Metabolic models and gene essentiality data reveal essential and conserved metabolism in prokaryotes
by Joana C. Xavier, Kiran Raosaheb Patil, Isabel Rocha Essential metabolic reactions are shaping constituents of metabolic networks, enabling viable and distinct phenotypes across diverse life forms. Here we analyse and compare modelling predictions of essential metabolic functions with experimental data and thereby identify core metabolic pathways in prokaryotes. Simulations of 15 manually curated genome-scale metabolic models were integrated with 36 large-scale gene essentiality datasets encompassing a wide variety of species of bacteria and archaea. Conservation of metabolic genes was estimated by analysing 79 represen...
Source: PLoS Computational Biology - November 16, 2018 Category: Biology Authors: Joana C. Xavier Source Type: research

Towards a molecular basis of ubiquitin signaling: A dual-scale simulation study of ubiquitin dimers
by Andrej Berg, Oleksandra Kukharenko, Martin Scheffner, Christine Peter Covalent modification of proteins by ubiquitin or ubiquitin chains is one of the most prevalent post-translational modifications in eukaryotes. Different types of ubiquitin chains are assumed to selectively signal respectively modified proteins for different fates. In support of this hypothesis, s tructural studies have shown that the eight possible ubiquitin dimers adopt different conformations. However, at least in some cases, these structures cannot sufficiently explain the molecular basis of the selective signaling mechanisms. This indicates that...
Source: PLoS Computational Biology - November 16, 2018 Category: Biology Authors: Andrej Berg Source Type: research

Patterning the insect eye: From stochastic to deterministic mechanisms
by Haleh Ebadi, Michael Perry, Keith Short, Konstantin Klemm, Claude Desplan, Peter F. Stadler, Anita Mehta While most processes in biology are highly deterministic, stochastic mechanisms are sometimes used to increase cellular diversity. In human and Drosophila eyes, photoreceptors sensitive to different wavelengths of light are distributed in stochastic patterns, and one such patterning system has bee n analyzed in detail in the Drosophila retina. Interestingly, some species in the dipteran family Dolichopodidae (the “long legged” flies, or “Doli”) instead exhibit highly orderly deterministic eye...
Source: PLoS Computational Biology - November 15, 2018 Category: Biology Authors: Haleh Ebadi Source Type: research

Ten simple rules for delivering live distance training in bioinformatics across the globe using webinars
by Denise Carvalho-Silva, Leyla Garcia, Sarah L. Morgan, Cath Brooksbank, Ian Dunham (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - November 15, 2018 Category: Biology Authors: Denise Carvalho-Silva Source Type: research

Ten simple rules for collaboratively writing a multi-authored paper
by Marieke A. Frassl, David P. Hamilton, Blaize A. Denfeld, Elvira de Eyto, Stephanie E. Hampton, Philipp S. Keller, Sapna Sharma, Abigail S. L. Lewis, Gesa A. Weyhenmeyer, Catherine M. O ’Reilly, Mary E. Lofton, Núria Catalán (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - November 15, 2018 Category: Biology Authors: Marieke A. Frassl Source Type: research

Cytoplasmic flows in starfish oocytes are fully determined by cortical contractions
by Nils Klughammer, Johanna Bischof, Nikolas D. Schnellb ächer, Andrea Callegari, Péter Lénárt, Ulrich S. Schwarz Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, such as oocytes and eggs in early animal development. Here we show that cytoplasmic flows in starfish oocytes, which can be imaged well with transmission light microscopy, are fully determined by the c ortical dynamics during surface contraction waves. We first show that the dynamics of the oocyte surface is highly symmetric around the animal-vegetal axis. We then mathematically solve the ...
Source: PLoS Computational Biology - November 15, 2018 Category: Biology Authors: Nils Klughammer Source Type: research

Inferring interaction partners from protein sequences using mutual information
by Anne-Florence Bitbol Functional protein-protein interactions are crucial in most cellular processes. They enable multi-protein complexes to assemble and to remain stable, and they allow signal transduction in various pathways. Functional interactions between proteins result in coevolution between the interacting partn ers, and thus in correlations between their sequences. Pairwise maximum-entropy based models have enabled successful inference of pairs of amino-acid residues that are in contact in the three-dimensional structure of multi-protein complexes, starting from the correlations in the sequence data of kno wn in...
Source: PLoS Computational Biology - November 13, 2018 Category: Biology Authors: Anne-Florence Bitbol Source Type: research

Bayesian phylodynamic inference with complex models
We present a framework for coalescent-based phylogenetic and phylodyn amic inference which enables highly-flexible modeling of demographic and epidemiological processes. This approach builds upon previous structured coalescent approaches and includes enhancements for computational speed, accuracy, and stability. A flexible markup language is described for translating parametric demographic or epidemiological models into a structured coalescent model enabling simultaneous estimation of demographic or epidemiological parameters and time-scaled phylogenies. We demonstrate the utility of these approaches by fitting compartment...
Source: PLoS Computational Biology - November 13, 2018 Category: Biology Authors: Erik M. Volz Source Type: research

Comparing Bayesian and non-Bayesian accounts of human confidence reports
by William T. Adler, Wei Ji Ma Humans can meaningfully report their confidence in a perceptual or cognitive decision. It is widely believed that these reports reflect the Bayesian probability that the decision is correct, but this hypothesis has not been rigorously tested against non-Bayesian alternatives. We use two perceptual categorization tasks in which Bayesian confidence reporting requires subjects to take sensory uncertainty into account in a specific way. We find that subjects do take sensory uncertainty into account when reporting confidence, suggesting that brain areas involved in reporting confidence can access...
Source: PLoS Computational Biology - November 13, 2018 Category: Biology Authors: William T. Adler Source Type: research

Moth olfactory receptor neurons adjust their encoding efficiency to temporal statistics of pheromone fluctuations
We report that responses of antennal olfactory receptor neurons to pheromone encounters follow the temporal fluctuations in such a way that the most frequent stimulus timescales are encoded with maximum accuracy. We also observe that the average coding precision of the neurons adjusted to the stimulus-timescale statistics at a given distance from the pheromone source is higher than if the same encoding model is applied at a shorter, non-matching, distance. Finally, the coding accuracy profile and the stimulus-timescale distribution are related in the manner predicted by the information theory for the many-to-one convergenc...
Source: PLoS Computational Biology - November 13, 2018 Category: Biology Authors: Marie Levakova Source Type: research

Oscillations in working memory and neural binding: A mechanism for multiple memories and their interactions
by Jason E. Pina, Mark Bodner, Bard Ermentrout Neural oscillations have been recorded and implicated in many different basic brain and cognitive processes. For example, oscillatory neural activity has been suggested to play a role in binding and in the maintenance of information in working memory. With respect to the latter, the majority of wo rk has focused primarily on oscillations in terms of providing a “code” in working memory. However, oscillations may additionally play a fundamental role by enabling or facilitating essential properties and behaviors that neuronal networks must exhibit in order to produc...
Source: PLoS Computational Biology - November 12, 2018 Category: Biology Authors: Jason E. Pina Source Type: research

Visual physiology of the layer 4 cortical circuit < i > in silico < /i >
by Anton Arkhipov, Nathan W. Gouwens, Yazan N. Billeh, Sergey Gratiy, Ramakrishnan Iyer, Ziqiang Wei, Zihao Xu, Reza Abbasi-Asl, Jim Berg, Michael Buice, Nicholas Cain, Nuno da Costa, Saskia de Vries, Daniel Denman, Severine Durand, David Feng, Tim Jarsky, Jerome Lecoq, Brian Lee, Lu Li, Stefan Mihalas, Gabriel K. Ocker, Shawn R. Olsen, R. Clay Reid, Gilberto Soler-Llavina, Staci A. Sorensen, Quanxin Wang, Jack Waters, Massimo Scanziani, Christof Koch Despite advances in experimental techniques and accumulation of large datasets concerning the composition and properties of the cortex, quantitative modeling of cortical cir...
Source: PLoS Computational Biology - November 12, 2018 Category: Biology Authors: Anton Arkhipov Source Type: research

Invasion and effective size of graph-structured populations
by Stefano Giaimo, Jordi Arranz, Arne Traulsen Population structure can strongly affect evolutionary dynamics. The most general way to describe population structures are graphs. An important observable on evolutionary graphs is the probability that a novel mutation spreads through the entire population. But what drives this spread of a mutatio n towards fixation? Here, we propose a novel way to understand the forces driving fixation by borrowing techniques from evolutionary demography to quantify the invasion fitness and the effective population size for different graphs. Our method is very general and even applies to wei...
Source: PLoS Computational Biology - November 12, 2018 Category: Biology Authors: Stefano Giaimo Source Type: research

Functional mechanisms underlie the emergence of a diverse range of plasticity phenomena
by James A. Henderson, Pulin Gong Diverse plasticity mechanisms are orchestrated to shape the spatiotemporal dynamics underlying brain functions. However, why these plasticity rules emerge and how their dynamics interact with neural activity to give rise to complex neural circuit dynamics remains largely unknown. Here we show that both Hebbian and homeostatic plasticity rules emerge from a functional perspective of neuronal dynamics whereby each neuron learns to encode its own activity in the population activity, so that the activity of the presynaptic neuron can be decoded from the activity of its postsynaptic neurons. W...
Source: PLoS Computational Biology - November 12, 2018 Category: Biology Authors: James A. Henderson Source Type: research

A regularity index for dendrites - local statistics of a neuron's input space
by Laura Anton-Sanchez, Felix Effenberger, Concha Bielza, Pedro Larra ñaga, Hermann C.z Neurons collect their inputs from other neurons by sending out arborized dendritic structures. However, the relationship between the shape of dendrites and the precise organization of synaptic inputs in the neural tissue remains unclear. Inputs could be distributed in tight clusters, entirely rand omly or else in a regular grid-like manner. Here, we analyze dendritic branching structures using a regularity indexR, based on average nearest neighbor distances between branch and termination points, characterizing their spatial dist...
Source: PLoS Computational Biology - November 12, 2018 Category: Biology Authors: Laura Anton-Sanchez Source Type: research

Comparative structural dynamic analysis of GTPases
by Hongyang Li, Xin-Qiu Yao, Barry J. Grant GTPases regulate a multitude of essential cellular processes ranging from movement and division to differentiation and neuronal activity. These ubiquitous enzymes operate by hydrolyzing GTP to GDP with associated conformational changes that modulate affinity for family-specific binding partners. T here are three major GTPase superfamilies: Ras-like GTPases, heterotrimeric G proteins and protein-synthesizing GTPases. Although they contain similar nucleotide-binding sites, the detailed mechanisms by which these structurally and functionally diverse superfamilies operate remain unc...
Source: PLoS Computational Biology - November 9, 2018 Category: Biology Authors: Hongyang Li Source Type: research

Correction: Assessment of < i > ab initio < /i > models of protein complexes by molecular dynamics
by The PLOS Computational Biology Staff (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - November 9, 2018 Category: Biology Authors: The PLOS Computational Biology Staff Source Type: research

Systematically benchmarking peptide-MHC binding predictors: From synthetic to naturally processed epitopes
This study reports the latest benchmarking on an extensive set of MHC-binding predictors by using newly available, untested data of both synthetic and naturally processed epitopes. 32 human leukocyte antigen (HLA) class I and 24 HLA class II alleles are included in the blind test set. Artificial neural network (ANN)-based approaches demonstrated better performance than regression-based machine learning and structural modeling. Among the 18 predictors benchmarked, ANN-based mhcflurry and nn_align perform the best for MHC class I 9-mer and class II 15-mer predictions, respectively, on binding/non-binding classification (Area...
Source: PLoS Computational Biology - November 8, 2018 Category: Biology Authors: Weilong Zhao Source Type: research

A benchmark driven guide to binding site comparison: An exhaustive evaluation using tailor-made data sets (ProSPECCTs)
by Christiane Ehrt, Tobias Brinkjost, Oliver Koch The automated comparison of protein-ligand binding sites provides useful insights into yet unexplored site similarities. Various stages of computational and chemical biology research can benefit from this knowledge. The search for putative off-targets and the establishment of polypharmacological e ffects by comparing binding sites led to promising results for numerous projects. Although many cavity comparison methods are available, a comprehensive analysis to guide the choice of a tool for a specific application is wanting. Moreover, the broad variety of binding site model...
Source: PLoS Computational Biology - November 8, 2018 Category: Biology Authors: Christiane Ehrt Source Type: research

Putting benchmarks in their rightful place: The heart of computational biology
by Bjoern Peters, Steven E. Brenner, Edwin Wang, Donna Slonim, Maricel G. Kann Research in computational biology has given rise to a vast number of methods developed to solve scientific problems. For areas in which many approaches exist, researchers have a hard time deciding which tool to select to address a scientific challenge, as essentially all publications introducing a new method will claim better performance than all others. Not all of these claims can be correct. Equally, for this same reason, developers struggle to demonstrate convincingly that they created a new and superior algorithm or implementation. Moreover...
Source: PLoS Computational Biology - November 8, 2018 Category: Biology Authors: Bjoern Peters Source Type: research

The Cultural Brain Hypothesis: How culture drives brain expansion, sociality, and life history
by Michael Muthukrishna, Michael Doebeli, Maciej Chudek, Joseph Henrich In the last few million years, the hominin brain more than tripled in size. Comparisons across evolutionary lineages suggest that this expansion may be part of a broader trend toward larger, more complex brains in many taxa. Efforts to understand the evolutionary forces driving brain expansion hav e focused on climatic, ecological, and social factors. Here, building on existing research on learning, we analytically and computationally model the predictions of two closely related hypotheses: The Cultural Brain Hypothesis and the Cumulative Cultural Bra...
Source: PLoS Computational Biology - November 8, 2018 Category: Biology Authors: Michael Muthukrishna Source Type: research

Modulation of voltage-dependent K < sup > + < /sup > conductances in photoreceptors trades off investment in contrast gain for bandwidth
by Francisco J. H. Heras, Mikko V ähäsöyrinki, Jeremy E. Niven Modulation is essential for adjusting neurons to prevailing conditions and differing demands. Yet understanding how modulators adjust neuronal properties to alter information processing remains unclear, as is the impact of neuromodulation on energy consumption. Here we combine two computational mo dels, one Hodgkin-Huxley type and the other analytic, to investigate the effects of neuromodulation uponDrosophila melanogaster photoreceptors. Voltage-dependent K+ conductances: (i) activate upon depolarisation to reduce membrane resistance and adjust...
Source: PLoS Computational Biology - November 6, 2018 Category: Biology Authors: Francisco J. H. Heras Source Type: research

A computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice
by Ruben Zamora, Sebastian Korff, Qi Mi, Derek Barclay, Lukas Schimunek, Riccardo Zucca, Xerxes D. Arsiwalla, Richard L. Simmons, Paul Verschure, Timothy R. Billiar, Yoram Vodovotz Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on th e timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and...
Source: PLoS Computational Biology - November 6, 2018 Category: Biology Authors: Ruben Zamora Source Type: research

Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA
by Giovanni B. Brandani, Shoji Takada ATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucle osome sliding by means of molecular dynamics simulations of the Snf2 remodeler translocase in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the translocase overwrites the original nucleosome energy landscape via steric and electrostatic interactions to indu...
Source: PLoS Computational Biology - November 5, 2018 Category: Biology Authors: Giovanni B. Brandani Source Type: research

Synthetic protein alignments by CCMgen quantify noise in residue-residue contact prediction
by Susann Vorberg, Stefan Seemayer, Johannes S öding Compensatory mutations between protein residues in physical contact can manifest themselves as statistical couplings between the corresponding columns in a multiple sequence alignment (MSA) of the protein family. Conversely, large coupling coefficients predict residues contacts. Methods for de-nov o protein structure prediction based on this approach are becoming increasingly reliable. Their main limitation is the strong systematic and statistical noise in the estimation of coupling coefficients, which has so far limited their application to very large protein fami...
Source: PLoS Computational Biology - November 5, 2018 Category: Biology Authors: Susann Vorberg Source Type: research

Prediction and classification in equation-free collective motion dynamics
by Keisuke Fujii, Takeshi Kawasaki, Yuki Inaba, Yoshinobu Kawahara Modeling the complex collective behavior is a challenging issue in several material and life sciences. The collective motion has been usually modeled by simple interaction rules and explained by global statistics. However, it remains difficult to bridge the gap between the dynamic properties of th e complex interaction and the emerging group-level functions. Here we introduce decomposition methods to directly extract and classify the latent global dynamics of nonlinear dynamical systems in an equation-free manner, even including complex interaction in few ...
Source: PLoS Computational Biology - November 5, 2018 Category: Biology Authors: Keisuke Fujii Source Type: research

Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
We present our structural models of the inward- and outward-facing conformations of ZnT2 as a blueprint prototype of the transporter conformations, including the putative permeation pathway and participating residues. The insights gained from this study may facilitate the delineation of the pathways of other zinc transporters, laying the foundations for the molecular basis underlying ion permeation. This may possibly facilitate the development of therapeutic interven tions in pathological states associated with zinc deficiency and other disorders based on loss-of-function mutations in solute carriers. (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - November 2, 2018 Category: Biology Authors: Yarden Golan Source Type: research

Modeling driver cells in developing neuronal networks
by Stefano Luccioli, David Angulo-Garcia, Rosa Cossart, Arnaud Malvache, Laura M ódol, Vitor Hugo Sousa, Paolo Bonifazi, Alessandro Torcini Spontaneous emergence of synchronized population activity is a characteristic feature of developing brain circuits. Recent experiments in the developing neo-cortex showed the existence ofdriver cells able to impact the synchronization dynamics when single-handedly stimulated. We have developed a spiking network model capable to reproduce the experimental results, thus identifying two classes of driver cells: functional hubs and low functionally connected (LC) neurons. The funct...
Source: PLoS Computational Biology - November 2, 2018 Category: Biology Authors: Stefano Luccioli Source Type: research

Active dendrites regulate the spatiotemporal spread of signaling microdomains
by Reshma Basak, Rishikesh Narayanan Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not know n if these channels regulate the spatiotemporal spread of signaling microdomains. Here, we employed a multiscale, morphologically realistic, conductance-based model of the hippocampal pyramidal neuron that accounted for experimental details of electrical and calcium-dependent biochemical sign...
Source: PLoS Computational Biology - November 1, 2018 Category: Biology Authors: Reshma Basak Source Type: research

Motif-Aware PRALINE: Improving the alignment of motif regions
by Maurits Dijkstra, Punto Bawono, Sanne Abeln, K. Anton Feenstra, Wan Fokkink, Jaap Heringa Protein or DNA motifs are sequence regions which possess biological importance. These regions are often highly conserved among homologous sequences. The generation of multiple sequence alignments (MSAs) with a correct alignment of the conserved sequence motifs is still difficult to achieve, due to the fact that the contribution of these typically short fragments is overshadowed by the rest of the sequence. Here we extended the PRALINE multiple sequence alignment program with a novel motif-aware MSA algorithm in order to address th...
Source: PLoS Computational Biology - November 1, 2018 Category: Biology Authors: Maurits Dijkstra Source Type: research

Efficient pedigree recording for fast population genetics simulation
by Jerome Kelleher, Kevin R. Thornton, Jaime Ashander, Peter L. Ralph In this paper we describe how to efficiently record the entire genetic history of a population in forwards-time, individual-based population genetics simulations with arbitrary breeding models, population structure and demography. This approach dramatically reduces the computational burden of trac king individual genomes by allowing us to simulate only those loci that may affect reproduction (those having non-neutral variants). The genetic history of the population is recorded as a succinct tree sequence as introduced in the software package msprime, on...
Source: PLoS Computational Biology - November 1, 2018 Category: Biology Authors: Jerome Kelleher Source Type: research

Molecular characterization of breast and lung tumors by integration of multiple data types with functional sparse-factor analysis
by Tycho Bismeijer, Sander Canisius, Lodewyk F. A. Wessels Effective cancer treatment is crucially dependent on the identification of the biological processes that drive a tumor. However, multiple processes may be active simultaneously in a tumor. Clustering is inherently unsuitable to this task as it assigns a tumor to a single cluster. In addition, the wide availability of multiple data types per tumor provides the opportunity to profile the processes driving a tumor more comprehensively. Here we introduce Functional Sparse-Factor Analysis (funcSFA) to address these challenges. FuncSFA integrates multiple data types to ...
Source: PLoS Computational Biology - October 31, 2018 Category: Biology Authors: Tycho Bismeijer Source Type: research

Steered molecular dynamics simulations reveal critical residues for (un)binding of substrates, inhibitors and a product to the malarial M1 aminopeptidase
by Daniel S. Moore, Conor Brines, Heather Jewhurst, John P. Dalton, Irina G. Tikhonova Malaria is a life-threatening disease spread by mosquitoes.Plasmodium falciparum M1 alanyl aminopeptidase (PfM1-AAP) is a promising target for the treatment of malaria. The recently solved crystal structures ofPfM1-AAP revealed that the buried active site can be accessed through two channel openings: a short N-terminal channel with the length of 8 Å and a long C-terminal channel with the length of 30 Å. It is unclear, however, how substrates and inhibitors migrate to the active site and a product of cleavage leaves. Here, we...
Source: PLoS Computational Biology - October 31, 2018 Category: Biology Authors: Daniel S. Moore Source Type: research

A Pareto approach to resolve the conflict between information gain and experimental costs: Multiple-criteria design of carbon labeling experiments
by Katharina N öh, Sebastian Niedenführ, Martin Beyß, Wolfgang Wiechert Science revolves around the best way of conducting an experiment to obtain insightful results. Experiments with maximal information content can be found by computational experimental design (ED) strategies that identify optimal conditions under which to perform the experiment. Several criteria hav e been proposed to measure the information content, each emphasizing different aspects of the design goal, i.e., reduction of uncertainty. Where experiments are complex or expensive, second sight is at the budget governing the achievable amou...
Source: PLoS Computational Biology - October 31, 2018 Category: Biology Authors: Katharina N öh Source Type: research

Predicting bioprocess targets of chemical compounds through integration of chemical-genetic and genetic interactions
We present here a formal description and rigorous benchmarking of the CG-TARGET method, showing that, compared to alternative enrichment-based approaches, it achieves similar or better accuracy while substantially improving the ability to control the false discovery rate of biological process predictions. Additional investigation of the compatibility of chemical-genetic and genetic interaction profiles revealed that one-third of observed chemical-genetic interactions contributed to the highest-confidence biological process predictions and that negative chemical-genetic interactions overwhelmingly formed the basis of these ...
Source: PLoS Computational Biology - October 30, 2018 Category: Biology Authors: Scott W. Simpkins Source Type: research

Modeling and subtleties of K-Ras and Calmodulin interaction
by Eduardo Garrido, Juan L ázaro, Montserrat Jaumot, Neus Agell, Jaime Rubio-Martinez K-Ras, one of the most common small GTPases of the cell, still presents many riddles, despite the intense efforts to unveil its mysteries. Such is the case of its interaction with Calmodulin, a small acidic protein known for its role as a calcium ion sensor. Although the interaction between these two proteins and its biological implications have been widely studied, a model of their interaction has not been performed. In the present work we analyse this intriguing interaction by computational means. To do so, both conventional mol...
Source: PLoS Computational Biology - October 30, 2018 Category: Biology Authors: Eduardo Garrido Source Type: research

Suboptimal community growth mediated through metabolite crossfeeding promotes species diversity in the gut microbiota
by Michael A. Henson, Poonam Phalak The gut microbiota represent a highly complex ecosystem comprised of approximately 1000 species that forms a mutualistic relationship with the human host. A critical attribute of the microbiota is high species diversity, which provides system robustness through overlapping and redundant metabolic capabilities. The gradual loss of bacterial diversity has been associated with a broad array of gut pathologies and diseases including malnutrition, obesity, diabetes and inflammatory bowel disease. We formulated anin silico community model of the gut microbiota by combining genome-scale metabo...
Source: PLoS Computational Biology - October 30, 2018 Category: Biology Authors: Michael A. Henson Source Type: research

Computational discovery of dynamic cell line specific Boolean Networks from multiplex time-course data
by Misbah Razzaq, Lo ïc Paulevé, Anne Siegel, Julio Saez-Rodriguez, Jérémie Bourdon, Carito Guziolowski Protein signaling networks are static views of dynamic processes where proteins go through many biochemical modifications such as ubiquitination and phosphorylation to propagate signals that regulate cells and can act as feed-back systems. Understanding the precise mechanisms underlying protein in teractions can elucidate how signaling and cell cycle progression occur within cells in different diseases such as cancer. Large-scale protein signaling networks contain an important number of experim...
Source: PLoS Computational Biology - October 29, 2018 Category: Biology Authors: Misbah Razzaq Source Type: research

Structural and dynamic basis of substrate permissiveness in hydroxycinnamoyltransferase (HCT)
by Ying-Chih Chiang, Olesya Levsh, Chun Kei Lam, Jing-Ke Weng, Yi Wang Substrate permissiveness has long been regarded as the raw materials for the evolution of new enzymatic functions. In land plants, hydroxycinnamoyltransferase (HCT) is an essential enzyme of the phenylpropanoid metabolism. Although essential enzymes are normally associated with high substrate spec ificity, HCT can utilize a variety of non-native substrates. To examine the structural and dynamic basis of substrate permissiveness in this enzyme, we report the crystal structure of HCT from Selaginella moellendorffii and molecular dynamics (MD) simulations...
Source: PLoS Computational Biology - October 26, 2018 Category: Biology Authors: Ying-Chih Chiang Source Type: research

Representations of regular and irregular shapes by deep Convolutional Neural Networks, monkey inferotemporal neurons and human judgments
In conclusion, the representations of abstract shape similarity a re highly comparable between macaque IT neurons and deep convolutional layers of CNNs that were trained to classify natural images, while human shape similarity judgments correlate better with the deepest layers. (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - October 26, 2018 Category: Biology Authors: Ioannis Kalfas Source Type: research

Modeling sensory-motor decisions in natural behavior
by Ruohan Zhang, Shun Zhang, Matthew H. Tong, Yuchen Cui, Constantin A. Rothkopf, Dana H. Ballard, Mary M. Hayhoe Although a standard reinforcement learning model can capture many aspects of reward-seeking behaviors, it may not be practical for modeling human natural behaviors because of the richness of dynamic environments and limitations in cognitive resources. We propose a modular reinforcement learning mo del that addresses these factors. Based on this model, a modular inverse reinforcement learning algorithm is developed to estimate both the rewards and discount factors from human behavioral data, which allows predic...
Source: PLoS Computational Biology - October 25, 2018 Category: Biology Authors: Ruohan Zhang Source Type: research

An agent-based model for drug-radiation interactions in the tumour microenvironment: Hypoxia-activated prodrug SN30000 in multicellular tumour spheroids
by Xinjian Mao, Sarah McManaway, Jagdish K. Jaiswal, Priyanka B. Patel, William R. Wilson, Kevin O. Hicks, Gib Bogle Multicellular tumour spheroids capture many characteristics of human tumour microenvironments, including hypoxia, and represent an experimentally tractablein vitro model for studying interactions between radiotherapy and anticancer drugs. However, interpreting spheroid data is challenging because of limited ability to observe cell fate within spheroids dynamically. To overcome this limitation, we have developed a hybrid continuum/agent-based model (ABM) for HCT116 tumour spheroids, parameterised using exper...
Source: PLoS Computational Biology - October 24, 2018 Category: Biology Authors: Xinjian Mao Source Type: research

Quantum chemistry reveals thermodynamic principles of redox biochemistry
by Adrian Jinich, Avi Flamholz, Haniu Ren, Sung-Jin Kim, Benjamin Sanchez-Lengeling, Charles A. R. Cotton, Elad Noor, Al án Aspuru-Guzik, Arren Bar-Even Thermodynamics dictates the structure and function of metabolism. Redox reactions drive cellular energy and material flow. Hence, accurately quantifying the thermodynamics of redox reactions should reveal design principles that shape cellular metabolism. However, only few redox potentials have bee n measured, and mostly with inconsistent experimental setups. Here, we develop a quantum chemistry approach to calculate redox potentials of biochemical reactions and dem...
Source: PLoS Computational Biology - October 24, 2018 Category: Biology Authors: Adrian Jinich Source Type: research

Dilution and titration of cell-cycle regulators may control cell size in budding yeast
by Frank S. Heldt, Reece Lunstone, John J. Tyson, B éla Novák The size of a cell sets the scale for all biochemical processes within it, thereby affecting cellular fitness and survival. Hence, cell size needs to be kept within certain limits and relatively constant over multiple generations. However, how cells measure their size and use this information to r egulate growth and division remains controversial. Here, we present two mechanistic mathematical models of the budding yeast (S.cerevisiae) cell cycle to investigate competing hypotheses on size control: inhibitor dilution and titration of nuclear sites....
Source: PLoS Computational Biology - October 24, 2018 Category: Biology Authors: Frank S. Heldt Source Type: research

A < i > k < /i > -mer-based method for the identification of phenotype-associated genomic biomarkers and predicting phenotypes of sequenced bacteria
by Erki Aun, Age Brauer, Veljo Kisand, Tanel Tenson, Maido Remm We have developed an easy-to-use and memory-efficient method called PhenotypeSeeker that (a) identifies phenotype-specific k-mers, (b) generates ak-mer-based statistical model for predicting a given phenotype and (c) predicts the phenotype from the sequencing data of a given bacterial isolate. The method was validated on 167Klebsiella pneumoniae isolates (virulence), 200Pseudomonas aeruginosa isolates (ciprofloxacin resistance) and 459Clostridium difficile isolates (azithromycin resistance). The phenotype prediction models trained from these datasets obtained...
Source: PLoS Computational Biology - October 22, 2018 Category: Biology Authors: Erki Aun Source Type: research

Predicting how and when hidden neurons skew measured synaptic interactions
by Braden A. W. Brinkman, Fred Rieke, Eric Shea-Brown, Michael A. Buice A major obstacle to understanding neural coding and computation is the fact that experimental recordings typically sample only a small fraction of the neurons in a circuit. Measured neural properties are skewed by interactions between recorded neurons and the “hidden” portion of the network. T o properly interpret neural data and determine how biological structure gives rise to neural circuit function, we thus need a better understanding of the relationships between measured effective neural properties and the true underlying physiological...
Source: PLoS Computational Biology - October 22, 2018 Category: Biology Authors: Braden A. W. Brinkman Source Type: research

Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents
by Sandra Giuliani, Arthur C. Silva, Joyce V. V. B. Borba, Pablo I. P. Ramos, Ross A. Paveley, Eugene N. Muratov, Carolina Horta Andrade, Nicholas Furnham The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where t he commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infe...
Source: PLoS Computational Biology - October 22, 2018 Category: Biology Authors: Sandra Giuliani Source Type: research

A multi-scale layer-resolved spiking network model of resting-state dynamics in macaque visual cortical areas
by Maximilian Schmidt, Rembrandt Bakker, Kelly Shen, Gleb Bezgin, Markus Diesmann, Sacha Jennifer van Albada Cortical activity has distinct features across scales, from the spiking statistics of individual cells to global resting-state networks. We here describe the first full-density multi-area spiking network model of cortex, using macaque visual cortex as a test system. The model represents each area by a microcircuit with area-specific architecture and features layer- and population-resolved connectivity between areas. Simulations reveal a structured asynchronous irregular ground state. In a metastable regime, the net...
Source: PLoS Computational Biology - October 18, 2018 Category: Biology Authors: Maximilian Schmidt Source Type: research

Virus and CTL dynamics in the extrafollicular and follicular tissue compartments in SIV-infected macaques
by Dominik Wodarz, Pamela J. Skinner, David N. Levy, Elizabeth Connick Data from SIV-infected macaques indicate that virus-specific cytotoxic T lymphocytes (CTL) are mostly present in the extrafollicular (EF) compartment of the lymphoid tissue, with reduced homing to the follicular (F) site. This contributes to the majority of the virus being present in the follicle and represents a barrier to virus control. Using mathematical models, we investigate these dynamics. Two models are analyzed. The first assumes that CTL can only become stimulated and expand in the extrafollicular compartment, with migration accounting for the...
Source: PLoS Computational Biology - October 18, 2018 Category: Biology Authors: Dominik Wodarz Source Type: research

Modeling large fluctuations of thousands of clones during hematopoiesis: The role of stem cell self-renewal and bursty progenitor dynamics in rhesus macaque
by Song Xu, Sanggu Kim, Irvin S. Y. Chen, Tom Chou In a recent clone-tracking experiment, millions of uniquely tagged hematopoietic stem cells (HSCs) were autologously transplanted into rhesus macaques and peripheral blood containing thousands of tags were sampled and sequenced over 14 years to quantify the abundance of hundreds to thousands of ta gs or “clones.” Two major puzzles of the data have been observed: consistent differences and massive temporal fluctuations of clone populations. The large sample-to-sample variability can lead clones to occasionally go “extinct” but “resurrect&rdquo...
Source: PLoS Computational Biology - October 18, 2018 Category: Biology Authors: Song Xu Source Type: research