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. Wed, 17 Mar 2010 16:30:47 +0100 http://www.medworm.com/index.php?rid=3358277&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FIEpOm4prVyg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000711 In this study, we investigated how these rules applied to whole axonal trees in neocortex by comparing their 3D structure to equivalent artificial arbors optimized for these rules. We discovered that neocortical axonal trees achieve a balance between these two rules so that a little more cellular material than necessary was used to substantially reduce conduction delays. Importantly, we suggest the nature of arbor branching balances time and material so that neocortical axons may communicate with a high degree of temporal precision, enabling accurate and rapid computation within local cortical networks. This approach could be applied to other neural structures to better understand the functional principles of brain design. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358277 Fri, 12 Mar 2010 00:00:00 +0100 3358277 http://www.medworm.com/index.php?rid=3358276&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FCkvI7na2Bx0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000710 This study highlights physical principles underlying biological mechanisms of stress response and adaptation. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358276 Fri, 12 Mar 2010 00:00:00 +0100 3358276 http://www.medworm.com/index.php?rid=3358275&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F3blnaKBfKm8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000709 Author Summary Bayesian model comparison provides a formal method for evaluating different computational models in the biological sciences. Emerging application domains include dynamical models of neuronal and biochemical networks based on differential equations. Much previous work in this area has focussed on selecting the single best model. This approach is useful but can become brittle if there are a large number of models to compare and if different subjects use different models. This paper shows that these problems can be overcome with the use of Family Level Inference and Bayesian Model Averaging within model families. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358275 Fri, 12 Mar 2010 00:00:00 +0100 3358275 http://www.medworm.com/index.php?rid=3358274&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FV7YF3hB0YBI%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000708 Author Summary In a hand-eye coordination task that requires continuous movement to correct for a disturbance, it turns out that signs of response to the disturbance appear no later in the elderly than in the young. The elderly motion is noisy and less efficient, however, and once movements in response to a disturbance begin, they are at a lower speed. One can model subject response by assuming that it results from combining noise and a response that is mathematically optimal given this noise, delay, and a least-squares sort of control objective. This modeling approach is appropriate for young and most elderly subjects. The model holds that increased noise should lead to no change in delay until response gets underway, but should make the response itself proceed at a slower speed. This is... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358274 Fri, 12 Mar 2010 00:00:00 +0100 3358274 http://www.medworm.com/index.php?rid=3358273&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F0nZNjvW_gdo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000707 Author Summary A major goal in biology is to understand the evolution of complex traits, such as the development of multicellular body plans. To a certain extent, complex traits are governed by regulated gene expression. The comparison expression data between species requires extra considerations than sequence comparison, because gene expression is not static and the level of expression is influenced by external conditions. Considering that co-expression patterns are often comparable across species, we developed a statistical model for cross-species clustering analysis. The model allows each species to create its own clusters of the genes but also encourages the species to borrow strength from each others' clusters of orthologous genes. The result is a pairing of clusters, one from each s... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358273 Fri, 12 Mar 2010 00:00:00 +0100 3358273 http://www.medworm.com/index.php?rid=3358272&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FoicOvqBcok8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000706 Author Summary Circadian rhythms are ~24 hour cycles in biochemical, physiological and behavioral processes observed in a diverse range of organisms including Cyanobacteria, Neurospora, Drosophila, mice and humans. In mammals, the dominant circadian pacemaker that drives daily rhythms is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is composed of a highly connected network of ~20,000 neurons. Within each individual SCN neuron core clock genes and proteins interact through intertwined regulatory loops to generate circadian oscillations on the molecular level. These neurons express daily rhythmicity in their firing frequency and other electrophysiological properties. The mechanisms by which the core clock produces synchronized rhythms in neural firing and gene e... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358272 Fri, 12 Mar 2010 00:00:00 +0100 3358272 http://www.medworm.com/index.php?rid=3358271&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FMyNWIJC9YX8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000705 Author Summary We developed a general-purpose biochemical simulation program, called Smoldyn. It represents proteins and other molecules of interest with point-like particles that diffuse, interact with surfaces, and react, all in continuous space. This high level of detail allows users to investigate spatial organization within cells and natural stochastic variability. Although similar to the MCell and ChemCell programs, Smoldyn is more accurate and runs faster. Smoldyn also supports many unique features, such as commands that a “virtual experimenter” can execute during simulations and automatic reaction network expansion for simulating protein complexes. We illustrate Smoldyn's capabilities with a model of signaling between yeast cells of opposite mating type. It investigates the ro... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358271 Fri, 12 Mar 2010 00:00:00 +0100 3358271 http://www.medworm.com/index.php?rid=3358270&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FW-M4MqOFSeI%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000704 Author Summary Investigation on how phenotypic diversity of genetically identical organisms is generated and regulated has focused on noise in gene expression. It is unknown to what extent noise in gene expression and genetic networks is evolvable, and by which mechanisms it evolves. The noise has several sources, e.g., noise in transcription initiation and during elongation. We focus on RNA polymerase (RNAP) pausing and show that it can regulate, to some extent, noise in gene expression. RNAP frequently pauses during elongation. The pausing frequency and average duration are sequence-specific, thus evolvable. The dependency of pause propensity on regulatory molecules makes pausing a mechanism adaptable to rapidly changing environments. We study, in a stochastic model of bacterial transcr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358270 Fri, 12 Mar 2010 00:00:00 +0100 3358270 http://www.medworm.com/index.php?rid=3358269&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FE7rMzRgb1Rs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000701 Author Summary The tiny brains of insects of about 1mm3 smoothly control a flying platform while avoiding obstacles, regulating its distance to objects and search for objects of interest. This is largely achieved through a complex hierarchical processing of signals from the multitude of ommatidia in their eye to a set of highly specialized neurons that are optimized to respond to specific properties of the visual world. One of these neurons, the Lobula Giant Movement Detector (LGMD) of the locust, has been recently shown to perform a functional multiplication of its synaptic inputs. If true, that would make the LGMD neuron a unique and highly sophisticated neuron that raises questions about the non-linear operations other neurons in other neuronal systems would be able to perform. Hence i... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358269 Fri, 12 Mar 2010 00:00:00 +0100 3358269 http://www.medworm.com/index.php?rid=3358268&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fyat0ZRtM_xc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000700 Author Summary When species evolve, their genes duplicate and diverge to allow for adaptation of their functional repertoires to the changing environment. In this scenario, unrelated genes can convergently evolve to produce proteins with the same molecular function, termed “functionally analogous.” A quantitative determination of the reaction similarities among functionally analogous enzymes could provide insight about the different structural solutions nature has used to evolve similar catalysts. Bond changes between substrates and products, and between successive reaction intermediates, were used to compare the reactions catalyzed and the mechanisms of catalysis for 95 pairs of functionally analogous enzymes. Less than half of the reactions catalyzed by unrelated enzymes, but define... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3358268 Fri, 12 Mar 2010 00:00:00 +0100 3358268 http://www.medworm.com/index.php?rid=3341914&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000702 Author Summary Activation of death receptors (TNFR and Fas) can trigger either survival or cell death according to the cell type and the cellular conditions. In other words, the same signal can have antagonist responses. On one hand, the cell can survive by activating the NFκB signalling pathway. On the other hand, it can die by apoptosis or necrosis. Apoptosis is a suicide mechanism, i.e., an orchestrated way to disrupt cellular components and pack them into specialized vesicles that can be easily removed from the environment, whereas necrosis is a type of death that involves release of intracellular components in the surrounding tissues, possibly causing inflammatory response and severe injury. We, biologists and theoreticians, have recapitulated and integrated known biological data fr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341914 Fri, 05 Mar 2010 00:00:00 +0100 3341914 http://www.medworm.com/index.php?rid=3341913&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000699 Author Summary Decades ago, Waddington, and later Kauffman, likened the dynamics of a differentiating cell to a marble rolling downhill on bumpy terrain—the epigenetic landscape. In this metaphor, the valleys of the landscape represent the paths that cells can follow towards a stable cell type, and the fate of the cell is determined by the constant modulation of the epigenetic landscape by internal and external signals. With new technologies for measuring single-cell gene expression, it is increasingly feasible to map out these valleys and how external variables influence cellular responses. Moreover, it is possible to quantify population level effects, such as what fraction of a population of cells arrives at one valley or another, and variability at the cellular level, such as how ind... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341913 Fri, 05 Mar 2010 00:00:00 +0100 3341913 http://www.medworm.com/index.php?rid=3341912&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000698 Author Summary Microarray expression experiments allow fast functional profiling of an organism's entire genome and significant efforts are devoted to analyzing the resulting data. Available genome sequences are also increasing quickly. However, it is unexplored how to use available functional genomics data to direct large-scale experiments in newly sequenced but poorly studied species. In this paper, we propose a strategy to systematically plan experimental treatments in the poorly studied species based on their model organism relatives. We consider both the accuracy of the datasets in capturing different biological processes and the redundancy between datasets. Quantifying the above information allows us to recommend a list of experimental treatments. We demonstrate the efficacy of this... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341912 Fri, 05 Mar 2010 00:00:00 +0100 3341912 http://www.medworm.com/index.php?rid=3341911&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000697 Author Summary To perceive your surroundings your brain must distinguish between different possible scenes, each of which is more or less likely. In order to disambiguate interpretations that are equally likely given sensory input, the brain aggregates multiple sensations to form an interpretation of the world consistent with each. For instance, when you judge the size of an object you are viewing, its distance influences its image size that projects to your eyes. To estimate its true size, your brain must use extra information to disambiguate whether it is a small, near object, or large, far object. If you touch the object your brain could use the felt distance to scale the apparent size of the object. Cognitive scientists do not fully understand the computations that make perceptual dis... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341911 Fri, 05 Mar 2010 00:00:00 +0100 3341911 http://www.medworm.com/index.php?rid=3341910&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000696 Author Summary Parameter estimation is a key issue in systems biology, as it represents the crucial step to obtaining predictions from computational models of biological systems. This issue is usually addressed by “fitting” the model simulations to the observed experimental data. Such approach does not take the measurement noise into full consideration. We introduce a new method built on the combination of Kalman filtering, statistical tests, and optimization techniques. The filter is well-known in control and estimation theory and has found application in a wide range of fields, such as inertial guidance systems, weather forecasting, and economics. We show how the statistics of the measurement noise can be optimally exploited and directly incorporated into the design of the estimatio... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341910 Fri, 05 Mar 2010 00:00:00 +0100 3341910 http://www.medworm.com/index.php?rid=3341909&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000695 Author Summary Protein-protein interactions (PPIs) are essential to life and various diseases states are associated with aberrant PPIs. Therefore significant efforts are dedicated to this new class of therapeutic targets. Even though it might not be possible to modulate the estimated 650,000 PPIs that regulate human life with drug-like compounds, a sizeable number of PPI should be druggable. Only 10-15% of the human genome is thought to be druggable with around 1000-3000 druggable protein targets. A hypothetical similar ratio for PPIs would bring the number of druggable PPIs to about 65,000, although no data can yet support such a hypothesis. PPI have been historically intricate to tackle with standard experimental and virtual screening techniques, possibly because of the shift in the che... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341909 Fri, 05 Mar 2010 00:00:00 +0100 3341909 http://www.medworm.com/index.php?rid=3341908&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000694 Author Summary The interior of a typical bacterial cell is a highly crowded place in which molecules must jostle and compete with each other in order to carry out their biological functions. The conditions under which such molecules are typically studied in vitro, however, are usually quite different: one or a few different types of molecules are studied as they freely diffuse in a dilute, aqueous solution. There is therefore a significant disconnect between the conditions under which molecules can be most usefully studied and the conditions under which such molecules usually “live”, and developing ways to bridge this gap is likely to be important for properly understanding molecular behavior in vivo. Toward this end, we show in this work that computer simulations can be used to model... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341908 Fri, 05 Mar 2010 00:00:00 +0100 3341908 http://www.medworm.com/index.php?rid=3341907&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000693 Author Summary Amyloid diseases are characterized by the presence of amyloid fibrils on organs and tissue in the body. Alzheimer's disease, Parkinson's diseases and Type II Diabetes are all examples of amyloid diseases. Determining the structure of amyloid fibrils is critical for understanding the mechanism of fibril formation as well as for the design of inhibitor molecules that can prevent aggregation. In the case of the Alzheimer Amyloid-β (Aβ) peptide, the structure of fibrils grown under conditions of mechanical agitation has been elucidated from a combination of simulation and experiments. However, the structures of the asymmetric quiescent Aβ fibrils (grown under conditions akin to physiological conditions) and of Alzheimer's brain–derived fibrils are not known. In this paper,... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341907 Fri, 05 Mar 2010 00:00:00 +0100 3341907 http://www.medworm.com/index.php?rid=3334633&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fq9N2DKWpUhQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000702 Author Summary Activation of death receptors (TNFR and Fas) can trigger either survival or cell death according to the cell type and the cellular conditions. In other words, the same signal can have antagonist responses. On one hand, the cell can survive by activating the NFκB signalling pathway. On the other hand, it can die by apoptosis or necrosis. Apoptosis is a suicide mechanism, i.e., an orchestrated way to disrupt cellular components and pack them into specialized vesicles that can be easily removed from the environment, whereas necrosis is a type of death that involves release of intracellular components in the surrounding tissues, possibly causing inflammatory response and severe injury. We, biologists and theoreticians, have recapitulated and integrated known biological data fr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334633 Fri, 05 Mar 2010 00:00:00 +0100 3334633 http://www.medworm.com/index.php?rid=3334632&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FLRERe85svQc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000699 Author Summary Decades ago, Waddington, and later Kauffman, likened the dynamics of a differentiating cell to a marble rolling downhill on bumpy terrain—the epigenetic landscape. In this metaphor, the valleys of the landscape represent the paths that cells can follow towards a stable cell type, and the fate of the cell is determined by the constant modulation of the epigenetic landscape by internal and external signals. With new technologies for measuring single-cell gene expression, it is increasingly feasible to map out these valleys and how external variables influence cellular responses. Moreover, it is possible to quantify population level effects, such as what fraction of a population of cells arrives at one valley or another, and variability at the cellular level, such as how ind... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334632 Fri, 05 Mar 2010 00:00:00 +0100 3334632 http://www.medworm.com/index.php?rid=3334631&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FJ1mNuniAzII%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000698 Author Summary Microarray expression experiments allow fast functional profiling of an organism's entire genome and significant efforts are devoted to analyzing the resulting data. Available genome sequences are also increasing quickly. However, it is unexplored how to use available functional genomics data to direct large-scale experiments in newly sequenced but poorly studied species. In this paper, we propose a strategy to systematically plan experimental treatments in the poorly studied species based on their model organism relatives. We consider both the accuracy of the datasets in capturing different biological processes and the redundancy between datasets. Quantifying the above information allows us to recommend a list of experimental treatments. We demonstrate the efficacy of this... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334631 Fri, 05 Mar 2010 00:00:00 +0100 3334631 http://www.medworm.com/index.php?rid=3334630&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FFtBB7JIOfnE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000697 Author Summary To perceive your surroundings your brain must distinguish between different possible scenes, each of which is more or less likely. In order to disambiguate interpretations that are equally likely given sensory input, the brain aggregates multiple sensations to form an interpretation of the world consistent with each. For instance, when you judge the size of an object you are viewing, its distance influences its image size that projects to your eyes. To estimate its true size, your brain must use extra information to disambiguate whether it is a small, near object, or large, far object. If you touch the object your brain could use the felt distance to scale the apparent size of the object. Cognitive scientists do not fully understand the computations that make perceptual dis... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334630 Fri, 05 Mar 2010 00:00:00 +0100 3334630 http://www.medworm.com/index.php?rid=3334629&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FjKJq3E1UzWE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000696 Author Summary Parameter estimation is a key issue in systems biology, as it represents the crucial step to obtaining predictions from computational models of biological systems. This issue is usually addressed by “fitting” the model simulations to the observed experimental data. Such approach does not take the measurement noise into full consideration. We introduce a new method built on the combination of Kalman filtering, statistical tests, and optimization techniques. The filter is well-known in control and estimation theory and has found application in a wide range of fields, such as inertial guidance systems, weather forecasting, and economics. We show how the statistics of the measurement noise can be optimally exploited and directly incorporated into the design of the estimatio... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334629 Fri, 05 Mar 2010 00:00:00 +0100 3334629 http://www.medworm.com/index.php?rid=3334628&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FmNydHQUaOhY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000695 Author Summary Protein-protein interactions (PPIs) are essential to life and various diseases states are associated with aberrant PPIs. Therefore significant efforts are dedicated to this new class of therapeutic targets. Even though it might not be possible to modulate the estimated 650,000 PPIs that regulate human life with drug-like compounds, a sizeable number of PPI should be druggable. Only 10-15% of the human genome is thought to be druggable with around 1000-3000 druggable protein targets. A hypothetical similar ratio for PPIs would bring the number of druggable PPIs to about 65,000, although no data can yet support such a hypothesis. PPI have been historically intricate to tackle with standard experimental and virtual screening techniques, possibly because of the shift in the che... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334628 Fri, 05 Mar 2010 00:00:00 +0100 3334628 http://www.medworm.com/index.php?rid=3334627&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FvpLfJnvqH7Q%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000694 Author Summary The interior of a typical bacterial cell is a highly crowded place in which molecules must jostle and compete with each other in order to carry out their biological functions. The conditions under which such molecules are typically studied in vitro, however, are usually quite different: one or a few different types of molecules are studied as they freely diffuse in a dilute, aqueous solution. There is therefore a significant disconnect between the conditions under which molecules can be most usefully studied and the conditions under which such molecules usually “live”, and developing ways to bridge this gap is likely to be important for properly understanding molecular behavior in vivo. Toward this end, we show in this work that computer simulations can be used to model... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334627 Fri, 05 Mar 2010 00:00:00 +0100 3334627 http://www.medworm.com/index.php?rid=3334626&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FD9TfLme164g%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000693 Author Summary Amyloid diseases are characterized by the presence of amyloid fibrils on organs and tissue in the body. Alzheimer's disease, Parkinson's diseases and Type II Diabetes are all examples of amyloid diseases. Determining the structure of amyloid fibrils is critical for understanding the mechanism of fibril formation as well as for the design of inhibitor molecules that can prevent aggregation. In the case of the Alzheimer Amyloid-β (Aβ) peptide, the structure of fibrils grown under conditions of mechanical agitation has been elucidated from a combination of simulation and experiments. However, the structures of the asymmetric quiescent Aβ fibrils (grown under conditions akin to physiological conditions) and of Alzheimer's brain–derived fibrils are not known. In this paper,... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3334626 Fri, 05 Mar 2010 00:00:00 +0100 3334626 http://www.medworm.com/index.php?rid=3341928&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000692 Author Summary Human disease is complex, arising from the interaction of many genetic and environmental factors. Efforts to personalize treatment have been thwarted by “phenotypic heterogeneity”, the apparent similarity of disease states with diverse underlying causes. One approach to resolve this heterogeneity is to redefine diseases on the basis of abnormal physiologic activities, which should allow grouping patients into categories with similar treatment response and prognosis. Physiologic activities can be identified and assessed through quantitative measurements of biomolecules—proteins, mRNAs, metabolites—in individual patient samples. The field of metabolomics involves the analysis of a broad array of metabolite levels from clinical fluid samples such as blood or urine and ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341928 Fri, 26 Feb 2010 00:00:00 +0100 3341928 http://www.medworm.com/index.php?rid=3341927&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000691 Author Summary The hippocampus is a part of the cerebral cortex intimately involved in learning and memory behavior. A common cellular model of learning is a long lasting form of long term potentiation (L-LTP) in the hippocampus, because it shares several characteristics with learning. For example, both learning and long term potentiation exhibit sensitivity to temporal patterns of synaptic inputs and share common intracellular events such as activation of specific intracellular signaling pathways. Therefore, understanding the pivotal molecules in the intracellular signaling pathways underlying temporal sensitivity of L-LTP in the hippocampus may illuminate mechanisms underlying learning. We developed a computational model to evaluate whether the signaling pathways leading to activation o... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341927 Fri, 26 Feb 2010 00:00:00 +0100 3341927 http://www.medworm.com/index.php?rid=3341926&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000690 Author Summary When a species is grown under optimal conditions the single-knockout of most of its genes is not likely to affect its viability. The resilience of biological systems to mutations is termed genetic robustness and its extent across different species has not yet been systematically described. Since the deletion of a gene can have varying consequences depending on the environmental conditions, the extent of species' genetic robustness reflects both the range of conditions (or environments) in which it can survive as well as the availability of alternative cellular routes (compensating for a gene's loss of function). Here, we developed a computational model for estimating the essentiality of metabolic reactions across natural-like environments and applied it to chart species' le... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341926 Fri, 26 Feb 2010 00:00:00 +0100 3341926 http://www.medworm.com/index.php?rid=3341925&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000689 Author Summary Proteins, synthesized as linear polymers of amino acids, fold up into compact native states, burying their hydrophobic amino acids into their interiors. Protein folding minimizes the non-specific interactions that unfolded protein chains can make, which include aggregation with other proteins and degradation by proteases. Unfortunately, even in the native state, proteins can partially unfold, opening up regions of their structure and making these adverse events possible. Some proteins, particularly those in harsh environments full of proteases, have evolved to virtually eliminate partial unfolding, significantly reducing their rate of degradation. This elimination of partial unfolding is termed “cooperative,” because unfolding is an all-or-none process. One class of pro... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341925 Fri, 26 Feb 2010 00:00:00 +0100 3341925 http://www.medworm.com/index.php?rid=3341924&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000688 Author Summary Cell migration is fundamental to human physiology and a phenomenon of long-standing interest in cell biology. It requires the concerted regulation of several dynamic processes that mediate physical anchorage of the cell and productive generation of protrusion and traction forces that propel the cell forward. In this work, we have developed a mathematical model that describes this interplay, cast at the level of biochemical signaling pathways activated at the front of a moving cell. Based on our analysis of the model and experimental confirmation of its basic predictions, we assert that coupled, counteracting feedback loops constitute a functional switch between maintenance and stalling of the cell protrusion speed. Our model successfully explains the dependence of this swit... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341924 Fri, 26 Feb 2010 00:00:00 +0100 3341924 http://www.medworm.com/index.php?rid=3341923&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000687 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341923 Fri, 26 Feb 2010 00:00:00 +0100 3341923 http://www.medworm.com/index.php?rid=3341922&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000686 Author Summary Understanding how relatively simple, single cell bacteria can communicate and coordinate their actions is important for explaining how complex multicellular behaviour can emerge without a central controller. Myxobacteria are particularly interesting in this respect because cells undergo multiple phases of coordinated behaviour during their life-cycle. One of the most fascinating and complex phases is the formation of fruiting bodies—large multicellular aggregates of cells formed in response to starvation. In this article we use evidence from the latest experimental data to construct a computational model explaining how cells can form fruiting bodies. Both in our model and in nature, cells move together in dense swarms, which collide to form aggregation centres. In particu... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341922 Fri, 26 Feb 2010 00:00:00 +0100 3341922 http://www.medworm.com/index.php?rid=3341921&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000685 In this study, we develop a “Computational Complementation” approach for the investigation of long-distance signalling networks during legume autoregulation of nodulation (AON). The key idea is to use computational modelling to complement the deficiency of an empirical model of an AON deficient mutant with hypothesised AON components. If the complementation restores a wild-type nodulation phenotype, the modelled hypotheses would be supported as reasonable. To evaluate the feasibility of this approach, we tested whether wild-type soybean cotyledons participate in AON, commonly controlled by “real” leaves. The test gave an affirmative result (i.e., cotyledons do have AON activity), which was subsequently confirmed by a graft experiment on real plants. Future applications of this appr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341921 Fri, 26 Feb 2010 00:00:00 +0100 3341921 http://www.medworm.com/index.php?rid=3341920&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000684 Author Summary Cell culture models are an important vehicle for understanding biological processes and evaluation of therapeutic reagents. More importantly, the literature suggests that tumor cells grown in 3D exhibit pronounced drug and radiation resistances that are remarkably similar to that of tumors in vivo. Therefore, the needs for quantifying 3D assays continue to grow. In this paper, we develop robust computational methods to integrate morphometric and molecular information for a panel of breast cancer cell lines that are grown in 3D. Specifically, morphometric traits are imaged through microscopy, and then quantified computationally. We then show that these morphometric traits can identify subtypes within this panel of breast cancer cell lines, and that the subtypes are clinicall... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341920 Fri, 26 Feb 2010 00:00:00 +0100 3341920 http://www.medworm.com/index.php?rid=3341919&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000673 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341919 Fri, 26 Feb 2010 00:00:00 +0100 3341919 http://www.medworm.com/index.php?rid=3341918&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000667 Metagenomics is a discipline that enables the genomic study of uncultured microorganisms. Faster, cheaper sequencing technologies and the ability to sequence uncultured microbes sampled directly from their habitats are expanding and transforming our view of the microbial world. Distilling meaningful information from the millions of new genomic sequences presents a serious challenge to bioinformaticians. In cultured microbes, the genomic data come from a single clone, making sequence assembly and annotation tractable. In metagenomics, the data come from heterogeneous microbial communities, sometimes containing more than 10,000 species, with the sequence data being noisy and partial. From sampling, to assembly, to gene calling and function prediction, bioinformatics faces new demands in inte... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341918 Fri, 26 Feb 2010 00:00:00 +0100 3341918 http://www.medworm.com/index.php?rid=3341917&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000655 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341917 Fri, 26 Feb 2010 00:00:00 +0100 3341917 http://www.medworm.com/index.php?rid=3341916&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000650 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341916 Fri, 26 Feb 2010 00:00:00 +0100 3341916 http://www.medworm.com/index.php?rid=3341915&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fimage.pcbi.v06.i02 Computational complementation. Autoregulation of nodulation (AON) is a long-distance, shoot-root signalling system for regulating nodule formation in legume plants. This visualisation, taken from a computational complementation experiment, demonstrates the possible allocation of an unidentified signal for inhibition of nodulation in soybean root. In this approach, an empirical model of a loss-of-function (non-AON) mutant is complemented with hypothetical AON mechanisms. If the resulting nodulation phenotype matches the wild-type plant, the hypotheses would be supported as reasonable. The first application of computational complementation predicted that soybean cotyledons participate in AON, which was subsequently confirmed by a real-plant experiment (see Han et al., doi:10.1371/journal.pcb... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341915 Fri, 26 Feb 2010 00:00:00 +0100 3341915 http://www.medworm.com/index.php?rid=3310820&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FBgnv96tB7nc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000692 Author Summary Human disease is complex, arising from the interaction of many genetic and environmental factors. Efforts to personalize treatment have been thwarted by “phenotypic heterogeneity”, the apparent similarity of disease states with diverse underlying causes. One approach to resolve this heterogeneity is to redefine diseases on the basis of abnormal physiologic activities, which should allow grouping patients into categories with similar treatment response and prognosis. Physiologic activities can be identified and assessed through quantitative measurements of biomolecules—proteins, mRNAs, metabolites—in individual patient samples. The field of metabolomics involves the analysis of a broad array of metabolite levels from clinical fluid samples such as blood or urine and ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310820 Fri, 26 Feb 2010 00:00:00 +0100 3310820 http://www.medworm.com/index.php?rid=3310819&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FUv9wdL83HSQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000691 Author Summary The hippocampus is a part of the cerebral cortex intimately involved in learning and memory behavior. A common cellular model of learning is a long lasting form of long term potentiation (L-LTP) in the hippocampus, because it shares several characteristics with learning. For example, both learning and long term potentiation exhibit sensitivity to temporal patterns of synaptic inputs and share common intracellular events such as activation of specific intracellular signaling pathways. Therefore, understanding the pivotal molecules in the intracellular signaling pathways underlying temporal sensitivity of L-LTP in the hippocampus may illuminate mechanisms underlying learning. We developed a computational model to evaluate whether the signaling pathways leading to activation o... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310819 Fri, 26 Feb 2010 00:00:00 +0100 3310819 http://www.medworm.com/index.php?rid=3310818&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FJRJ5o2CKg7A%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000690 Author Summary When a species is grown under optimal conditions the single-knockout of most of its genes is not likely to affect its viability. The resilience of biological systems to mutations is termed genetic robustness and its extent across different species has not yet been systematically described. Since the deletion of a gene can have varying consequences depending on the environmental conditions, the extent of species' genetic robustness reflects both the range of conditions (or environments) in which it can survive as well as the availability of alternative cellular routes (compensating for a gene's loss of function). Here, we developed a computational model for estimating the essentiality of metabolic reactions across natural-like environments and applied it to chart species' le... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310818 Fri, 26 Feb 2010 00:00:00 +0100 3310818 http://www.medworm.com/index.php?rid=3310817&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fu9H3Ehvnjz8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000689 Author Summary Proteins, synthesized as linear polymers of amino acids, fold up into compact native states, burying their hydrophobic amino acids into their interiors. Protein folding minimizes the non-specific interactions that unfolded protein chains can make, which include aggregation with other proteins and degradation by proteases. Unfortunately, even in the native state, proteins can partially unfold, opening up regions of their structure and making these adverse events possible. Some proteins, particularly those in harsh environments full of proteases, have evolved to virtually eliminate partial unfolding, significantly reducing their rate of degradation. This elimination of partial unfolding is termed “cooperative,” because unfolding is an all-or-none process. One class of pro... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310817 Fri, 26 Feb 2010 00:00:00 +0100 3310817 http://www.medworm.com/index.php?rid=3310816&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FaLoeDVx0kG4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000688 Author Summary Cell migration is fundamental to human physiology and a phenomenon of long-standing interest in cell biology. It requires the concerted regulation of several dynamic processes that mediate physical anchorage of the cell and productive generation of protrusion and traction forces that propel the cell forward. In this work, we have developed a mathematical model that describes this interplay, cast at the level of biochemical signaling pathways activated at the front of a moving cell. Based on our analysis of the model and experimental confirmation of its basic predictions, we assert that coupled, counteracting feedback loops constitute a functional switch between maintenance and stalling of the cell protrusion speed. Our model successfully explains the dependence of this swit... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310816 Fri, 26 Feb 2010 00:00:00 +0100 3310816 http://www.medworm.com/index.php?rid=3310815&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F5pJeEBZKCak%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000687 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310815 Fri, 26 Feb 2010 00:00:00 +0100 3310815 http://www.medworm.com/index.php?rid=3310814&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F2Mfsjt-sCsE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000686 Author Summary Understanding how relatively simple, single cell bacteria can communicate and coordinate their actions is important for explaining how complex multicellular behaviour can emerge without a central controller. Myxobacteria are particularly interesting in this respect because cells undergo multiple phases of coordinated behaviour during their life-cycle. One of the most fascinating and complex phases is the formation of fruiting bodies—large multicellular aggregates of cells formed in response to starvation. In this article we use evidence from the latest experimental data to construct a computational model explaining how cells can form fruiting bodies. Both in our model and in nature, cells move together in dense swarms, which collide to form aggregation centres. In particu... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310814 Fri, 26 Feb 2010 00:00:00 +0100 3310814 http://www.medworm.com/index.php?rid=3310813&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fr1bGmL8hM68%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000685 In this study, we develop a “Computational Complementation” approach for the investigation of long-distance signalling networks during legume autoregulation of nodulation (AON). The key idea is to use computational modelling to complement the deficiency of an empirical model of an AON deficient mutant with hypothesised AON components. If the complementation restores a wild-type nodulation phenotype, the modelled hypotheses would be supported as reasonable. To evaluate the feasibility of this approach, we tested whether wild-type soybean cotyledons participate in AON, commonly controlled by “real” leaves. The test gave an affirmative result (i.e., cotyledons do have AON activity), which was subsequently confirmed by a graft experiment on real plants. Future applications of this appr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310813 Fri, 26 Feb 2010 00:00:00 +0100 3310813 http://www.medworm.com/index.php?rid=3310812&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F--BROMNBKkE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000684 Author Summary Cell culture models are an important vehicle for understanding biological processes and evaluation of therapeutic reagents. More importantly, the literature suggests that tumor cells grown in 3D exhibit pronounced drug and radiation resistances that are remarkably similar to that of tumors in vivo. Therefore, the needs for quantifying 3D assays continue to grow. In this paper, we develop robust computational methods to integrate morphometric and molecular information for a panel of breast cancer cell lines that are grown in 3D. Specifically, morphometric traits are imaged through microscopy, and then quantified computationally. We then show that these morphometric traits can identify subtypes within this panel of breast cancer cell lines, and that the subtypes are clinicall... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310812 Fri, 26 Feb 2010 00:00:00 +0100 3310812 http://www.medworm.com/index.php?rid=3310811&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FDRQ6J6dGDp4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000673 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310811 Fri, 26 Feb 2010 00:00:00 +0100 3310811 http://www.medworm.com/index.php?rid=3310810&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FsSKCquW8LIs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000667 Metagenomics is a discipline that enables the genomic study of uncultured microorganisms. Faster, cheaper sequencing technologies and the ability to sequence uncultured microbes sampled directly from their habitats are expanding and transforming our view of the microbial world. Distilling meaningful information from the millions of new genomic sequences presents a serious challenge to bioinformaticians. In cultured microbes, the genomic data come from a single clone, making sequence assembly and annotation tractable. In metagenomics, the data come from heterogeneous microbial communities, sometimes containing more than 10,000 species, with the sequence data being noisy and partial. From sampling, to assembly, to gene calling and function prediction, bioinformatics faces new demands in inte... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310810 Fri, 26 Feb 2010 00:00:00 +0100 3310810 http://www.medworm.com/index.php?rid=3310809&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F0hXb8aGYu7s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000655 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310809 Fri, 26 Feb 2010 00:00:00 +0100 3310809 http://www.medworm.com/index.php?rid=3310808&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fep2E7oQ0-cg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000650 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310808 Fri, 26 Feb 2010 00:00:00 +0100 3310808 http://www.medworm.com/index.php?rid=3310807&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FdW_GfiMiKoE%2Finfo%253Adoi%252F10.1371%252Fimage.pcbi.v06.i02 Computational complementation. Autoregulation of nodulation (AON) is a long-distance, shoot-root signalling system for regulating nodule formation in legume plants. This visualisation, taken from a computational complementation experiment, demonstrates the possible allocation of an unidentified signal for inhibition of nodulation in soybean root. In this approach, an empirical model of a loss-of-function (non-AON) mutant is complemented with hypothetical AON mechanisms. If the resulting nodulation phenotype matches the wild-type plant, the hypotheses would be supported as reasonable. The first application of computational complementation predicted that soybean cotyledons participate in AON, which was subsequently confirmed by a real-plant experiment (see Han et al., doi:10.1371/journal.pcb... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3310807 Fri, 26 Feb 2010 00:00:00 +0100 3310807 http://www.medworm.com/index.php?rid=3341933&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000683 Author Summary Highly pathogenic avian influenza H5N1 continues to spread rapidly between flocks of poultry in many parts of the world including areas in Southeast Asia and Africa where infection has become endemic. Meanwhile the number of human cases and fatalities are steadily accumulating. As a result, the control of outbreaks in poultry remains both a key public and animal health priority. In Vietnam control policies have evolved from a policy of reliance upon drastic “stamping out” measures to regular mass vaccination campaigns. Using Bayesian data augmentation techniques in order to take into account the unobserved infection times, we found that this has led to a significant reduction in the daily probability of transmission between communes but that the time taken to detect out... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341933 Fri, 19 Feb 2010 00:00:00 +0100 3341933 http://www.medworm.com/index.php?rid=3341932&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000682 Author Summary Lymphocytes of the immune system ensure the body defense by the expression of receptors which are specific of targets, termed antigens. Each lymphocyte, deriving from the same original clone, expresses the same unique receptor. To achieve the production of receptors covering the wide variety of antigens, lymphocytes use a specialized genetic mechanism consisting of gene rearrangements. For instance, the genes encoding the receptor of the alpha chain of the T lymphocyte receptor (TRA) spread over a 1500 Kb genetic region which includes around 100 V genes, 60 J genes, and a single C gene. To constitute a functional alpha chain, one of the V and one of the J genes rearrange together to form a single exon. The precise definition of these V-J combinations is essential to underst... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341932 Fri, 19 Feb 2010 00:00:00 +0100 3341932 http://www.medworm.com/index.php?rid=3341931&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000681 Author Summary To gain access to sites of inflammation, leukocytes must first adhere to the blood vessel wall using integrin molecules. It has been hypothesized that integrin clustering is essential for sustaining adhesion prior to transmigration into the inflamed tissue. We cannot challenge such hypotheses directly because it is infeasible to measure molecular level events during the leukocyte adhesion process. At best correlative relationships have been made. The alternative approach undertaken was to experimentally challenge the hypothesized mechanisms in silico. We used object-oriented, software engineering methods to build and execute multi-level, multi-attribute analogues of leukocytes and binding surfaces. The simulated leukocytes contained diffusible objects (representing integrin... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341931 Fri, 19 Feb 2010 00:00:00 +0100 3341931 http://www.medworm.com/index.php?rid=3341930&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000680 Author Summary Visual cues typically provide ambiguous information about the orientation of our body in space. When we perceive relative motion between ourselves and the environment, it could have been caused by our movement within the environment, or the movement of the environment around us, or the simultaneous movements of both our body and the environment. The nervous system must resolve this ambiguity for efficient control of our body posture during stance. Here, we show that the nervous system could solve this problem by optimally combining visual signals with physical motion cues. Sensory ambiguity is a central problem during cue combination. Our results thus have implications on how the nervous system could resolve sensory ambiguity in other cue combination tasks. (Source: PLoS Co... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341930 Fri, 19 Feb 2010 00:00:00 +0100 3341930 http://www.medworm.com/index.php?rid=3341929&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000679 Author Summary Neurons in many parts of the brain fire spikes rhythmically and synchronously in many behaviorally and functionally relevant contexts. There are many mechanisms for producing oscillatory synchronization between populations of biological oscillators. One way to produce synchrony is that the population of oscillators receives common correlated input. In this paper, we study a population of oscillating neurons (mitral cells) that are not directly coupled to each other but receive broadband correlated input from a second population of neurons (granule cells). The granule cell population, in turn, receives inputs from the mitral cells; hence, the mitral and granule cells are reciprocally connected. Correlated input to the oscillating mitral cells produces tighter synchrony in th... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341929 Fri, 19 Feb 2010 00:00:00 +0100 3341929 http://www.medworm.com/index.php?rid=3287179&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FqdCuKasfWKg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000683 Author Summary Highly pathogenic avian influenza H5N1 continues to spread rapidly between flocks of poultry in many parts of the world including areas in Southeast Asia and Africa where infection has become endemic. Meanwhile the number of human cases and fatalities are steadily accumulating. As a result, the control of outbreaks in poultry remains both a key public and animal health priority. In Vietnam control policies have evolved from a policy of reliance upon drastic “stamping out” measures to regular mass vaccination campaigns. Using Bayesian data augmentation techniques in order to take into account the unobserved infection times, we found that this has led to a significant reduction in the daily probability of transmission between communes but that the time taken to detect out... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3287179 Fri, 19 Feb 2010 00:00:00 +0100 3287179 http://www.medworm.com/index.php?rid=3287178&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FeU2qQmHWBYQ%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000682 Author Summary Lymphocytes of the immune system ensure the body defense by the expression of receptors which are specific of targets, termed antigens. Each lymphocyte, deriving from the same original clone, expresses the same unique receptor. To achieve the production of receptors covering the wide variety of antigens, lymphocytes use a specialized genetic mechanism consisting of gene rearrangements. For instance, the genes encoding the receptor of the alpha chain of the T lymphocyte receptor (TRA) spread over a 1500 Kb genetic region which includes around 100 V genes, 60 J genes, and a single C gene. To constitute a functional alpha chain, one of the V and one of the J genes rearrange together to form a single exon. The precise definition of these V-J combinations is essential to underst... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3287178 Fri, 19 Feb 2010 00:00:00 +0100 3287178 http://www.medworm.com/index.php?rid=3287177&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FgxwfwpI66Xk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000681 Author Summary To gain access to sites of inflammation, leukocytes must first adhere to the blood vessel wall using integrin molecules. It has been hypothesized that integrin clustering is essential for sustaining adhesion prior to transmigration into the inflamed tissue. We cannot challenge such hypotheses directly because it is infeasible to measure molecular level events during the leukocyte adhesion process. At best correlative relationships have been made. The alternative approach undertaken was to experimentally challenge the hypothesized mechanisms in silico. We used object-oriented, software engineering methods to build and execute multi-level, multi-attribute analogues of leukocytes and binding surfaces. The simulated leukocytes contained diffusible objects (representing integrin... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3287177 Fri, 19 Feb 2010 00:00:00 +0100 3287177 http://www.medworm.com/index.php?rid=3287176&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F-YHloxX_tak%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000680 Author Summary Visual cues typically provide ambiguous information about the orientation of our body in space. When we perceive relative motion between ourselves and the environment, it could have been caused by our movement within the environment, or the movement of the environment around us, or the simultaneous movements of both our body and the environment. The nervous system must resolve this ambiguity for efficient control of our body posture during stance. Here, we show that the nervous system could solve this problem by optimally combining visual signals with physical motion cues. Sensory ambiguity is a central problem during cue combination. Our results thus have implications on how the nervous system could resolve sensory ambiguity in other cue combination tasks. (Source: PLoS Co... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3287176 Fri, 19 Feb 2010 00:00:00 +0100 3287176 http://www.medworm.com/index.php?rid=3287175&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FmFgVTcyefJk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000679 Author Summary Neurons in many parts of the brain fire spikes rhythmically and synchronously in many behaviorally and functionally relevant contexts. There are many mechanisms for producing oscillatory synchronization between populations of biological oscillators. One way to produce synchrony is that the population of oscillators receives common correlated input. In this paper, we study a population of oscillating neurons (mitral cells) that are not directly coupled to each other but receive broadband correlated input from a second population of neurons (granule cells). The granule cell population, in turn, receives inputs from the mitral cells; hence, the mitral and granule cells are reciprocally connected. Correlated input to the oscillating mitral cells produces tighter synchrony in th... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3287175 Fri, 19 Feb 2010 00:00:00 +0100 3287175 http://www.medworm.com/index.php?rid=3341941&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000678 Author Summary The good operation of cells relies on a coordination between chromosome structure and genetic regulation which is yet to be understood. This can be seen in particular from the transcription machinery: in some eukaryotes and bacteria, transcription of highly active genes occurs within discrete foci called transcription factories, where RNA polymerases, transcription factors and their target genes co-localize. The mechanisms underlying the formation of these foci and the resulting topological structure of the chromosome remain to be elucidated. Here, we propose a thermodynamic framework based on a polymer description of DNA in which genes effectively interact through attractive forces in physical space. The formation of transcription foci then corresponds to a self-organizing... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341941 Fri, 12 Feb 2010 00:00:00 +0100 3341941 http://www.medworm.com/index.php?rid=3341940&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000677 Author Summary Human color perception arises by comparing the signals from cones with peak sensitivities, at long (L), medium (M) and short (S) wavelengths. In dichromats, a characteristic distribution of S and M cones supports blue-yellow color vision: a few S and mostly M. When L cones are added, allowing red-green color vision, the S proportion remains low, increasing slowly with increasing retinal eccentricity, but the L/M proportion can vary 5-fold without affecting red-green color perception. We offer a unified explanation of these striking facts. First, we find that the spatial-chromatic statistics of natural scenes are largely symmetric between the L, M and S sensitivity bands. Thus, attenuation of blue light in the optical media, and chromatic aberration after long-wavelength acc... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341940 Fri, 12 Feb 2010 00:00:00 +0100 3341940 http://www.medworm.com/index.php?rid=3341939&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000676 Author Summary Bacteria have evolved various mechanisms for surviving unpredictable changes and stresses in the environment, such as nutrient limitation. One common survival mechanism is the two-component system, where a sensor protein responds to a particular type of stress by activating a regulator in the cell. These regulators can in turn activate genes that produce proteins for stress-appropriate responses. The activated regulator often positively regulates transcription of its own operon containing the sensor and regulator genes leading to a feedback loop. This is interesting, because positive feedback is usually associated with a slower response time than negative feedback and therefore negative feedback would often be selected for by evolution. Here we analyze a mathematical model ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341939 Fri, 12 Feb 2010 00:00:00 +0100 3341939 http://www.medworm.com/index.php?rid=3341938&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000675 Author Summary Networks of neurons in the brain are connected together by specialized signaling devices called synapses. One way an active neuron relays its activity to other neurons is by releasing small amounts of chemical transmitters from its presynaptic terminals which induce electrical activity in postsynaptic neurons connected to it. Memories are formed when synapses in the network encoding the memory change their strength in order to stabilize the network. The decision whether or not a synapse becomes potentiated is controlled by delicate variations in the amount of Ca2+ ions that flow across the membrane at the postsynaptic site, and by the pattern of influx over time. The mechanisms of activation of regulatory enzymes that decode this Ca2+ signal have been extensively studied un... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341938 Fri, 12 Feb 2010 00:00:00 +0100 3341938 http://www.medworm.com/index.php?rid=3341937&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000674 Author Summary Although different environmental stresses trigger specific sets of protective changes in the gene expression of yeast, the adaptive responses to these stresses also share some common features. We hypothesize that minimization of metabolic costs may contribute to shaping such adaptive responses. If this is so, then such pressure should be more noticeable in the costliest biosynthetic processes. One of these is protein synthesis. Thus, we analyze the set of genes and proteins whose expression changes during the responses and look for evidence to support or falsify our hypothesis. We find that protein properties that are indicative of protein cost correlate to changes in gene expression in a way that is consistent with that hypothesis for a large number of adaptive responses. ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341937 Fri, 12 Feb 2010 00:00:00 +0100 3341937 http://www.medworm.com/index.php?rid=3341936&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000672 Author Summary Genes involved in a common pathway or function are frequently found near each other on bacterial chromosomes. A number of hypotheses have been previously presented to explain this observation. A particularly influential theory is the selfish operon model, which posits that horizontal transfer could promote gene clustering by favouring transfer of arrangements of genes that are close together. Subsequent theoretical development and analysis of genomic data have contributed to the debate about the plausibility of this model. Here, by re-examining the evolutionary dynamics of gene clusters, we provide and discuss conditions under which gene clusters can evolve. We find that first, some form of bias for clustering is required for clusters to evolve. This bias can be in the form... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341936 Fri, 12 Feb 2010 00:00:00 +0100 3341936 http://www.medworm.com/index.php?rid=3341935&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000671 Author Summary Peripheral blood is the most readily accessible human tissue for clinical studies and experimental research more generally. Large-scale molecular profiling technologies have enabled measurements of mRNA expression on the scale of whole genomes. Understanding the relationships between human blood gene expression profiles and clinical traits is extremely useful for inferring causal factors for human disease and for studying drug response. Biological pathways and the complex behaviors they induce are not static, but change dynamically in response to external factors such as intake/uptake of nutrients and administration of drugs. We employed a randomized, two-arm cross-over design to assess the effects of fasting and feeding on the dynamic changes of blood transcriptional netwo... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341935 Fri, 12 Feb 2010 00:00:00 +0100 3341935 http://www.medworm.com/index.php?rid=3341934&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000670 Author Summary Recent brain imaging and neurophysiological studies suggest that the striatum, the start of the basal ganglia circuit, plays a major role in value-based decision making and behavioral disorders such as drug addiction. The plasticity of synaptic input from the cerebral cortex to output neurons of the striatum, which are medium spiny neurons, depends on interactions between glutamate input from the cortex and dopaminergic input from the midbrain. It also links sensory and cognitive states in the cortex with reward-oriented action outputs. The mechanisms involved in molecular cascades that transmit glutamate and dopamine inputs to changes in postsynaptic glutamate receptors are very complex and it is difficult to intuitively understand the mechanism. Therefore, a biochemical n... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3341934 Fri, 12 Feb 2010 00:00:00 +0100 3341934 http://www.medworm.com/index.php?rid=3266364&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F2EEzTwFv-js%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000678 Author Summary The good operation of cells relies on a coordination between chromosome structure and genetic regulation which is yet to be understood. This can be seen in particular from the transcription machinery: in some eukaryotes and bacteria, transcription of highly active genes occurs within discrete foci called transcription factories, where RNA polymerases, transcription factors and their target genes co-localize. The mechanisms underlying the formation of these foci and the resulting topological structure of the chromosome remain to be elucidated. Here, we propose a thermodynamic framework based on a polymer description of DNA in which genes effectively interact through attractive forces in physical space. The formation of transcription foci then corresponds to a self-organizing... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266364 Fri, 12 Feb 2010 00:00:00 +0100 3266364 http://www.medworm.com/index.php?rid=3266363&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FX07vkbNm83o%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000677 Author Summary Human color perception arises by comparing the signals from cones with peak sensitivities, at long (L), medium (M) and short (S) wavelengths. In dichromats, a characteristic distribution of S and M cones supports blue-yellow color vision: a few S and mostly M. When L cones are added, allowing red-green color vision, the S proportion remains low, increasing slowly with increasing retinal eccentricity, but the L/M proportion can vary 5-fold without affecting red-green color perception. We offer a unified explanation of these striking facts. First, we find that the spatial-chromatic statistics of natural scenes are largely symmetric between the L, M and S sensitivity bands. Thus, attenuation of blue light in the optical media, and chromatic aberration after long-wavelength acc... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266363 Fri, 12 Feb 2010 00:00:00 +0100 3266363 http://www.medworm.com/index.php?rid=3266362&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FrbG4N0MSB1I%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000676 Author Summary Bacteria have evolved various mechanisms for surviving unpredictable changes and stresses in the environment, such as nutrient limitation. One common survival mechanism is the two-component system, where a sensor protein responds to a particular type of stress by activating a regulator in the cell. These regulators can in turn activate genes that produce proteins for stress-appropriate responses. The activated regulator often positively regulates transcription of its own operon containing the sensor and regulator genes leading to a feedback loop. This is interesting, because positive feedback is usually associated with a slower response time than negative feedback and therefore negative feedback would often be selected for by evolution. Here we analyze a mathematical model ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266362 Fri, 12 Feb 2010 00:00:00 +0100 3266362 http://www.medworm.com/index.php?rid=3266361&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FFeZ7ZaMNgKY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000675 Author Summary Networks of neurons in the brain are connected together by specialized signaling devices called synapses. One way an active neuron relays its activity to other neurons is by releasing small amounts of chemical transmitters from its presynaptic terminals which induce electrical activity in postsynaptic neurons connected to it. Memories are formed when synapses in the network encoding the memory change their strength in order to stabilize the network. The decision whether or not a synapse becomes potentiated is controlled by delicate variations in the amount of Ca2+ ions that flow across the membrane at the postsynaptic site, and by the pattern of influx over time. The mechanisms of activation of regulatory enzymes that decode this Ca2+ signal have been extensively studied un... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266361 Fri, 12 Feb 2010 00:00:00 +0100 3266361 http://www.medworm.com/index.php?rid=3266360&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FBFmBEBBVCyA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000674 Author Summary Although different environmental stresses trigger specific sets of protective changes in the gene expression of yeast, the adaptive responses to these stresses also share some common features. We hypothesize that minimization of metabolic costs may contribute to shaping such adaptive responses. If this is so, then such pressure should be more noticeable in the costliest biosynthetic processes. One of these is protein synthesis. Thus, we analyze the set of genes and proteins whose expression changes during the responses and look for evidence to support or falsify our hypothesis. We find that protein properties that are indicative of protein cost correlate to changes in gene expression in a way that is consistent with that hypothesis for a large number of adaptive responses. ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266360 Fri, 12 Feb 2010 00:00:00 +0100 3266360 http://www.medworm.com/index.php?rid=3266359&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FhOKLT2pMCsc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000672 Author Summary Genes involved in a common pathway or function are frequently found near each other on bacterial chromosomes. A number of hypotheses have been previously presented to explain this observation. A particularly influential theory is the selfish operon model, which posits that horizontal transfer could promote gene clustering by favouring transfer of arrangements of genes that are close together. Subsequent theoretical development and analysis of genomic data have contributed to the debate about the plausibility of this model. Here, by re-examining the evolutionary dynamics of gene clusters, we provide and discuss conditions under which gene clusters can evolve. We find that first, some form of bias for clustering is required for clusters to evolve. This bias can be in the form... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266359 Fri, 12 Feb 2010 00:00:00 +0100 3266359 http://www.medworm.com/index.php?rid=3266358&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fdtnp6_bSktk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000671 Author Summary Peripheral blood is the most readily accessible human tissue for clinical studies and experimental research more generally. Large-scale molecular profiling technologies have enabled measurements of mRNA expression on the scale of whole genomes. Understanding the relationships between human blood gene expression profiles and clinical traits is extremely useful for inferring causal factors for human disease and for studying drug response. Biological pathways and the complex behaviors they induce are not static, but change dynamically in response to external factors such as intake/uptake of nutrients and administration of drugs. We employed a randomized, two-arm cross-over design to assess the effects of fasting and feeding on the dynamic changes of blood transcriptional netwo... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266358 Fri, 12 Feb 2010 00:00:00 +0100 3266358 http://www.medworm.com/index.php?rid=3266357&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FmhAzdArNUxw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000670 Author Summary Recent brain imaging and neurophysiological studies suggest that the striatum, the start of the basal ganglia circuit, plays a major role in value-based decision making and behavioral disorders such as drug addiction. The plasticity of synaptic input from the cerebral cortex to output neurons of the striatum, which are medium spiny neurons, depends on interactions between glutamate input from the cortex and dopaminergic input from the midbrain. It also links sensory and cognitive states in the cortex with reward-oriented action outputs. The mechanisms involved in molecular cascades that transmit glutamate and dopamine inputs to changes in postsynaptic glutamate receptors are very complex and it is difficult to intuitively understand the mechanism. Therefore, a biochemical n... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3266357 Fri, 12 Feb 2010 00:00:00 +0100 3266357 http://www.medworm.com/index.php?rid=3262176&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000669 Author Summary Rheumatoid arthritis (RA) is a frequently occurring, chronic, debilitating disease. TNFα plays a pivotal role in regulating its inflammatory response. TNFα inhibition with TNF receptor 2-Fc fusion protein (TNFR2-Fc) was effective in the treatment of RA. However, quite a few patients may not achieve good clinical outcomes after TNFR2-Fc therapy, and the high dosage of TNFR2-Fc in clinical treatment usually causes some side effects, such as injection site reactions. Enhancing the affinity of TNFR2-Fc to TNFα would be of benefit to its therapeutic effect on RA, and may reduce the clinical dosage. We modeled the interactions of TNFα and TNFR2, and figured out the sites that may be critical for ligand-receptor binding. A high affinity TNFR2-Fc variant (E92N/W89Y) was obtaine... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262176 Fri, 05 Feb 2010 00:00:00 +0100 3262176 http://www.medworm.com/index.php?rid=3262175&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000668 Author Summary Proteins function through their interactions with other biological molecules, including other proteins. Often times, these interactions underlie cellular processes that go awry in disease. Therefore, modulating these interactions with small molecules is an active area of research for new drugs to treat diseases and new chemical tools to dissect cellular interaction networks. However, targeting protein–protein interactions has proven to be more challenging than the typical drug targets found on individual proteins. Here, we present a computational approach that aims to help in this challenge by identifying regions of protein–protein interfaces that may be amenable to targeting by small molecules. Through a comprehensive analysis of all known protein structures, we identi... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262175 Fri, 05 Feb 2010 00:00:00 +0100 3262175 http://www.medworm.com/index.php?rid=3262174&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000666 Author Summary Understanding of cellular processes is impossible without quantitative estimates of how quickly cells in an organism divide and die. The most widely used approach to measure rates of cell turnover in humans is by labeling dividing cells with deuterium given in the form of deuterated glucose or heavy water. Surprisingly, quantitative estimates of the rates of cell turnover obtained from accumulation and decay of the labeled nucleotides in the cell population varied between different studies. We demonstrate that these differences were not likely to arise because of different mathematical models used in data fitting, since the previously used models have an identical mathematical structure. We extend these previous models to allow for cell populations with different rates of t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262174 Fri, 05 Feb 2010 00:00:00 +0100 3262174 http://www.medworm.com/index.php?rid=3262173&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000665 Author Summary A Molecular Interaction Map (MIM) akin to a circuit diagram of an electric device can give a comprehensive view of cellular processes and help understand complex protein functions in cells. To this end, we generated a MIM focused on the p53-Mdm2-MdmX network proteins and performed computer simulations to help understand how Mdm2 and MdmX may regulate p53. Proper regulation of p53 is important for cell survival: elevated levels of p53 can lead to cell death, and decreased levels of p53 can lead to cancer. Mdm2 and MdmX are structurally homologous proteins that regulate p53. Mdm2 negatively regulates p53 by degradation, but MdmX regulation of p53 is not well understood. Recently, Mdm2 and MdmX have been recognized as potential cancer therapeutic targets. In an effort to bette... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262173 Fri, 05 Feb 2010 00:00:00 +0100 3262173 http://www.medworm.com/index.php?rid=3262172&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000664 Author Summary Synonymous mutations are mutations that change the nucleotide sequence of a gene without changing the amino-acid sequence. Because these mutations don't alter the expressed protein, they are frequently also called silent mutations. Yet increasing evidence demonstrates that synonymous mutations are not that silent. In particular, experimental work in Escherichia coli has shown that the choice of synonymous codons near the start codon can greatly influence protein production. Codons that allow the mRNA to fold into a stable secondary structure seem to inhibit efficient translation initiation. This observation suggests that selection should prefer reduced mRNA stability near the start codon in many organisms. Here, we show that this prediction generally holds true in most orga... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262172 Fri, 05 Feb 2010 00:00:00 +0100 3262172 http://www.medworm.com/index.php?rid=3262171&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000663 Author Summary Unraveling the molecular details of the interaction between apolipoprotein E and the amyloid β peptide will yield insights into the relationship between Alzheimer's disease and lipid transport and metabolism. The isoform E4 of apolipoprotein E has been shown to be closely related to Alzheimer's disease. We have therefore used a computational approach to depict a detailed interaction map for this peptide-lipoprotein interaction. The simulation shows that the specific formation of the lipoprotein isoform E4 and the peptide complex affects the structure of the lipoprotein and the peptide. We suggest that this is related to some of the pathogenic effects in Alzheimer's disease. Our results provide a molecular model to work with for the design of potential therapeutic agents ca... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262171 Fri, 05 Feb 2010 00:00:00 +0100 3262171 http://www.medworm.com/index.php?rid=3262170&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000662 Author Summary Many human diseases are related to each other through shared causes or even shared pathology. Knowledge of these relationships has long been exploited to treat similar diseases with the same therapies. However, most of the traditional approaches to discover these relationships have depended on subjective measures, such as similarity in symptoms, or incomplete knowledge, such as genes with mutations. Here we present the first approach integrating high-throughput datasets such as mRNA expression and large-scale protein-protein interaction networks to discover human disease relationships in a systematic and quantitative way. We discover 138 significant pathological similarities between 54 human diseases ranging from lung cancer, schizophrenia, and malaria. We also discovered a... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262170 Fri, 05 Feb 2010 00:00:00 +0100 3262170 http://www.medworm.com/index.php?rid=3243127&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F1TZC01FYiDg%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000669 Author Summary Rheumatoid arthritis (RA) is a frequently occurring, chronic, debilitating disease. TNFα plays a pivotal role in regulating its inflammatory response. TNFα inhibition with TNF receptor 2-Fc fusion protein (TNFR2-Fc) was effective in the treatment of RA. However, quite a few patients may not achieve good clinical outcomes after TNFR2-Fc therapy, and the high dosage of TNFR2-Fc in clinical treatment usually causes some side effects, such as injection site reactions. Enhancing the affinity of TNFR2-Fc to TNFα would be of benefit to its therapeutic effect on RA, and may reduce the clinical dosage. We modeled the interactions of TNFα and TNFR2, and figured out the sites that may be critical for ligand-receptor binding. A high affinity TNFR2-Fc variant (E92N/W89Y) was obtaine... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243127 Fri, 05 Feb 2010 00:00:00 +0100 3243127 http://www.medworm.com/index.php?rid=3243126&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F8lhZ9MCnSQU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000668 Author Summary Proteins function through their interactions with other biological molecules, including other proteins. Often times, these interactions underlie cellular processes that go awry in disease. Therefore, modulating these interactions with small molecules is an active area of research for new drugs to treat diseases and new chemical tools to dissect cellular interaction networks. However, targeting protein–protein interactions has proven to be more challenging than the typical drug targets found on individual proteins. Here, we present a computational approach that aims to help in this challenge by identifying regions of protein–protein interfaces that may be amenable to targeting by small molecules. Through a comprehensive analysis of all known protein structures, we identi... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243126 Fri, 05 Feb 2010 00:00:00 +0100 3243126 http://www.medworm.com/index.php?rid=3243125&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fdm-jQl8lMD4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000666 Author Summary Understanding of cellular processes is impossible without quantitative estimates of how quickly cells in an organism divide and die. The most widely used approach to measure rates of cell turnover in humans is by labeling dividing cells with deuterium given in the form of deuterated glucose or heavy water. Surprisingly, quantitative estimates of the rates of cell turnover obtained from accumulation and decay of the labeled nucleotides in the cell population varied between different studies. We demonstrate that these differences were not likely to arise because of different mathematical models used in data fitting, since the previously used models have an identical mathematical structure. We extend these previous models to allow for cell populations with different rates of t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243125 Fri, 05 Feb 2010 00:00:00 +0100 3243125 http://www.medworm.com/index.php?rid=3243124&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FWSSuVpUWz3M%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000665 Author Summary A Molecular Interaction Map (MIM) akin to a circuit diagram of an electric device can give a comprehensive view of cellular processes and help understand complex protein functions in cells. To this end, we generated a MIM focused on the p53-Mdm2-MdmX network proteins and performed computer simulations to help understand how Mdm2 and MdmX may regulate p53. Proper regulation of p53 is important for cell survival: elevated levels of p53 can lead to cell death, and decreased levels of p53 can lead to cancer. Mdm2 and MdmX are structurally homologous proteins that regulate p53. Mdm2 negatively regulates p53 by degradation, but MdmX regulation of p53 is not well understood. Recently, Mdm2 and MdmX have been recognized as potential cancer therapeutic targets. In an effort to bette... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243124 Fri, 05 Feb 2010 00:00:00 +0100 3243124 http://www.medworm.com/index.php?rid=3243123&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FKqg2jn1Q1Wo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000664 Author Summary Synonymous mutations are mutations that change the nucleotide sequence of a gene without changing the amino-acid sequence. Because these mutations don't alter the expressed protein, they are frequently also called silent mutations. Yet increasing evidence demonstrates that synonymous mutations are not that silent. In particular, experimental work in Escherichia coli has shown that the choice of synonymous codons near the start codon can greatly influence protein production. Codons that allow the mRNA to fold into a stable secondary structure seem to inhibit efficient translation initiation. This observation suggests that selection should prefer reduced mRNA stability near the start codon in many organisms. Here, we show that this prediction generally holds true in most orga... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243123 Fri, 05 Feb 2010 00:00:00 +0100 3243123 http://www.medworm.com/index.php?rid=3243122&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F81FKCebmsL8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000663 Author Summary Unraveling the molecular details of the interaction between apolipoprotein E and the amyloid β peptide will yield insights into the relationship between Alzheimer's disease and lipid transport and metabolism. The isoform E4 of apolipoprotein E has been shown to be closely related to Alzheimer's disease. We have therefore used a computational approach to depict a detailed interaction map for this peptide-lipoprotein interaction. The simulation shows that the specific formation of the lipoprotein isoform E4 and the peptide complex affects the structure of the lipoprotein and the peptide. We suggest that this is related to some of the pathogenic effects in Alzheimer's disease. Our results provide a molecular model to work with for the design of potential therapeutic agents ca... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243122 Fri, 05 Feb 2010 00:00:00 +0100 3243122 http://www.medworm.com/index.php?rid=3243121&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fz7fA0afjsp0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000662 Author Summary Many human diseases are related to each other through shared causes or even shared pathology. Knowledge of these relationships has long been exploited to treat similar diseases with the same therapies. However, most of the traditional approaches to discover these relationships have depended on subjective measures, such as similarity in symptoms, or incomplete knowledge, such as genes with mutations. Here we present the first approach integrating high-throughput datasets such as mRNA expression and large-scale protein-protein interaction networks to discover human disease relationships in a systematic and quantitative way. We discover 138 significant pathological similarities between 54 human diseases ranging from lung cancer, schizophrenia, and malaria. We also discovered a... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3243121 Fri, 05 Feb 2010 00:00:00 +0100 3243121 http://www.medworm.com/index.php?rid=3262190&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000661 Author Summary The fundamental understanding of metabolism in organisms which can only be achieved by integrated studies on their biology using a systems biology approach will aid in the design of future metabolic engineering strategies. Metabolic network reconstruction provides insight into the molecular mechanisms of a particular organism. An annotated genome containing the specific metabolic genes found in a particular organism can be used to reconstruct its metabolic network. The correlation between the genome and metabolism is made by searching gene databases or by searching protein databases with a known EC number in order to find the associated gene. The success of the search process is critically dependent upon the consistency and reliability of the underlying data. Therefore we h... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262190 Fri, 29 Jan 2010 00:00:00 +0100 3262190 http://www.medworm.com/index.php?rid=3262189&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000660 Author Summary Evolution, in viruses and other organisms, is the result of random genetic diversification by mutation or recombination and selection for survival. In most organisms, evolution is too slow to be observed directly and the evolutionary past has to be reconstructed from static snapshots of the population. This reconstruction requires simple models of evolution that typically neglect selection or recombination. In vigorously evolving organisms like HIV, such assumptions are questionable. However, HIV evolves rapidly enough that substantial evolution is observable during a chronic HIV infection within single patients. Using such time series data of evolution, we estimate the effective recombination rate of HIV (the rate of viral sex) to be similar to the mutation rate, rather th... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262189 Fri, 29 Jan 2010 00:00:00 +0100 3262189 http://www.medworm.com/index.php?rid=3262188&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000659 Author Summary Cellular function is widely believed to be organized in a modular fashion. On all scales and at all levels of complexity, relatively independent sub-units perform relatively independent sub-tasks. This functional modularity must be reflected in the topology of molecular networks. But how a functional module should be represented in an interaction network is an open question. On a small scale, one can identify a protein-complex as a module in protein-interaction networks (PIN), i.e., modules are understood as densely linked (interacting) groups of proteins, that are only sparsely interacting with the rest of the network. In this contribution, we show that extrapolating this concept of cohesively linked clusters of proteins as modules to the scale of the entire PIN inevitably... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262188 Fri, 29 Jan 2010 00:00:00 +0100 3262188 http://www.medworm.com/index.php?rid=3262187&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000658 Author Summary It is well known that female gender is an independent risk factor for some types of cardiac arrhythmias. However, it has been difficult to determine how much of a role physiological concentrations of circulating sex steroid hormones play in gender linked arrhythmia susceptibility because the cardiac system is so extraordinarily complex. Here we employ a computational strategy, based on experimental measurements, to tease out the individual contributions of estrogen, progesterone and testosterone on cardiac electrical behavior and then make predictions about their effects in combination and in the presence of drugs. The computational models convincingly reproduce observed fluctuations of QT intervals (as recorded on the ECG (electrocardiogram), the QT interval reflects the t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262187 Fri, 29 Jan 2010 00:00:00 +0100 3262187 http://www.medworm.com/index.php?rid=3262186&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000657 Author Summary Cardiac cell injury and death is a key component of cardiac diseases such as heart failure or myocardial infarction, thus it is important to understand the earliest steps leading up to irreversible cell damage. Mitochondria are the organelles responsible for generating the energy required to keep the cell running, yet they are particularly vulnerable to damage by toxic byproducts of metabolism, which include reactive oxygen species (ROS). ROS wreak havoc on cellular functions by attacking proteins, lipids and DNA, so the cardiac cell has evolved sophisticated defenses to remove them. The work we present in this paper using a computer model of the mitochondrial network describes how ROS generated inside the cell can spread from one mitochondrion to the next in a positive fee... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262186 Fri, 29 Jan 2010 00:00:00 +0100 3262186 http://www.medworm.com/index.php?rid=3262185&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000656 Author Summary Computer simulations can provide valuable information to communities preparing for epidemics. These simulations can be used to investigate the effectiveness of various intervention strategies in reducing or delaying the peak of an epidemic. We have made a detailed influenza epidemic simulator for the United States publicly available so that others may use the software to inform public policy or adapt it to suit their needs. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262185 Fri, 29 Jan 2010 00:00:00 +0100 3262185 http://www.medworm.com/index.php?rid=3262184&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000654 Author Summary Cellular systems are dynamic in nature, perform various biological functions and can adapt to their environment through compositional and structural remodeling. This remodeling is initiated by the binding of external ligands to receptor proteins on the cell surface or other stimuli resulting in the activation of various signaling pathways. The activation of signaling pathways in turn results in altered gene-expression which leads to changes in the molecular composition both inside and outside the cell. Thus, a thorough study of the complex interconnectivity of signaling pathways using dynamic data is necessary to understand the biological function and environmental adaptation. Protein phosphorylation is a key event in the activation of signaling pathways. We have developed ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262184 Fri, 29 Jan 2010 00:00:00 +0100 3262184 http://www.medworm.com/index.php?rid=3262183&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000653 Author Summary Due to the sheer number of neurons and the complexity of their interactions, the modelling of brain activity is particularly challenging. How can computationally tractable models of brain function be developed that are nevertheless biologically plausible? The “mean field” approach, borrowed from statistical physics, is to model the average activity of populations of neurons rather than the behaviour of individual neurons. While a large number of promising theories have been developed with this approach, they fall short of biological fidelity in the way interactions between distant populations have been modelled. In particular, it is often assumed that all neurons interact via connections of very similar conduction velocity, when in fact experiment suggests quite the opp... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262183 Fri, 29 Jan 2010 00:00:00 +0100 3262183 http://www.medworm.com/index.php?rid=3262182&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000652 Author Summary We develop a computational pipeline for predicting the functions of transcription factor motifs, through DNA sequence analysis. The pipeline is applied to the newly sequenced genome of the jewel wasp, Nasonia vitripennis. It exploits the wealth of molecular data available in another insect species, the fruitfly Drosophila melanogaster, and uses cross-species comparison to its advantage. Our main contribution is to show how this can be done despite the large evolutionary divergence between the two species. The methodology presented here may be applied more generally to other scenarios (genomes) where comparative regulatory genomics must deal with large evolutionary divergences. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262182 Fri, 29 Jan 2010 00:00:00 +0100 3262182 http://www.medworm.com/index.php?rid=3262181&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000651 Author Summary Cortical areas V1, V2 and V3 each contain a complete and orderly representation of the visual environment, and their detailed layout is often studied. Here we discuss and compare algebraic mapping functions providing a transformation from visual field to cortical maps. Such algebraic models allow prediction of the layout in individuals from sparse data and advance our understanding of the mapping principles guiding the cortical organization in this important brain region. We show the deficiencies in previous work and provide the first plausible account of the combined layout of the first three visual maps, deriving an optimal compromise between the desirable principles of local isotropy of the maps and the extent of cortex that they occupy. This formal mapping scheme has on... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262181 Fri, 29 Jan 2010 00:00:00 +0100 3262181 http://www.medworm.com/index.php?rid=3262180&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000640 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262180 Fri, 29 Jan 2010 00:00:00 +0100 3262180 http://www.medworm.com/index.php?rid=3262179&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000621 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262179 Fri, 29 Jan 2010 00:00:00 +0100 3262179 http://www.medworm.com/index.php?rid=3262178&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000563 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262178 Fri, 29 Jan 2010 00:00:00 +0100 3262178 http://www.medworm.com/index.php?rid=3262177&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fimage.pcbi.v06.i01 The checkerboard strategy. Many experiments suggest that the sustainability of an ecosystem depends on its spatial structure; when a local subpopulation goes extinct the empty habitat patch is "rescued" by immigrants from nearby patches. Trying to protect endangered species via the construction of conservation corridors, the engineer faces a Goldilocks problem: weak migration does not allow for the rescue of empty patches; strong migration leads to spatial coherence and global extinction. In this work, the authors show that maximum sustainability is achieved when the migration rate is tuned to the value that yields a checkerboard spatial pattern (see Ben Zion et al., doi:10.1371/journal.pcbi.1000643). Image Credit: Gur Yaari (Yale University) (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262177 Fri, 29 Jan 2010 00:00:00 +0100 3262177 http://www.medworm.com/index.php?rid=3219847&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FsZkeURvEE1s%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000661 Author Summary The fundamental understanding of metabolism in organisms which can only be achieved by integrated studies on their biology using a systems biology approach will aid in the design of future metabolic engineering strategies. Metabolic network reconstruction provides insight into the molecular mechanisms of a particular organism. An annotated genome containing the specific metabolic genes found in a particular organism can be used to reconstruct its metabolic network. The correlation between the genome and metabolism is made by searching gene databases or by searching protein databases with a known EC number in order to find the associated gene. The success of the search process is critically dependent upon the consistency and reliability of the underlying data. Therefore we h... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219847 Fri, 29 Jan 2010 00:00:00 +0100 3219847 http://www.medworm.com/index.php?rid=3219846&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FUE3_ARAYAyU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000660 Author Summary Evolution, in viruses and other organisms, is the result of random genetic diversification by mutation or recombination and selection for survival. In most organisms, evolution is too slow to be observed directly and the evolutionary past has to be reconstructed from static snapshots of the population. This reconstruction requires simple models of evolution that typically neglect selection or recombination. In vigorously evolving organisms like HIV, such assumptions are questionable. However, HIV evolves rapidly enough that substantial evolution is observable during a chronic HIV infection within single patients. Using such time series data of evolution, we estimate the effective recombination rate of HIV (the rate of viral sex) to be similar to the mutation rate, rather th... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219846 Fri, 29 Jan 2010 00:00:00 +0100 3219846 http://www.medworm.com/index.php?rid=3219845&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FYnuzvwhrmE0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000659 Author Summary Cellular function is widely believed to be organized in a modular fashion. On all scales and at all levels of complexity, relatively independent sub-units perform relatively independent sub-tasks. This functional modularity must be reflected in the topology of molecular networks. But how a functional module should be represented in an interaction network is an open question. On a small scale, one can identify a protein-complex as a module in protein-interaction networks (PIN), i.e., modules are understood as densely linked (interacting) groups of proteins, that are only sparsely interacting with the rest of the network. In this contribution, we show that extrapolating this concept of cohesively linked clusters of proteins as modules to the scale of the entire PIN inevitably... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219845 Fri, 29 Jan 2010 00:00:00 +0100 3219845 http://www.medworm.com/index.php?rid=3219844&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F7oFS6AE7KlU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000658 Author Summary It is well known that female gender is an independent risk factor for some types of cardiac arrhythmias. However, it has been difficult to determine how much of a role physiological concentrations of circulating sex steroid hormones play in gender linked arrhythmia susceptibility because the cardiac system is so extraordinarily complex. Here we employ a computational strategy, based on experimental measurements, to tease out the individual contributions of estrogen, progesterone and testosterone on cardiac electrical behavior and then make predictions about their effects in combination and in the presence of drugs. The computational models convincingly reproduce observed fluctuations of QT intervals (as recorded on the ECG (electrocardiogram), the QT interval reflects the t... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219844 Fri, 29 Jan 2010 00:00:00 +0100 3219844 http://www.medworm.com/index.php?rid=3219843&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FvWQAQayMsJ0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000657 Author Summary Cardiac cell injury and death is a key component of cardiac diseases such as heart failure or myocardial infarction, thus it is important to understand the earliest steps leading up to irreversible cell damage. Mitochondria are the organelles responsible for generating the energy required to keep the cell running, yet they are particularly vulnerable to damage by toxic byproducts of metabolism, which include reactive oxygen species (ROS). ROS wreak havoc on cellular functions by attacking proteins, lipids and DNA, so the cardiac cell has evolved sophisticated defenses to remove them. The work we present in this paper using a computer model of the mitochondrial network describes how ROS generated inside the cell can spread from one mitochondrion to the next in a positive fee... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219843 Fri, 29 Jan 2010 00:00:00 +0100 3219843 http://www.medworm.com/index.php?rid=3219842&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Fsrxs6nTyQi0%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000656 Author Summary Computer simulations can provide valuable information to communities preparing for epidemics. These simulations can be used to investigate the effectiveness of various intervention strategies in reducing or delaying the peak of an epidemic. We have made a detailed influenza epidemic simulator for the United States publicly available so that others may use the software to inform public policy or adapt it to suit their needs. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219842 Fri, 29 Jan 2010 00:00:00 +0100 3219842 http://www.medworm.com/index.php?rid=3219841&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F8yZeefxid_Q%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000654 Author Summary Cellular systems are dynamic in nature, perform various biological functions and can adapt to their environment through compositional and structural remodeling. This remodeling is initiated by the binding of external ligands to receptor proteins on the cell surface or other stimuli resulting in the activation of various signaling pathways. The activation of signaling pathways in turn results in altered gene-expression which leads to changes in the molecular composition both inside and outside the cell. Thus, a thorough study of the complex interconnectivity of signaling pathways using dynamic data is necessary to understand the biological function and environmental adaptation. Protein phosphorylation is a key event in the activation of signaling pathways. We have developed ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219841 Fri, 29 Jan 2010 00:00:00 +0100 3219841 http://www.medworm.com/index.php?rid=3219840&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FUv8aH8bz1eU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000653 Author Summary Due to the sheer number of neurons and the complexity of their interactions, the modelling of brain activity is particularly challenging. How can computationally tractable models of brain function be developed that are nevertheless biologically plausible? The “mean field” approach, borrowed from statistical physics, is to model the average activity of populations of neurons rather than the behaviour of individual neurons. While a large number of promising theories have been developed with this approach, they fall short of biological fidelity in the way interactions between distant populations have been modelled. In particular, it is often assumed that all neurons interact via connections of very similar conduction velocity, when in fact experiment suggests quite the opp... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219840 Fri, 29 Jan 2010 00:00:00 +0100 3219840 http://www.medworm.com/index.php?rid=3219839&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FnZRcccEGPuo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000652 Author Summary We develop a computational pipeline for predicting the functions of transcription factor motifs, through DNA sequence analysis. The pipeline is applied to the newly sequenced genome of the jewel wasp, Nasonia vitripennis. It exploits the wealth of molecular data available in another insect species, the fruitfly Drosophila melanogaster, and uses cross-species comparison to its advantage. Our main contribution is to show how this can be done despite the large evolutionary divergence between the two species. The methodology presented here may be applied more generally to other scenarios (genomes) where comparative regulatory genomics must deal with large evolutionary divergences. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219839 Fri, 29 Jan 2010 00:00:00 +0100 3219839 http://www.medworm.com/index.php?rid=3219838&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F78diXLuVoDA%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000651 Author Summary Cortical areas V1, V2 and V3 each contain a complete and orderly representation of the visual environment, and their detailed layout is often studied. Here we discuss and compare algebraic mapping functions providing a transformation from visual field to cortical maps. Such algebraic models allow prediction of the layout in individuals from sparse data and advance our understanding of the mapping principles guiding the cortical organization in this important brain region. We show the deficiencies in previous work and provide the first plausible account of the combined layout of the first three visual maps, deriving an optimal compromise between the desirable principles of local isotropy of the maps and the extent of cortex that they occupy. This formal mapping scheme has on... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219838 Fri, 29 Jan 2010 00:00:00 +0100 3219838 http://www.medworm.com/index.php?rid=3219837&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F4MDplzTWqjI%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000640 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219837 Fri, 29 Jan 2010 00:00:00 +0100 3219837 http://www.medworm.com/index.php?rid=3219836&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FeoycxNpC3BU%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000621 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219836 Fri, 29 Jan 2010 00:00:00 +0100 3219836 http://www.medworm.com/index.php?rid=3219835&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FksG2saClth8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000563 (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219835 Fri, 29 Jan 2010 00:00:00 +0100 3219835 http://www.medworm.com/index.php?rid=3219834&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F9BcECLfR4PQ%2Finfo%253Adoi%252F10.1371%252Fimage.pcbi.v06.i01 The checkerboard strategy. Many experiments suggest that the sustainability of an ecosystem depends on its spatial structure; when a local subpopulation goes extinct the empty habitat patch is "rescued" by immigrants from nearby patches. Trying to protect endangered species via the construction of conservation corridors, the engineer faces a Goldilocks problem: weak migration does not allow for the rescue of empty patches; strong migration leads to spatial coherence and global extinction. In this work, the authors show that maximum sustainability is achieved when the migration rate is tuned to the value that yields a checkerboard spatial pattern (see Ben Zion et al., doi:10.1371/journal.pcbi.1000643). Image Credit: Gur Yaari (Yale University) (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3219834 Fri, 29 Jan 2010 00:00:00 +0100 3219834 http://www.medworm.com/index.php?rid=3262197&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000649 Author Summary Genomic DNA is largely covered by proteins that compete with one another for binding to regulatory sequences. Most of these proteins are in the form of nucleosomes. How nucleosomes come to occupy particular sites and thereby compete with sequence specific transcription factors is a central problem in developing a systems-level understanding of gene regulation. Here, we performed a series of computational analyses using high-resolution nucleosome position data that has recently become available in yeast, thanks to advances in DNA sequencing technology. Analysis of these data, combined with data on the location and occupancy of transcription factors genome-wide, shows that the precise location of nucleosomes as determined by nucleosome sequence specificity is often less impor... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262197 Fri, 22 Jan 2010 00:00:00 +0100 3262197 http://www.medworm.com/index.php?rid=3262196&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000648 Author Summary Proteins play a critical role in human disease; bacteria, viruses, and parasites have unique proteins that can interfere with human health, and dysfunctional human proteins can likewise lead to illness. In order to find cures, scientists often try to identify small molecules (drugs) that can inhibit disease-causing proteins. The goal is to identify a molecule that can fit snugly into the pockets and grooves, or “active sites,” on the protein's surface. Unfortunately, drugs that inhibit a single disease-causing protein are problematic. A single protein can evolve to evade drug action. Additionally, when only one protein is targeted, drug potency is often diminished. Single drugs that simultaneously target multiple disease-causing proteins are much more effective. On the ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262196 Fri, 22 Jan 2010 00:00:00 +0100 3262196 http://www.medworm.com/index.php?rid=3262195&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000647 In this study a consensus model of G protein coupled receptor kinase (GRK)-mediated receptor regulation was formulated based on quantitative measures of six processes involved in β2AR regulation. This model was then used to simulate the consequences of manipulating key rates associated with the GRK-mediated β2AR regulation, leading to predictions which will provide a useful framework for further tests and elaborations of the model in basic and clinical research. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262195 Fri, 22 Jan 2010 00:00:00 +0100 3262195 http://www.medworm.com/index.php?rid=3262194&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000646 Author Summary Visual crowding refers to the phenomenon that objects become more difficult to recognize when other objects surround them. Recently there has been an explosion of studies on crowding, driven, in part, by the belief that understanding crowding will help to understand a range of visual behaviours, including object recognition, visual search, reading, and texture recognition. Given the long-standing interest in the topic and its relevance for a wide range of research fields, it is quite surprising that after nearly a century of research the mechanisms underlying crowding are still as poorly understood as they are today. A nearly complete lack of quantitative models seems to be one of the main reasons for this. Here, we present a mathematical, biologically motivated model of fe... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262194 Fri, 22 Jan 2010 00:00:00 +0100 3262194 http://www.medworm.com/index.php?rid=3262193&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000645 Author Summary In studies of protein folding evidence exists for early compaction in the unfolded state, although it is unclear whether these compact conformations contain specific secondary structures (through hydrophilic interactions) or whether compaction is a non-specific hydrophobic-driven effect. Here we combine single-molecule fluorescence spectroscopy and molecular dynamics simulation to demonstrate peptide hydrogen-bond-driven polypeptide-chain collapse involving secondary structure formation as the key process in the early stage of folding. Partial structuring in unfolded polypeptide chains is shown to lead to faster contact formation kinetics than would be expected if the unfolded state were populated by featureless random-coils. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262193 Fri, 22 Jan 2010 00:00:00 +0100 3262193 http://www.medworm.com/index.php?rid=3262192&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000644 Author Summary Antibodies are proteins that are key elements of the immune system and increasingly used as drugs. Antibodies bind tightly and specifically to antigens to block their activity or to mark them for destruction. Three-dimensional structures of the antibody-antigen complexes are useful for understanding their mechanism and for designing improved antibody drugs. Experimental determination of structures is laborious and not always possible, so we have developed tools to predict structures of antibody-antigen complexes computationally. Computer-predicted models of antibodies, or homology models, typically have errors which can frustrate algorithms for prediction of protein-protein interfaces (docking), and result in incorrect predictions. Here, we have created and tested a new doc... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262192 Fri, 22 Jan 2010 00:00:00 +0100 3262192 http://www.medworm.com/index.php?rid=3262191&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000643 Author Summary No one can produce all his needs by himself. Personal autarky poses a serious danger of collapse in cases of illness, drought, etc. Trade reduces the impact of local catastrophes, thus increasing economic stability. However, the recent series of econo-crises revealed that globalization induces coherence among markets and jeopardizes their sustainability against global failures. Economists try to identify the optimal tariff that balances between the dangers of autarky and the risk of correlated failure. The same problem appears in ecosystems with a population divided among local habitat patches. “Optimal tariff” is translated to optimal migration rate: how should one manipulate connectivity among patches in order to achieve maximum sustainability? Recolonization of habit... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262191 Fri, 22 Jan 2010 00:00:00 +0100 3262191 http://www.medworm.com/index.php?rid=3197157&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FgvvPHVXvsSk%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000649 Author Summary Genomic DNA is largely covered by proteins that compete with one another for binding to regulatory sequences. Most of these proteins are in the form of nucleosomes. How nucleosomes come to occupy particular sites and thereby compete with sequence specific transcription factors is a central problem in developing a systems-level understanding of gene regulation. Here, we performed a series of computational analyses using high-resolution nucleosome position data that has recently become available in yeast, thanks to advances in DNA sequencing technology. Analysis of these data, combined with data on the location and occupancy of transcription factors genome-wide, shows that the precise location of nucleosomes as determined by nucleosome sequence specificity is often less impor... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197157 Fri, 22 Jan 2010 00:00:00 +0100 3197157 http://www.medworm.com/index.php?rid=3197156&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FXkYGF5mFk-A%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000648 Author Summary Proteins play a critical role in human disease; bacteria, viruses, and parasites have unique proteins that can interfere with human health, and dysfunctional human proteins can likewise lead to illness. In order to find cures, scientists often try to identify small molecules (drugs) that can inhibit disease-causing proteins. The goal is to identify a molecule that can fit snugly into the pockets and grooves, or “active sites,” on the protein's surface. Unfortunately, drugs that inhibit a single disease-causing protein are problematic. A single protein can evolve to evade drug action. Additionally, when only one protein is targeted, drug potency is often diminished. Single drugs that simultaneously target multiple disease-causing proteins are much more effective. On the ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197156 Fri, 22 Jan 2010 00:00:00 +0100 3197156 http://www.medworm.com/index.php?rid=3197155&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FCE6mLLV_rV8%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000647 In this study a consensus model of G protein coupled receptor kinase (GRK)-mediated receptor regulation was formulated based on quantitative measures of six processes involved in β2AR regulation. This model was then used to simulate the consequences of manipulating key rates associated with the GRK-mediated β2AR regulation, leading to predictions which will provide a useful framework for further tests and elaborations of the model in basic and clinical research. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197155 Fri, 22 Jan 2010 00:00:00 +0100 3197155 http://www.medworm.com/index.php?rid=3197154&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FWskOFWjoJfc%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000646 Author Summary Visual crowding refers to the phenomenon that objects become more difficult to recognize when other objects surround them. Recently there has been an explosion of studies on crowding, driven, in part, by the belief that understanding crowding will help to understand a range of visual behaviours, including object recognition, visual search, reading, and texture recognition. Given the long-standing interest in the topic and its relevance for a wide range of research fields, it is quite surprising that after nearly a century of research the mechanisms underlying crowding are still as poorly understood as they are today. A nearly complete lack of quantitative models seems to be one of the main reasons for this. Here, we present a mathematical, biologically motivated model of fe... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197154 Fri, 22 Jan 2010 00:00:00 +0100 3197154 http://www.medworm.com/index.php?rid=3197153&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2F4I_wW8JzPvE%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000645 Author Summary In studies of protein folding evidence exists for early compaction in the unfolded state, although it is unclear whether these compact conformations contain specific secondary structures (through hydrophilic interactions) or whether compaction is a non-specific hydrophobic-driven effect. Here we combine single-molecule fluorescence spectroscopy and molecular dynamics simulation to demonstrate peptide hydrogen-bond-driven polypeptide-chain collapse involving secondary structure formation as the key process in the early stage of folding. Partial structuring in unfolded polypeptide chains is shown to lead to faster contact formation kinetics than would be expected if the unfolded state were populated by featureless random-coils. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197153 Fri, 22 Jan 2010 00:00:00 +0100 3197153 http://www.medworm.com/index.php?rid=3197152&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FjQhGxc_5iOw%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000644 Author Summary Antibodies are proteins that are key elements of the immune system and increasingly used as drugs. Antibodies bind tightly and specifically to antigens to block their activity or to mark them for destruction. Three-dimensional structures of the antibody-antigen complexes are useful for understanding their mechanism and for designing improved antibody drugs. Experimental determination of structures is laborious and not always possible, so we have developed tools to predict structures of antibody-antigen complexes computationally. Computer-predicted models of antibodies, or homology models, typically have errors which can frustrate algorithms for prediction of protein-protein interfaces (docking), and result in incorrect predictions. Here, we have created and tested a new doc... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197152 Fri, 22 Jan 2010 00:00:00 +0100 3197152 http://www.medworm.com/index.php?rid=3197151&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FLMmwndJIF08%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000643 Author Summary No one can produce all his needs by himself. Personal autarky poses a serious danger of collapse in cases of illness, drought, etc. Trade reduces the impact of local catastrophes, thus increasing economic stability. However, the recent series of econo-crises revealed that globalization induces coherence among markets and jeopardizes their sustainability against global failures. Economists try to identify the optimal tariff that balances between the dangers of autarky and the risk of correlated failure. The same problem appears in ecosystems with a population divided among local habitat patches. “Optimal tariff” is translated to optimal migration rate: how should one manipulate connectivity among patches in order to achieve maximum sustainability? Recolonization of habit... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3197151 Fri, 22 Jan 2010 00:00:00 +0100 3197151 http://www.medworm.com/index.php?rid=3262202&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000642 We present a Bayesian method to identify genetic interactions and more eQTLs by treating co-expressed genes as a module. Our method provides a tool to study genetic interactions in human disease models. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262202 Fri, 15 Jan 2010 00:00:00 +0100 3262202 http://www.medworm.com/index.php?rid=3262201&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000641 Author Summary Understanding the genetic background of diseases is crucial to medical research, with implications in diagnosis, treatment and drug development. As molecular approaches to this challenge are time consuming and costly, computational approaches offer an efficient alternative. Such approaches aim at prioritizing genes in a genomic interval of interest according to their predicted strength-of-association with a given disease. State-of-the-art prioritization problems are based on the observation that genes causing similar diseases tend to lie close to one another in a network of protein-protein interactions. Here we develop a novel prioritization approach that uses the network data in a global manner and can tie not only single genes but also whole protein machineries with a giv... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262201 Fri, 15 Jan 2010 00:00:00 +0100 3262201 http://www.medworm.com/index.php?rid=3262200&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000639 Author Summary Intensive research on cancer has led to an understanding of many individual genes that may be important for the initiation and progression of tumors. However, since cancer is a progressive disease that results from accumulation of multiple mutations likely acting in concert, individual markers can only provide limited insights into cellular mechanisms that underlie tumorigenesis. For this reason, recent studies focus on identification of “sub-network markers”, that is, functionally associated genes that exhibit coordinate changes in molecular expression during cancer progression. However, expression of genes is most frequently interrogated at the mRNA level, which captures functional activity of genes only to a limited extent. Screening of protein expression, on the oth... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262200 Fri, 15 Jan 2010 00:00:00 +0100 3262200 http://www.medworm.com/index.php?rid=3262199&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000638 Author Summary Exploration is a central component of human and animal behavior that has been studied in rodents for almost a century. It is presently one of the main models for studying the interface between behavior, genetics, drugs, and the brain. Until recently the exploration of an open field by rodents has been considered to be largely stochastic. Lately, this behavior is being gradually deciphered, revealing reference places called home bases, from which the animals perform roundtrips into the environment, tracing well-trodden paths whose features contribute to our understanding of navigation, locational memory, cognition-, and emotion-related behavior. Using advanced computational tools we discover so-called knots, preferred places visited sporadically by mice. Mice perform in thes... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262199 Fri, 15 Jan 2010 00:00:00 +0100 3262199 http://www.medworm.com/index.php?rid=3262198&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Fwww.ploscompbiol.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000637 Author Summary Synchronization phenomena are pervasive in biology, creating collective behavior out of local interactions between neurons, cells, or animals. On the other hand, many of these systems function in the presence of large amounts of noise or disturbances, making one wonder how meaningful behavior can arise in these highly perturbed conditions. In this paper we show mathematically, in a general context, that synchronization is actually a means to protect interconnected systems from effects of noise and disturbances. One possible mechanism for synchronization is that the systems jointly create and then share a common signal, such as a mean electrical field or a global chemical concentration, which in turn makes each system directly connected to all others. Conversely, extracting ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3262198 Fri, 15 Jan 2010 00:00:00 +0100 3262198 http://www.medworm.com/index.php?rid=3175209&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FaTa8v8wZMD4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000642 We present a Bayesian method to identify genetic interactions and more eQTLs by treating co-expressed genes as a module. Our method provides a tool to study genetic interactions in human disease models. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3175209 Fri, 15 Jan 2010 00:00:00 +0100 3175209 http://www.medworm.com/index.php?rid=3175208&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FJxqM1sXuVBo%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000641 Author Summary Understanding the genetic background of diseases is crucial to medical research, with implications in diagnosis, treatment and drug development. As molecular approaches to this challenge are time consuming and costly, computational approaches offer an efficient alternative. Such approaches aim at prioritizing genes in a genomic interval of interest according to their predicted strength-of-association with a given disease. State-of-the-art prioritization problems are based on the observation that genes causing similar diseases tend to lie close to one another in a network of protein-protein interactions. Here we develop a novel prioritization approach that uses the network data in a global manner and can tie not only single genes but also whole protein machineries with a giv... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3175208 Fri, 15 Jan 2010 00:00:00 +0100 3175208 http://www.medworm.com/index.php?rid=3175207&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FjC0n6C8xbQs%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000639 Author Summary Intensive research on cancer has led to an understanding of many individual genes that may be important for the initiation and progression of tumors. However, since cancer is a progressive disease that results from accumulation of multiple mutations likely acting in concert, individual markers can only provide limited insights into cellular mechanisms that underlie tumorigenesis. For this reason, recent studies focus on identification of “sub-network markers”, that is, functionally associated genes that exhibit coordinate changes in molecular expression during cancer progression. However, expression of genes is most frequently interrogated at the mRNA level, which captures functional activity of genes only to a limited extent. Screening of protein expression, on the oth... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3175207 Fri, 15 Jan 2010 00:00:00 +0100 3175207 http://www.medworm.com/index.php?rid=3175206&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FwnDOs1NMvH4%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000638 Author Summary Exploration is a central component of human and animal behavior that has been studied in rodents for almost a century. It is presently one of the main models for studying the interface between behavior, genetics, drugs, and the brain. Until recently the exploration of an open field by rodents has been considered to be largely stochastic. Lately, this behavior is being gradually deciphered, revealing reference places called home bases, from which the animals perform roundtrips into the environment, tracing well-trodden paths whose features contribute to our understanding of navigation, locational memory, cognition-, and emotion-related behavior. Using advanced computational tools we discover so-called knots, preferred places visited sporadically by mice. Mice perform in thes... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3175206 Fri, 15 Jan 2010 00:00:00 +0100 3175206 http://www.medworm.com/index.php?rid=3175205&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FtUeI2VhMrbY%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000637 Author Summary Synchronization phenomena are pervasive in biology, creating collective behavior out of local interactions between neurons, cells, or animals. On the other hand, many of these systems function in the presence of large amounts of noise or disturbances, making one wonder how meaningful behavior can arise in these highly perturbed conditions. In this paper we show mathematically, in a general context, that synchronization is actually a means to protect interconnected systems from effects of noise and disturbances. One possible mechanism for synchronization is that the systems jointly create and then share a common signal, such as a mean electrical field or a global chemical concentration, which in turn makes each system directly connected to all others. Conversely, extracting ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3175205 Fri, 15 Jan 2010 00:00:00 +0100 3175205 http://www.medworm.com/index.php?rid=3152824&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FssG9Fxx9tng%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000636 Author Summary Prediction of enzymatic function of experimentally uncharacterised sequences is an important task in annotation of sequence databases. While all the information on an enzyme's specificity is necessarily contained in its sequence, prediction methods using sequence alone often do not perform all that well. Obviously, structural information – if available – will yield precious hints on the function and relative importance of specific sequence positions with respect to substrate specificity. We propose a novel method (Active Site Classification, ASC) for enzyme classification bringing together structural information and sequence information. Our ASC web server allows users to build predictive models in an automated way focused on relevant enzyme residues and furthermore to ... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3152824 Fri, 08 Jan 2010 00:00:00 +0100 3152824 http://www.medworm.com/index.php?rid=3152823&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2Frawu3ThKQ8k%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000635 Author Summary Observing a complex biological system in steady state is often insufficient for a thorough understanding of its working. For such inference, perturbation experiments are necessary and are traditionally employed. In this work we focus on perturbations in which a gene is knocked out and as a result multiple genes change their expression levels. We aim to use a given set of perturbation experiments to predict the results of new experiments. Using a large cohort of gene knockout experiments in yeast, we show that the emerging map of causal relations has a very simple structure that can be utilized for the prediction task. The resulting prediction scheme, and its extension to more complex functional maps, greatly improve on extant approaches, increasing the coverage of known rel... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3152823 Fri, 08 Jan 2010 00:00:00 +0100 3152823 http://www.medworm.com/index.php?rid=3152822&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FV0mu51k_YaI%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000634 Author Summary Structure-based drug design has become a powerful tool in modern drug discovery pipelines. A critical prerequisite is a structure of the target protein close to its ligand bound conformation which is often difficult to determine experimentally. In many cases, a structure of the unbound receptor is available, but conformational changes with respect to the ligand-bound form preclude it from being used as a basis for structure-based drug design. We have developed a computational approach to predict the structure of protein/ligand complexes based solely on the unbound conformation, the ligand, and easy-to-assess experimental data. We tested our protocol on proteins that undergo substantial structural rearrangements upon binding a ligand and were able to predict structures of pr... PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3152822 Fri, 08 Jan 2010 00:00:00 +0100 3152822 http://www.medworm.com/index.php?rid=3135229&cid=s_31988_62_f&fid=31988&url=http%3A%2F%2Ffeedproxy.google.com%2F%7Er%2Fploscompbiol%2FNewArticles%2F%7E3%2FErcqlfNR5_o%2Finfo%253Adoi%252F10.1371%252Fjournal.pcbi.1000633 We present a Bayesian network model that rigorously disentangles direct from indirect dependencies and show that this greatly improves contact prediction. Additionally, we develop an informative prior that takes into account that the probability for residues to be in contact depends on their primary sequence separation, and that highly conserved residues tend to participate in a larger number of contacts. With this prior, the accuracy of the contact predictions is dramatically improved. (Source: PLoS Computational Biology) PLoS Computational Biology journals http://www.medworm.com/rss/comments.php?id=3135229 Fri, 01 Jan 2010 00:00:00 +0100 3135229