaEQx4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002292 by Alessandro Ambrosi, Ingrid K. Glad, Danilo Pellin, Claudia Cattoglio, Fulvio Mavilio, Clelia Di Serio, Arnoldo Frigessi Integration of retroviral vectors in the human genome follows non random patterns that favor insertional deregulation of gene expression and may cause risks of insertional mutagenesis when used in clinical gene therapy. Understanding how viral vectors integrate into the human genome is a key issue in predicting these risks. We provide a new statistical method to compare retroviral integration patterns. We identified the positions where vectors derived from the Human Immunodeficiency Virus (HIV) and the Moloney Murine Leukemia Virus (MLV) show different integration behaviors in human hematopoietic progenitor cells. Non-parametric density estimation was used to iden... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465044 Thu, 01 Dec 2011 05:00:00 +0100 5465044 http://www.medworm.com/index.php?rid=5465043&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fz7f70hvUDmM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002270 by Dmitry A. Fedosov, Huan Lei, Bruce Caswell, Subra Suresh, George E. Karniadakis Red blood cells (RBCs) infected by a Plasmodium parasite in malaria may lose their membrane deformability with a relative membrane stiffening more than ten-fold in comparison with healthy RBCs leading to potential capillary occlusions. Moreover, infected RBCs are able to adhere to other healthy and parasitized cells and to the vascular endothelium resulting in a substantial disruption of normal blood circulation. In the present work, we simulate infected RBCs in malaria using a multiscale RBC model based on the dissipative particle dynamics method, coupling scales at the sub-cellular level with scales at the vessel size. Our objective is to conduct a full validation of the RBC model with a diverse set o... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465043 Thu, 01 Dec 2011 05:00:00 +0100 5465043 http://www.medworm.com/index.php?rid=5465042&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FGDi5q3gSADM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002278 by Dov Greenbaum, Andrea Sboner, Xinmeng Jasmine Mu, Mark Gerstein Open source and open data have been driving forces in bioinformatics in the past. However, privacy concerns may soon change the landscape, limiting future access to important data sets, including personal genomics data. Here we survey this situation in some detail, describing, in particular, how the large scale of the data from personal genomic sequencing makes it especially hard to share data, exacerbating the privacy problem. We also go over various aspects of genomic privacy: first, there is basic identifiability of subjects having their genome sequenced. However, even for individuals who have consented to be identified, there is the prospect of very detailed future characterization of their genotype, which, unantic... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465042 Thu, 01 Dec 2011 05:00:00 +0100 5465042 http://www.medworm.com/index.php?rid=5465041&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FKkD-DqimG9s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002256 by Andrew T. Kwon, Alice Yi Chou, David J. Arenillas, Wyeth W. Wasserman We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nu... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465041 Thu, 01 Dec 2011 05:00:00 +0100 5465041 http://www.medworm.com/index.php?rid=5465040&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FjjeW11a7amU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002228 by Thadeous Kacmarczyk, Peter Waltman, Ashley Bate, Patrick Eichenberger, Richard Bonneau The increasing abundance of large-scale, high-throughput datasets for many closely related organisms provides opportunities for comparative analysis via the simultaneous biclustering of datasets from multiple species. These analyses require a reformulation of how to organize multi-species datasets and visualize comparative genomics data analyses results. Recently, we developed a method, multi-species cMonkey, which integrates heterogeneous high-throughput datatypes from multiple species to identify conserved regulatory modules. Here we present an integrated data visualization system, built upon the Gaggle, enabling exploration of our method's results (available at http://meatwad.bio.nyu.edu/cmmr.... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465040 Thu, 01 Dec 2011 05:00:00 +0100 5465040 http://www.medworm.com/index.php?rid=5465039&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fwfc7kOkl9N8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002272 by Ke Xu, Kevin T. Morgan, Abby Todd Gehris, Timothy C. Elston, Shawn M. Gomez Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5465039 Thu, 01 Dec 2011 05:00:00 +0100 5465039 http://www.medworm.com/index.php?rid=5417321&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FX03tEy_OvX8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002259 by Pedro Madrigal, Noa Sela, Simon M. Lin (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417321 Thu, 17 Nov 2011 05:00:00 +0100 5417321 http://www.medworm.com/index.php?rid=5417320&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FLFT4MvZGFP8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002288 by Avraham Ben-Shimon, Masha Y. Niv Protein kinases are key signaling enzymes that catalyze the transfer of γ-phosphate from an ATP molecule to a phospho-accepting residue in the substrate. Unraveling the molecular features that govern the preference of kinases for particular residues flanking the phosphoacceptor is important for understanding kinase specificities toward their substrates and for designing substrate-like peptidic inhibitors. We applied ANCHORSmap, a new fragment-based computational approach for mapping amino acid side chains on protein surfaces, to predict and characterize the preference of kinases toward Arginine binding. We focus on positions P−2 and P−5, commonly occupied by Arginine (Arg) in substrates of basophilic Ser/Thr kinases. The method accurately ident... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417320 Thu, 17 Nov 2011 05:00:00 +0100 5417320 http://www.medworm.com/index.php?rid=5417319&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FqNEeFeEYI2s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002287 by Zhuo Song, Yang Cao, David C. Samuels The activity of polymerase γ is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-γ might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-γ that models its activities on the level of individual nucleotides for the replication of mtDNA. This method gives us insights into the pausing of two pol-γ variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-γ (exo−) in premature aging mouse models. To measure the pausing, we analyzed simulation results for the longest time for the polymerase to move forward one nuc... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417319 Thu, 17 Nov 2011 05:00:00 +0100 5417319 http://www.medworm.com/index.php?rid=5417318&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FMILBsTvO5Hg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002284 by Michael E. Wall, Sindhu Raghavan, Judith D. Cohn, John Dunbar Recent studies have noted extensive inconsistencies in gene start sites among orthologous genes in related microbial genomes. Here we provide the first documented evidence that imposing gene start consistency improves the accuracy of gene start-site prediction. We applied an algorithm using a genome majority vote (GMV) scheme to increase the consistency of gene starts among orthologs. We used a set of validated Escherichia coli genes as a standard to quantify accuracy. Results showed that the GMV algorithm can correct hundreds of gene prediction errors in sets of five or ten genomes while introducing few errors. Using a conservative calculation, we project that GMV would resolve many inconsistencies and errors in publicl... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417318 Thu, 17 Nov 2011 05:00:00 +0100 5417318 http://www.medworm.com/index.php?rid=5417317&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FGKKiiNmEMLo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002282 by Alfonso Pérez-Escudero, Gonzalo G. de Polavieja Animals living in groups make movement decisions that depend, among other factors, on social interactions with other group members. Our present understanding of social rules in animal collectives is mainly based on empirical fits to observations, with less emphasis in obtaining first-principles approaches that allow their derivation. Here we show that patterns of collective decisions can be derived from the basic ability of animals to make probabilistic estimations in the presence of uncertainty. We build a decision-making model with two stages: Bayesian estimation and probabilistic matching. In the first stage, each animal makes a Bayesian estimation of which behavior is best to perform taking into account personal information about... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417317 Thu, 17 Nov 2011 05:00:00 +0100 5417317 http://www.medworm.com/index.php?rid=5417316&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F1R-iYDli3Pg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002281 by Zachary P. Kilpatrick, Bard Ermentrout Gamma rhythms (30–100 Hz) are an extensively studied synchronous brain state responsible for a number of sensory, memory, and motor processes. Experimental evidence suggests that fast-spiking interneurons are responsible for carrying the high frequency components of the rhythm, while regular-spiking pyramidal neurons fire sparsely. We propose that a combination of spike frequency adaptation and global inhibition may be responsible for this behavior. Excitatory neurons form several clusters that fire every few cycles of the fast oscillation. This is first shown in a detailed biophysical network model and then analyzed thoroughly in an idealized model. We exploit the fact that the timescale of adaptation is much slower than that of the other v... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417316 Thu, 17 Nov 2011 05:00:00 +0100 5417316 http://www.medworm.com/index.php?rid=5417315&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FvxN9HP5iJYw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002280 This article presents the first attempt to formalize the optimization of experimental design with the aim of comparing models of brain function based on neuroimaging data. We demonstrate our approach in the context of Dynamic Causal Modelling (DCM), which relates experimental manipulations to observed network dynamics (via hidden neuronal states) and provides an inference framework for selecting among candidate models. Here, we show how to optimize the sensitivity of model selection by choosing among experimental designs according to their respective model selection accuracy. Using Bayesian decision theory, we (i) derive the Laplace-Chernoff risk for model selection, (ii) disclose its relationship with classical design optimality criteria and (iii) assess its sensitivity to basic modelling... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417315 Thu, 17 Nov 2011 05:00:00 +0100 5417315 http://www.medworm.com/index.php?rid=5417314&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FEX2iZgZsDIg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002275 by Zhiming Dai, Xianhua Dai Sequence changes in coding region and regulatory region of the gene itself (cis) determine most of gene expression divergence between closely related species. But gene expression divergence between yeast species is not correlated with evolution of primary nucleotide sequence. This indicates that other factors in cis direct gene expression divergence. Here, we studied the contribution of DNA three-dimensional structural evolution as cis to gene expression divergence. We found that the evolution of DNA structure in coding regions and gene expression divergence are correlated in yeast. Similar result was also observed between Drosophila species. DNA structure is associated with the binding of chromatin remodelers and histone modifiers to DNA sequences in codin... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417314 Thu, 17 Nov 2011 05:00:00 +0100 5417314 http://www.medworm.com/index.php?rid=5417313&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FFCcc_Mpx83E%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002274 by Andrew J. Yates, Minus Van Baalen, Rustom Antia Vaccines that elicit protective cytotoxic T lymphocytes (CTL) may improve on or augment those designed primarily to elicit antibody responses. However, we have little basis for estimating the numbers of CTL required for sterilising immunity at an infection site. To address this we begin with a theoretical estimate obtained from measurements of CTL surveillance rates and the growth rate of a virus. We show how this estimate needs to be modified to account for (i) the dynamics of CTL-infected cell conjugates, and (ii) features of the virus lifecycle in infected cells. We show that provided the inoculum size of the virus is low, the dynamics of CTL-infected cell conjugates can be ignored, but knowledge of virus life-histories is required... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417313 Thu, 17 Nov 2011 05:00:00 +0100 5417313 http://www.medworm.com/index.php?rid=5417312&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FZu2F9zCAgXY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002265 by Rutger Hermsen, David W. Erickson, Terence Hwa Cells employ a myriad of signaling circuits to detect environmental signals and drive specific gene expression responses. A common motif in these circuits is inducible auto-activation: a transcription factor that activates its own transcription upon activation by a ligand or by post-transcriptional modification. Examples range from the two-component signaling systems in bacteria and plants to the genetic circuits of animal viruses such as HIV. We here present a theoretical study of such circuits, based on analytical calculations, numerical computations, and simulation. Our results reveal several surprising characteristics. They show that auto-activation can drastically enhance the sensitivity of the circuit's response to input signals:... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417312 Thu, 17 Nov 2011 05:00:00 +0100 5417312 http://www.medworm.com/index.php?rid=5417311&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fvro1TgJeJEw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002254 by Man Yi Yim, Ad Aertsen, Arvind Kumar The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background act... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417311 Thu, 17 Nov 2011 05:00:00 +0100 5417311 http://www.medworm.com/index.php?rid=5417310&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FCNQvVvrp1V0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002247 by Joshua H. Goldwyn, Eric Shea-Brown Conductance-based equations for electrically active cells form one of the most widely studied mathematical frameworks in computational biology. This framework, as expressed through a set of differential equations by Hodgkin and Huxley, synthesizes the impact of ionic currents on a cell's voltage—and the highly nonlinear impact of that voltage back on the currents themselves—into the rapid push and pull of the action potential. Later studies confirmed that these cellular dynamics are orchestrated by individual ion channels, whose conformational changes regulate the conductance of each ionic current. Thus, kinetic equations familiar from physical chemistry are the natural setting for describing conductances; for small-to-moderate numbers of chan... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417310 Thu, 17 Nov 2011 05:00:00 +0100 5417310 http://www.medworm.com/index.php?rid=5417309&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FrHQlndhMH7E%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002218 by Ralf Steuer, Steffen Waldherr, Victor Sourjik, Markus Kollmann Cellular signaling networks have evolved an astonishing ability to function reliably and with high fidelity in uncertain environments. A crucial prerequisite for the high precision exhibited by many signaling circuits is their ability to keep the concentrations of active signaling compounds within tightly defined bounds, despite strong stochastic fluctuations in copy numbers and other detrimental influences. Based on a simple mathematical formalism, we identify topological organizing principles that facilitate such robust control of intracellular concentrations in the face of multifarious perturbations. Our framework allows us to judge whether a multiple-input-multiple-output reaction network is robust against large per... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417309 Thu, 17 Nov 2011 05:00:00 +0100 5417309 http://www.medworm.com/index.php?rid=5417308&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FbtJ2mmHCurM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002190 We present a network framework for analyzing multi-level regulation in higher eukaryotes based on systematic integration of various high-throughput datasets. The network, namely the integrated regulatory network, consists of three major types of regulation: TF→gene, TF→miRNA and miRNA→gene. We identified the target genes and target miRNAs for a set of TFs based on the ChIP-Seq binding profiles, the predicted targets of miRNAs using annotated 3′UTR sequences and conservation information. Making use of the system-wide RNA-Seq profiles, we classified transcription factors into positive and negative regulators and assigned a sign for each regulatory interaction. Other types of edges such as protein-protein interactions and potential intra-regulations between miRNAs based on the embeddi... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5417308 Thu, 17 Nov 2011 05:00:00 +0100 5417308 http://www.medworm.com/index.php?rid=5396617&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FqutP5WmuwmM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002273 by Anna Kuchina, Lorena Espinar, Jordi Garcia-Ojalvo, Gürol M. Süel Cells must make reliable decisions under fluctuating extracellular conditions, but also be flexible enough to adapt to such changes. How cells reconcile these seemingly contradictory requirements through the dynamics of cellular decision-making is poorly understood. To study this issue we quantitatively measured gene expression and protein localization in single cells of the model organism Bacillus subtilis during the progression to spore formation. We found that sporulation proceeded through noisy and reversible steps towards an irreversible, all-or-none commitment point. Specifically, we observed cell-autonomous and spontaneous bursts of gene expression and transient protein localization events during sporulation.... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396617 Thu, 10 Nov 2011 05:00:00 +0100 5396617 http://www.medworm.com/index.php?rid=5396616&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FSK6h9q8qblw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002271 by Alexandra Jilkine, Sigurd B. Angenent, Lani F. Wu, Steven J. Altschuler Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered “off” state is desired? And, what limits the spread of clusters when an “on” state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396616 Thu, 10 Nov 2011 05:00:00 +0100 5396616 http://www.medworm.com/index.php?rid=5396615&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FCwxzoCeIOJc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002267 by Assieh Saadatpour, Rui-Sheng Wang, Aijun Liao, Xin Liu, Thomas P. Loughran, István Albert, Réka Albert The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396615 Thu, 10 Nov 2011 05:00:00 +0100 5396615 http://www.medworm.com/index.php?rid=5396614&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fi-utrwb-ebI%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002266 by Yuichi Katori, Kazuhiro Sakamoto, Naohiro Saito, Jun Tanji, Hajime Mushiake, Kazuyuki Aihara The prefrontal cortex (PFC) plays a crucial role in flexible cognitive behavior by representing task relevant information with its working memory. The working memory with sustained neural activity is described as a neural dynamical system composed of multiple attractors, each attractor of which corresponds to an active state of a cell assembly, representing a fragment of information. Recent studies have revealed that the PFC not only represents multiple sets of information but also switches multiple representations and transforms a set of information to another set depending on a given task context. This representational switching between different sets of information is possibly generated ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396614 Thu, 10 Nov 2011 05:00:00 +0100 5396614 http://www.medworm.com/index.php?rid=5396613&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fftd60v9qLic%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002264 by Krešimir Josić, José Manuel López, William Ott, LieJune Shiau, Matthew R. Bennett The creation of protein from DNA is a dynamic process consisting of numerous reactions, such as transcription, translation and protein folding. Each of these reactions is further comprised of hundreds or thousands of sub-steps that must be completed before a protein is fully mature. Consequently, the time it takes to create a single protein depends on the number of steps in the reaction chain and the nature of each step. One way to account for these reactions in models of gene regulatory networks is to incorporate dynamical delay. However, the stochastic nature of the reactions necessary to produce protein leads to a waiting time that is randomly distributed. Here, we use queueing theory to examin... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396613 Thu, 10 Nov 2011 05:00:00 +0100 5396613 http://www.medworm.com/index.php?rid=5396612&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FkjR9kXoCFKA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002263 by Joshua Lequieu, Anirikh Chakrabarti, Satyaprakash Nayak, Jeffrey D. Varner Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396612 Thu, 10 Nov 2011 05:00:00 +0100 5396612 http://www.medworm.com/index.php?rid=5396611&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FDVlwAgfKz8g%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002262 by Gautham Vivek Sridharan, Soha Hassoun, Kyongbum Lee Modularity analysis offers a route to better understand the organization of cellular biochemical networks as well as to derive practically useful, simplified models of these complex systems. While there is general agreement regarding the qualitative properties of a biochemical module, there is no clear consensus on the quantitative criteria that may be used to systematically derive these modules. In this work, we investigate cyclical interactions as the defining characteristic of a biochemical module. We utilize a round trip distance metric, termed Shortest Retroactive Distance (ShReD), to characterize the retroactive connectivity between any two reactions in a biochemical network and to group together network components that mutu... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396611 Thu, 10 Nov 2011 05:00:00 +0100 5396611 http://www.medworm.com/index.php?rid=5396610&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F3yO05r15I4c%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002226 by Arjun Narayanan, Lawrence L. LeClaire, Diane L. Barber, Matthew P. Jacobson Actin filament assembly by the actin-related protein (Arp) 2/3 complex is necessary to build many cellular structures, including lamellipodia at the leading edge of motile cells and phagocytic cups, and to move endosomes and intracellular pathogens. The crucial role of the Arp2/3 complex in cellular processes requires precise spatiotemporal regulation of its activity. While binding of nucleation-promoting factors (NPFs) has long been considered essential to Arp2/3 complex activity, we recently showed that phosphorylation of the Arp2 subunit is also necessary for Arp2/3 complex activation. Using molecular dynamics simulations and biochemical assays with recombinant Arp2/3 complex, we now show how phosphoryla... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5396610 Thu, 10 Nov 2011 05:00:00 +0100 5396610 http://www.medworm.com/index.php?rid=5374945&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FPb915z4Y2Uw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002261 by Bruno M.C. Martins, Peter S. Swain Sensing extracellular changes initiates signal transduction and is the first stage of cellular decision-making. Yet relatively little is known about why one form of sensing biochemistry has been selected over another. To gain insight into this question, we studied the sensing characteristics of one of the biochemically simplest of sensors: the allosteric transcription factor. Such proteins, common in microbes, directly transduce the detection of a sensed molecule to changes in gene regulation. Using the Monod-Wyman-Changeux model, we determined six sensing characteristics – the dynamic range, the Hill number, the intrinsic noise, the information transfer capacity, the static gain, and the mean response time – as a function of the biochemical p... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374945 Thu, 03 Nov 2011 04:00:00 +0100 5374945 http://www.medworm.com/index.php?rid=5374944&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FYGPrcqPAe70%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002260 by Philipp M. Altrock, Arne Traulsen, Floyd A. Reed In isolated populations underdominance leads to bistable evolutionary dynamics: below a certain mutant allele frequency the wildtype succeeds. Above this point, the potentially underdominant mutant allele fixes. In subdivided populations with gene flow there can be stable states with coexistence of wildtypes and mutants: polymorphism can be maintained because of a migration-selection equilibrium, i.e., selection against rare recent immigrant alleles that tend to be heterozygous. We focus on the stochastic evolutionary dynamics of systems where demographic fluctuations in the coupled populations are the main source of internal noise. We discuss the influence of fitness, migration rate, and the relative sizes of two interacting populat... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374944 Thu, 03 Nov 2011 04:00:00 +0100 5374944 http://www.medworm.com/index.php?rid=5374943&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FW7MKvXWhCfM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002258 This study presents a state-of-the-art strategy in constructing interspecies disease networks that provide crucial information on regulatory relationships among genes, leading to better understanding of the disease molecular mechanisms. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374943 Thu, 03 Nov 2011 04:00:00 +0100 5374943 http://www.medworm.com/index.php?rid=5374942&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FUvnfpC8EBj4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002255 We describe a statistical framework for QTL mapping using bulk segregant analysis (BSA) based on high throughput, short-read sequencing. Our proposed approach is based on a smoothed version of the standard statistic, and takes into account variation in allele frequency estimates due to sampling of segregants to form bulks as well as variation introduced during the sequencing of bulks. Using simulation, we explore the impact of key experimental variables such as bulk size and sequencing coverage on the ability to detect QTLs. Counterintuitively, we find that relatively large bulks maximize the power to detect QTLs even though this implies weaker selection and less extreme allele frequency differences. Our simulation studies suggest that with large bulks and sufficient sequencing depth, the ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374942 Thu, 03 Nov 2011 04:00:00 +0100 5374942 http://www.medworm.com/index.php?rid=5374941&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FHusCw1W0zbo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002253 by Sohrab Saeb, Cornelius Weber, Jochen Triesch Various optimality principles have been proposed to explain the characteristics of coordinated eye and head movements during visual orienting behavior. At the same time, researchers have suggested several neural models to underly the generation of saccades, but these do not include online learning as a mechanism of optimization. Here, we suggest an open-loop neural controller with a local adaptation mechanism that minimizes a proposed cost function. Simulations show that the characteristics of coordinated eye and head movements generated by this model match the experimental data in many aspects, including the relationship between amplitude, duration and peak velocity in head-restrained and the relative contribution of eye and head to the... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374941 Thu, 03 Nov 2011 04:00:00 +0100 5374941 http://www.medworm.com/index.php?rid=5374940&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FRcbQYD4GXMw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002251 by Natalia L. Komarova, Craig J. Thalhauser There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374940 Thu, 03 Nov 2011 04:00:00 +0100 5374940 http://www.medworm.com/index.php?rid=5374939&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FpU5WC94h5Pg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002233 by E. P. Raposo, F. Bartumeus, M. G. E. da Luz, P. J. Ribeiro-Neto, T. A. Souza, G. M. Viswanathan Theoretical and empirical investigations of search strategies typically have failed to distinguish the distinct roles played by density versus patchiness of resources. It is well known that motility and diffusivity of organisms often increase in environments with low density of resources, but thus far there has been little progress in understanding the specific role of landscape heterogeneity and disorder on random, non-oriented motility. Here we address the general question of how the landscape heterogeneity affects the efficiency of encounter interactions under global constant density of scarce resources. We unveil the key mechanism coupling the landscape structure with optimal search ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374939 Thu, 03 Nov 2011 04:00:00 +0100 5374939 http://www.medworm.com/index.php?rid=5374938&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FMQJKabWwZyw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002223 by Melissa J. Morine, Audrey C. Tierney, Ben van Ommen, Hannelore Daniel, Sinead Toomey, Ingrid M. F. Gjelstad, Isobel C. Gormley, Pablo Pérez-Martinez, Christian A. Drevon, Jose López-Miranda, Helen M. Roche Understanding the molecular link between diet and health is a key goal in nutritional systems biology. As an alternative to pathway analysis, we have developed a joint multivariate and network-based approach to analysis of a dataset of habitual dietary records, adipose tissue transcriptomics and comprehensive plasma marker profiles from human volunteers with the Metabolic Syndrome. With this approach we identified prominent co-expressed sub-networks in the global metabolic network, which showed correlated expression with habitual n-3 PUFA intake and urinary levels of the oxidat... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374938 Thu, 03 Nov 2011 04:00:00 +0100 5374938 http://www.medworm.com/index.php?rid=5374937&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FMtRf2bRhays%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002211 by Lars Buesing, Johannes Bill, Bernhard Nessler, Wolfgang Maass The organization of computations in networks of spiking neurons in the brain is still largely unknown, in particular in view of the inherently stochastic features of their firing activity and the experimentally observed trial-to-trial variability of neural systems in the brain. In principle there exists a powerful computational framework for stochastic computations, probabilistic inference by sampling, which can explain a large number of macroscopic experimental data in neuroscience and cognitive science. But it has turned out to be surprisingly difficult to create a link between these abstract models for stochastic computations and more detailed models of the dynamics of networks of spiking neurons. Here we create such ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5374937 Thu, 03 Nov 2011 04:00:00 +0100 5374937 http://www.medworm.com/index.php?rid=5355190&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fjy_xdy6vIHQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002244 We describe the successes and challenges we encountered while bringing this unit to high school students, discuss how we addressed these challenges, and make suggestions for future versions of this curriculum.We believe that our curriculum can be a valuable seed for further development of computational activities aimed at high school biology students. Further, our experiences may be of value to others teaching computational biology at this level. Our curriculum can be obtained at http://ecsite.cs.colorado.edu/?page_id=149#biology or by contacting the authors. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355190 Thu, 27 Oct 2011 04:00:00 +0100 5355190 http://www.medworm.com/index.php?rid=5355189&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Foyz3Rl4s2X0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002242 by Fran Lewitter, Philip E. Bourne (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355189 Thu, 27 Oct 2011 04:00:00 +0100 5355189 http://www.medworm.com/index.php?rid=5355188&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FyBm-LyOAplQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002243 by David Form, Fran Lewitter (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355188 Thu, 27 Oct 2011 04:00:00 +0100 5355188 http://www.medworm.com/index.php?rid=5355187&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FOPUDrr_4Dvs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002245 by Allegra Via, Javier De Las Rivas, Teresa K. Attwood, David Landsman, Michelle D. Brazas, Jack A. M. Leunissen, Anna Tramontano, Maria Victoria Schneider (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355187 Thu, 27 Oct 2011 04:00:00 +0100 5355187 http://www.medworm.com/index.php?rid=5355186&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FTWDutLyx_ro%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002232 by Magali Michaut (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355186 Thu, 27 Oct 2011 04:00:00 +0100 5355186 http://www.medworm.com/index.php?rid=5355185&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F6KOS0dqGisU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002257 by Marko Sysi-Aho, Andrey Ermolov, Peddinti V. Gopalacharyulu, Abhishek Tripathi, Tuulikki Seppänen-Laakso, Johanna Maukonen, Ismo Mattila, Suvi T. Ruohonen, Laura Vähätalo, Laxman Yetukuri, Taina Härkönen, Erno Lindfors, Janne Nikkilä, Jorma Ilonen, Olli Simell, Maria Saarela, Mikael Knip, Samuel Kaski, Eriika Savontaus, Matej Orešič Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese pred... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355185 Thu, 27 Oct 2011 04:00:00 +0100 5355185 http://www.medworm.com/index.php?rid=5355184&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FcLvAzstbkSA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002250 by Joel Zylberberg, Jason Timothy Murphy, Michael Robert DeWeese Sparse coding algorithms trained on natural images can accurately predict the features that excite visual cortical neurons, but it is not known whether such codes can be learned using biologically realistic plasticity rules. We have developed a biophysically motivated spiking network, relying solely on synaptically local information, that can predict the full diversity of V1 simple cell receptive field shapes when trained on natural images. This represents the first demonstration that sparse coding principles, operating within the constraints imposed by cortical architecture, can successfully reproduce these receptive fields. We further prove, mathematically, that sparseness and decorrelation are the key ingredients that... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355184 Thu, 27 Oct 2011 04:00:00 +0100 5355184 http://www.medworm.com/index.php?rid=5355183&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FApUwBOdPXH0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002249 by Jeffrey D. Fitzgerald, Ryan J. Rowekamp, Lawrence C. Sincich, Tatyana O. Sharpee Conventional methods used to characterize multidimensional neural feature selectivity, such as spike-triggered covariance (STC) or maximally informative dimensions (MID), are limited to Gaussian stimuli or are only able to identify a small number of features due to the curse of dimensionality. To overcome these issues, we propose two new dimensionality reduction methods that use minimum and maximum information models. These methods are information theoretic extensions of STC that can be used with non-Gaussian stimulus distributions to find relevant linear subspaces of arbitrary dimensionality. We compare these new methods to the conventional methods in two ways: with biologically-inspired simulated neu... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355183 Thu, 27 Oct 2011 04:00:00 +0100 5355183 http://www.medworm.com/index.php?rid=5355182&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F4Uzb-E4JZfo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002248 by Itai Hayut, Erika E. Fanselow, Barry W. Connors, David Golomb Somatostatin-expressing, low threshold-spiking (LTS) cells and fast-spiking (FS) cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS) pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is cont... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355182 Thu, 27 Oct 2011 04:00:00 +0100 5355182 http://www.medworm.com/index.php?rid=5355181&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FZFzvRujS7bw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002246 by Heidi Koldsø, Pernille Noer, Julie Grouleff, Henriette Elisabeth Autzen, Steffen Sinning, Birgit Schiøtt Monoamine transporters are responsible for termination of synaptic signaling and are involved in depression, control of appetite, and anxiety amongst other neurological processes. Despite extensive efforts, the structures of the monoamine transporters and the transport mechanism of ions and substrates are still largely unknown. Structural knowledge of the human serotonin transporter (hSERT) is much awaited for understanding the mechanistic details of substrate translocation and binding of antidepressants and drugs of abuse. The publication of the crystal structure of the homologous leucine transporter has resulted in homology models of the monoamine transporters. Here we prese... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355181 Thu, 27 Oct 2011 04:00:00 +0100 5355181 http://www.medworm.com/index.php?rid=5355180&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FtZVSoovlGxw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002235 by Nicholas J. Gustafson, Nathaniel D. Daw Reinforcement learning (RL) provides an influential characterization of the brain's mechanisms for learning to make advantageous choices. An important problem, though, is how complex tasks can be represented in a way that enables efficient learning. We consider this problem through the lens of spatial navigation, examining how two of the brain's location representations—hippocampal place cells and entorhinal grid cells—are adapted to serve as basis functions for approximating value over space for RL. Although much previous work has focused on these systems' roles in combining upstream sensory cues to track location, revisiting these representations with a focus on how they support this downstream decision function offers complementary ins... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355180 Thu, 27 Oct 2011 04:00:00 +0100 5355180 http://www.medworm.com/index.php?rid=5355179&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FqmfE4p40bGc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002231 by Matthieu Gilson, Timothée Masquelier, Etienne Hugues Spike timing-dependent plasticity (STDP) has been shown to enable single neurons to detect repeatedly presented spatiotemporal spike patterns. This holds even when such patterns are embedded in equally dense random spiking activity, that is, in the absence of external reference times such as a stimulus onset. Here we demonstrate, both analytically and numerically, that STDP can also learn repeating rate-modulated patterns, which have received more experimental evidence, for example, through post-stimulus time histograms (PSTHs). Each input spike train is generated from a rate function using a stochastic sampling mechanism, chosen to be an inhomogeneous Poisson process here. Learning is feasible provided significant covarying rat... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355179 Thu, 27 Oct 2011 04:00:00 +0100 5355179 http://www.medworm.com/index.php?rid=5355178&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FyiJ_3aMagzU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002229 In this study, by use of computer simulations, we explore the scenario where chromatin conformations emerge from its interaction with diffusing molecular factors. Our aim is to understand the physical mechanisms whereby stable, non-random conformations are established on the Xic's, how complex architectural changes are reliably regulated, and how they lead to opposite structures on the two alleles. In particular, comparison against current experimental data indicates that a few key cis-regulatory regions orchestrate the organization of the Xic, and that two major molecular regulators are involved. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355178 Thu, 27 Oct 2011 04:00:00 +0100 5355178 http://www.medworm.com/index.php?rid=5355177&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fc7S5tYdBlzM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002219 by Mijung Park, Jonathan W. Pillow The linear receptive field describes a mapping from sensory stimuli to a one-dimensional variable governing a neuron's spike response. However, traditional receptive field estimators such as the spike-triggered average converge slowly and often require large amounts of data. Bayesian methods seek to overcome this problem by biasing estimates towards solutions that are more likely a priori, typically those with small, smooth, or sparse coefficients. Here we introduce a novel Bayesian receptive field estimator designed to incorporate locality, a powerful form of prior information about receptive field structure. The key to our approach is a hierarchical receptive field model that flexibly adapts to localized structure in both spacetime and spatiotempor... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355177 Thu, 27 Oct 2011 04:00:00 +0100 5355177 http://www.medworm.com/index.php?rid=5355176&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fgy3TPY_XBqk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002216 by Laurence D. Parnell, Pierre Lindenbaum, Khader Shameer, Giovanni Marco Dall'Olio, Daniel C. Swan, Lars Juhl Jensen, Simon J. Cockell, Brent S. Pedersen, Mary E. Mangan, Christopher A. Miller, Istvan Albert (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5355176 Thu, 27 Oct 2011 04:00:00 +0100 5355176 http://www.medworm.com/index.php?rid=5343413&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FihtzAtAdqc4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002195 by Sean R. Eddy Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the “multiple segment Viterbi” (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343413 Thu, 20 Oct 2011 04:00:00 +0100 5343413 http://www.medworm.com/index.php?rid=5343412&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fz55mPiNtL3s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002252 by Sean A. Rands Although social behaviour can bring many benefits to an individual, there are also costs that may be incurred whenever the members of a social group interact. The formation of dominance hierarchies could offer a means of reducing some of the costs of social interaction, but individuals within the hierarchy may end up paying differing costs dependent upon their position within the hierarchy. These differing interaction costs may therefore influence the behaviour of the group, as subordinate individuals may experience very different benefits and costs to dominants when the group is conducting a given behaviour. Here, a state-dependent dynamic game is described which considers a pair of social foragers where there is a set dominance relationship within the pair. The mode... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343412 Thu, 20 Oct 2011 04:00:00 +0100 5343412 http://www.medworm.com/index.php?rid=5343411&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FrK13FSFLaFY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002241 by Byron N. Roberts, David J. Christini Reperfusion injury results from pathologies of cardiac myocyte physiology that develop when previously ischemic myocardium experiences a restoration of normal perfusion. Events in the development of reperfusion injury begin with the restoration of a proton gradient upon reperfusion, which then allows the sodium-proton exchanger (NHE) to increase flux, removing protons from the intracellular space while importing sodium. The resulting sodium overload drives increased reverse-mode sodium-calcium exchanger (NCX) activity, creating a secondary calcium overload that has pathologic consequences. One of the attempts to reduce reperfusion-related damage, NHE inhibition, has shown little clinical benefit, and only when NHE inhibitors are given prior to r... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343411 Thu, 20 Oct 2011 04:00:00 +0100 5343411 http://www.medworm.com/index.php?rid=5343410&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FAtnmYbtCEeY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002240 We examined this argument for breast cancer. Surprisingly, we found that gene expression signatures—unrelated to cancer—of the effect of postprandial laughter, of mice social defeat and of skin fibroblast localization were all significantly associated with breast cancer outcome. We next compared 47 published breast cancer outcome signatures to signatures made of random genes. Twenty-eight of them (60%) were not significantly better outcome predictors than random signatures of identical size and 11 (23%) were worst predictors than the median random signature. More than 90% of random signatures >100 genes were significant outcome predictors. We next derived a metagene, called meta-PCNA, by selecting the 1% genes most positively correlated with proliferation marker PCNA in a compendium of... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343410 Thu, 20 Oct 2011 04:00:00 +0100 5343410 http://www.medworm.com/index.php?rid=5343409&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F1I5nK_OY1sw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002239 by Tatjana Tchumatchenko, Fred Wolf Many sensory or cognitive events are associated with dynamic current modulations in cortical neurons. This raises an urgent demand for tractable model approaches addressing the merits and limits of potential encoding strategies. Yet, current theoretical approaches addressing the response to mean- and variance-encoded stimuli rarely provide complete response functions for both modes of encoding in the presence of correlated noise. Here, we investigate the neuronal population response to dynamical modifications of the mean or variance of the synaptic bombardment using an alternative threshold model framework. In the variance and mean channel, we provide explicit expressions for the linear and non-linear frequency response functions in the presence of ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343409 Thu, 20 Oct 2011 04:00:00 +0100 5343409 http://www.medworm.com/index.php?rid=5343408&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FjfRSyxrfCF0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002238 by Özlem Demir, Roberta Baronio, Faezeh Salehi, Christopher D. Wassman, Linda Hall, G. Wesley Hatfield, Richard Chamberlin, Peter Kaiser, Richard H. Lathrop, Rommie E. Amaro The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343408 Thu, 20 Oct 2011 04:00:00 +0100 5343408 http://www.medworm.com/index.php?rid=5343407&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FamHRKm7UTEE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002237 by Kate M. Mitchell, Francisca Mutapi, Nicholas J. Savill, Mark E. J. Woolhouse Urogenital schistosomiasis is a tropical disease infecting more than 100 million people in sub-Saharan Africa. Individuals in endemic areas endure repeated infections with long-lived schistosome worms, and also encounter larval and egg stages of the life cycle. Protective immunity against infection develops slowly with age. Distinctive age-related patterns of infection and specific antibody responses are seen in endemic areas, including an infection ‘peak shift’ and a switch in the antibody types produced. Deterministic models describing changing levels of infection and antibody with age in homogeneously exposed populations were developed to identify the key mechanisms underlying the antibody switch, a... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343407 Thu, 20 Oct 2011 04:00:00 +0100 5343407 http://www.medworm.com/index.php?rid=5343406&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F0AJ6QOfoyjM%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002236 We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent (“animat”) evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its “fit” to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better mea... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343406 Thu, 20 Oct 2011 04:00:00 +0100 5343406 http://www.medworm.com/index.php?rid=5343405&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FoLDILrtfE38%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002234 We present a novel, knowledge-based method for loop sampling that leverages homologous torsion angle information to estimate a continuous joint backbone dihedral angle density at each loop position. The φ,ψ distributions are estimated via a Dirichlet process mixture of hidden Markov models (DPM-HMM). Models are quickly generated based on samples from these distributions and were enriched using an end-to-end distance filter. The performance of the DPM-HMM method was evaluated against a diverse test set in a leave-one-out approach. Candidates as low as 0.45 Å RMSD and with a worst case of 3.66 Å were produced. For the canonical loops like the immunoglobulin complementarity-determining regions (mean RMSD 7.0 Å), this sampling method produces a population of loop structures to around 3.66... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343405 Thu, 20 Oct 2011 04:00:00 +0100 5343405 http://www.medworm.com/index.php?rid=5343404&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FiBR_5cS6ins%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002230 by Alexis P. Yelton, Brian C. Thomas, Sheri L. Simmons, Paul Wilmes, Adam Zemla, Michael P. Thelen, Nicholas Justice, Jillian F. Banfield During microbial evolution, genome rearrangement increases with increasing sequence divergence. If the relationship between synteny and sequence divergence can be modeled, gene clusters in genomes of distantly related organisms exhibiting anomalous synteny can be identified and used to infer functional conservation. We applied the phylogenetic pairwise comparison method to establish and model a strong correlation between synteny and sequence divergence in all 634 available Archaeal and Bacterial genomes from the NCBI database and four newly assembled genomes of uncultivated Archaea from an acid mine drainage (AMD) community. In parallel, we establis... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343404 Thu, 20 Oct 2011 04:00:00 +0100 5343404 http://www.medworm.com/index.php?rid=5343403&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FlDqAF8xwo1M%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002227 We present a nonparametric Bayesian model for discovering prognostic cancer subtypes by integrating gene expression and copy number variation data. Our model is constructed from a hierarchy of Dirichlet Processes and addresses three key challenges in data fusion: (i) To separate concordant from discordant signals, (ii) to select informative features, (iii) to estimate the number of disease subtypes. Concordance of signals is assessed individually for each patient, giving us an additional level of insight into the underlying disease structure. We exemplify the power of our model in prostate cancer and breast cancer and show that it outperforms competing methods. In the prostate cancer data, we identify an entirely new subtype with extremely poor survival outcome and show how other analyses ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343403 Thu, 20 Oct 2011 04:00:00 +0100 5343403 http://www.medworm.com/index.php?rid=5343402&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F2dBum5mc8A8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002225 by Tyrone Ryba, Ichiro Hiratani, Takayo Sasaki, Dana Battaglia, Michael Kulik, Jinfeng Zhang, Stephen Dalton, David M. Gilbert Many types of epigenetic profiling have been used to classify stem cells, stages of cellular differentiation, and cancer subtypes. Existing methods focus on local chromatin features such as DNA methylation and histone modifications that require extensive analysis for genome-wide coverage. Replication timing has emerged as a highly stable cell type-specific epigenetic feature that is regulated at the megabase-level and is easily and comprehensively analyzed genome-wide. Here, we describe a cell classification method using 67 individual replication profiles from 34 mouse and human cell lines and stem cell-derived tissues, including new data for mesendoderm, defi... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343402 Thu, 20 Oct 2011 04:00:00 +0100 5343402 http://www.medworm.com/index.php?rid=5343401&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Ftwycim_WQpo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002224 by Julia Tsitron, Addison D. Ault, James R. Broach, Alexandre V. Morozov Combinatorial sensor arrays, such as the olfactory system, can detect a large number of analytes using a relatively small number of receptors. However, the complex pattern of receptor responses to even a single analyte, coupled with the non-linearity of responses to mixtures of analytes, makes quantitative prediction of compound concentrations in a mixture a challenging task. Here we develop a physical model that explicitly takes receptor-ligand interactions into account, and apply it to infer concentrations of highly related sugar nucleotides from the output of four engineered G-protein-coupled receptors. We also derive design principles that enable accurate mixture discrimination with cross-specific sensor arra... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343401 Thu, 20 Oct 2011 04:00:00 +0100 5343401 http://www.medworm.com/index.php?rid=5343400&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FYB4Bb3LCLto%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002221 This article discusses the correspondence of the synthetic experiments with the known hierarchy of the prefrontal cortex, the supplementary motor area, and the primary motor cortex for action generation. We speculate that deterministic dynamical structures organized in the prefrontal cortex could be essential because they can account for the generation of both intentional behaviors of fixed action sequences and spontaneous behaviors of pseudo-stochastic action sequences by the same mechanism. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343400 Thu, 20 Oct 2011 04:00:00 +0100 5343400 http://www.medworm.com/index.php?rid=5343399&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FISUKN2fz-9k%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1002204 by Benjamin A. Hall, Judith P. Armitage, Mark S. P. Sansom Transmembrane α-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock α-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=5343399 Thu, 20 Oct 2011 04:00:00 +0100 5343399