A biophysically detailed computational model of bladder small DRG neuron soma
by Darshan Mandge, Rohit Manchanda Bladder small DRG neurons, which are putative nociceptors pivotal to urinary bladder function, express more than a dozen different ionic membrane mechanisms: ion channels, pumps and exchangers. Small-conductance Ca2+-activated K+ (SKCa) channels which were earlier thought to be gated solely by intracellular Ca2+ concentration ([Ca]i) have recently been shown to exhibit inward rectification with respect to membrane potential. The effect of SKCa inward rectification on the excitability of these neurons is unknown. Furthermore, studies on the role of KCa channels in repetitive firing and th...
Source: PLoS Computational Biology - July 18, 2018 Category: Biology Authors: Darshan Mandge Source Type: research

Stochastic resonance enhances the rate of evidence accumulation during combined brain stimulation and perceptual decision-making
by Onno van der Groen, Matthew F. Tang, Nicole Wenderoth, Jason B. Mattingley Perceptual decision-making relies on the gradual accumulation of noisy sensory evidence. It is often assumed that such decisions are degraded by adding noise to a stimulus, or to the neural systems involved in the decision making process itself. But it has been suggested that adding an optimal amo unt of noise can, under appropriate conditions, enhance the quality of subthreshold signals in nonlinear systems, a phenomenon known asstochastic resonance. Here we asked whether perceptual decisions made by human observers obey these stochastic resona...
Source: PLoS Computational Biology - July 18, 2018 Category: Biology Authors: Onno van der Groen Source Type: research

A quantitative physical model of the TMS-induced discharge artifacts in EEG
by Dominik Freche, Jodie Naim-Feil, Avi Peled, Nava Levit-Binnun, Elisha Moses The combination of Transcranial Magnetic Stimulation (TMS) with Electroencephalography (EEG) exposes the brain’s global response to localized and abrupt stimulations. However, large electric artifacts are induced in the EEG by the TMS, obscuring crucial stages of the brain’s response. Artifact removal is commonly performed by data processing techniques. However, an experimentally verified physical model for the origin and structure of the TMS-induced discharge artifacts, by which these methods can be justified or evaluated, is still...
Source: PLoS Computational Biology - July 17, 2018 Category: Biology Authors: Dominik Freche Source Type: research

Microheterogeneity-induced conduction slowing and wavefront collisions govern macroscopic conduction behavior: A computational and experimental study
In this study, we investigated how acellular microheterogeneiti es affect macroscopic conduction under conditions of normal and reduced excitability by utilizing a novel platform of pairedin vitro andin silico studies to examine the mechanisms of conduction. Regular patterns of nonconductive micro-obstacles were created in confluent monolayers of the previously described engineered-excitable Ex293 cell line. Increasing the relative ratio of obstacle size to intra-obstacle strand width resulted in significant conduction slowing up to 23.6% and a significant increase in wavefront curvature anisotropy, a measure of spatial va...
Source: PLoS Computational Biology - July 16, 2018 Category: Biology Authors: Tanmay A. Gokhale Source Type: research

Interaction of the human erythrocyte Band 3 anion exchanger 1 (AE1, SLC4A1) with lipids and glycophorin A: Molecular organization of the Wright (Wr) blood group antigen
In this study, we have used molecular dynamics simulations to provide the first realistic model of the dimeric membrane domain of human Band 3 in an asymmetric lipid bilayer containing a full complement of phospholipids, including phosphatidylinositol 4,5–bisphosphate (PIP2) and cholesterol, and its partner membrane protein Glycophorin A (GPA). The simulations show that the annular layer in the inner leaflet surrounding Band 3 was enriched in phosphatidylserine and PIP2 molecules. Cholesterol was also enriched around Band 3 but also at the dimer interface. The interaction of these lipids with specific sites on Band 3...
Source: PLoS Computational Biology - July 16, 2018 Category: Biology Authors: Antreas C. Kalli Source Type: research

Cancerin: A computational pipeline to infer cancer-associated ceRNA interaction networks
by Duc Do, Serdar Bozdag MicroRNAs (miRNAs) inhibit expression of target genes by binding to their RNA transcripts. It has been recently shown that RNA transcripts targeted by the same miRNA could “compete” for the miRNA molecules and thereby indirectly regulate each other. Experimental evidence has suggested that the aberration of such miRNA-mediated interaction between RNAs—called competing endogenous RNA (ceRNA) interaction—can play important roles in tumorigenesis. Given the difficulty of deciphering context-specific miRNA binding, and the existence of various gene regulatory factors such as DN...
Source: PLoS Computational Biology - July 16, 2018 Category: Biology Authors: Duc Do Source Type: research

miRAW: A deep learning-based approach to predict microRNA targets by analyzing whole microRNA transcripts
We present a novel approach for miRNA target prediction based on Deep Learning (DL) which, rather than in corporating any knowledge (such as seed regions), investigates the entire miRNA and 3’TR mRNA nucleotides to learn a uninhibited set of feature descriptors related to the targeting process. We collected more than 150,000 experimentally validated homo sapiens miRNA:gene targets and cross referenced them with different CLIP-Seq, CLASH and iPAR-CLIP datasets to obtain ∼20,000 validated miRNA:gene exact target sites. Using this data, we implemented and trained a deep neural network—composed of autoencoders ...
Source: PLoS Computational Biology - July 13, 2018 Category: Biology Authors: Albert Pla Source Type: research

Modelling how responsiveness to interferon improves interferon-free treatment of hepatitis C virus infection
by Vishnu Venugopal, Pranesh Padmanabhan, Rubesh Raja, Narendra M. Dixit Direct-acting antiviral agents (DAAs) for hepatitis C treatment tend to fare better in individuals who are also likely to respond well to interferon-alpha (IFN), a surprising correlation given that DAAs target specific viral proteins whereas IFN triggers a generic antiviral immune response. Here, we posit a causal relationship between IFN-responsiveness and DAA treatment outcome. IFN-responsiveness restricts viral replication, which would prevent the growth of viral variants resistant to DAAs and improve treatment outcome. To test this hypothesis, we...
Source: PLoS Computational Biology - July 12, 2018 Category: Biology Authors: Vishnu Venugopal Source Type: research

Phase-lags in large scale brain synchronization: Methodological considerations and in-silico analysis
by Spase Petkoski, J. Matias Palva, Viktor K. Jirsa Architecture of phase relationships among neural oscillations is central for their functional significance but has remained theoretically poorly understood. We use phenomenological model of delay-coupled oscillators with increasing degree of topological complexity to identify underlying principles by which the spatio-temporal structure of the brain governs the phase lags between oscillatory activity at distant regions. Phase relations and their regions of stability are derived and numerically confirmed for two oscillators and for networks with randomly distributed or clu...
Source: PLoS Computational Biology - July 10, 2018 Category: Biology Authors: Spase Petkoski Source Type: research

Information-theoretic analysis of realistic odor plumes: What cues are useful for determining location?
by Sebastian D. Boie, Erin G. Connor, Margaret McHugh, Katherine I. Nagel, G. Bard Ermentrout, John P. Crimaldi, Jonathan D. Victor Many species rely on olfaction to navigate towards food sources or mates. Olfactory navigation is a challenging task since odor environments are typically turbulent. While time-averaged odor concentration varies smoothly with the distance to the source, instaneous concentrations are intermittent a nd obtaining stable averages takes longer than the typical intervals between animals’ navigation decisions. How to effectively sample from the odor distribution to determine sampling location ...
Source: PLoS Computational Biology - July 10, 2018 Category: Biology Authors: Sebastian D. Boie Source Type: research

Correction: A mechanistic pan-cancer pathway model informed by multi-omics data interprets stochastic cell fate responses to drugs and mitogens
by The PLOS Computational Biology Staff (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - July 9, 2018 Category: Biology Authors: The PLOS Computational Biology Staff Source Type: research

Gain control with A-type potassium current: < i > IA < /i > as a switch between divisive and subtractive inhibition
In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, ifIA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, ifIA is weak or insufficient...
Source: PLoS Computational Biology - July 9, 2018 Category: Biology Authors: Joshua H. Goldwyn Source Type: research

The importance of mechanical constraints for proper polarization and psuedo-cleavage furrow generation in the early < i > Caenorhabditis elegans < /i > embryo
by Bet ül Senay Aras, Y. C. Zhou, Adriana Dawes, Ching-Shan Chou Intracellular polarization, where a cell specifies a spatial axis by segregation of specific factors, is a fundamental biological process. In the early embryo of the nematode wormCaenorhabditis elegans (C. elegans), polarization is often accompanied by deformations of the cortex, a highly contractile structure consisting of actin filaments cross-linked by the motor protein myosin (actomyosin). It has been suggested that the eggshell surrounding the early embryo plays a role in polarization although its function is not understood. Here we develop a mathe...
Source: PLoS Computational Biology - July 9, 2018 Category: Biology Authors: Bet ül Senay Aras Source Type: research

Differential roles of sleep spindles and sleep slow oscillations in memory consolidation
In this study, using a realistic computational model of the thalamocortical network, we tested the role of Non-Rapid Eye Move ment (NREM) sleep in memory consolidation. We found that sleep spindles (the hallmark of N2 stage sleep) and slow oscillations (the hallmark of N3 stage sleep) both promote replay of the spike sequences learned in the awake state and replay was localized around the trained network locations. Memory performance improved after a period of NREM sleep but not after the same time period in awake. When multiple memories were trained, the local nature of the spike sequence replay during spindles allowed re...
Source: PLoS Computational Biology - July 9, 2018 Category: Biology Authors: Yina Wei Source Type: research

Excitable neuronal assemblies with adaptation as a building block of brain circuits for velocity-controlled signal propagation
by Hesam Setareh, Moritz Deger, Wulfram Gerstner The time scale of neuronal network dynamics is determined by synaptic interactions and neuronal signal integration, both of which occur on the time scale of milliseconds. Yet many behaviors like the generation of movements or vocalizations of sounds occur on the much slower time scale of seconds. Here we ask the question of how neuronal networks of the brain can support reliable behavior on this time scale. We argue that excitable neuronal assemblies with spike-frequency adaptation may serve as building blocks that can flexibly adjust the speed of execution of neural circui...
Source: PLoS Computational Biology - July 6, 2018 Category: Biology Authors: Hesam Setareh Source Type: research

Subgraphs of functional brain networks identify dynamical constraints of cognitive control
In this study, we use a quantitative appro ach to identify distinct topological motifs of functional interactions and examine how their expression relates to cognitive control processes and behavior. In particular, we acquire fMRI BOLD signal in twenty-eight healthy subjects as they perform two cognitive control tasks—a Stroop interference task and a local-global perception switching task using Navon figures—each with low and high cognitive control demand conditions. Based on these data, we construct dynamic functional brain networks and use a parts-based, network decomposition technique called non-negative mat...
Source: PLoS Computational Biology - July 6, 2018 Category: Biology Authors: Ankit N. Khambhati Source Type: research

A local uPAR-plasmin-TGF < i > β < /i > 1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the < i > in vitro < /i > effect of fibrinogen variants
by Sonja E. M. Boas, Joao Carvalho, Marloes van den Broek, Ester M. Weijers, Marie-Jos é Goumans, Pieter Koolwijk, Roeland M. H. Merks In experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting. More sprouts form on high molecular weight (HMW) than on low molecular weight (LMW) fibrin. It is unclea r what mechanisms regulate the number and the positions of the vascular-like structures in cell cultures. To address this question, we propose a mechanistic simulation model of endothelial...
Source: PLoS Computational Biology - July 6, 2018 Category: Biology Authors: Sonja E. M. Boas Source Type: research

Unsupervised clustering of temporal patterns in high-dimensional neuronal ensembles using a novel dissimilarity measure
by Lukas Grossberger, Francesco P. Battaglia, Martin Vinck Temporally ordered multi-neuron patterns likely encode information in the brain. We introduce an unsupervised method, SPOTDisClust (Spike Pattern Optimal Transport Dissimilarity Clustering), for their detection from high-dimensional neural ensembles. SPOTDisClust measures similarity between two en semble spike patterns by determining the minimum transport cost of transforming their corresponding normalized cross-correlation matrices into each other (SPOTDis). Then, it performs density-based clustering based on the resulting inter-pattern dissimilarity matrix. SPOT...
Source: PLoS Computational Biology - July 6, 2018 Category: Biology Authors: Lukas Grossberger Source Type: research

Age-dependent Pavlovian biases influence motor decision-making
by Xiuli Chen, Robb B. Rutledge, Harriet R. Brown, Raymond J. Dolan, Sven Bestmann, Joseph M. Galea Motor decision-making is an essential component of everyday life which requires weighing potential rewards and punishments against the probability of successfully executing an action. To achieve this, humans rely on two key mechanisms; a flexible, instrumental, value-dependent process and a hardwi red, Pavlovian, value-independent process. In economic decision-making, age-related decline in risk taking is explained by reduced Pavlovian biases that promote action toward reward. Although healthy ageing has also been associate...
Source: PLoS Computational Biology - July 6, 2018 Category: Biology Authors: Xiuli Chen Source Type: research

COBRAme: A computational framework for genome-scale models of metabolism and gene expression
by Colton J. Lloyd, Ali Ebrahim, Laurence Yang, Zachary A. King, Edward Catoiu, Edward J. O ’Brien, Joanne K. Liu, Bernhard O. Palsson Genome-scale models of metabolism and macromolecular expression (ME-models) explicitly compute the optimal proteome composition of a growing cell. ME-models expand upon the well-established genome-scale models of metabolism (M-models), and they enable a new fundamental understanding of cellular gr owth. ME-models have increased predictive capabilities and accuracy due to their inclusion of the biosynthetic costs for the machinery of life, but they come with a significant increase in ...
Source: PLoS Computational Biology - July 5, 2018 Category: Biology Authors: Colton J. Lloyd Source Type: research

Paxillin phosphorylation at serine 273 and its effects on Rac, Rho and adhesion dynamics
by Kaixi Tang, Colton G. Boudreau, Claire M. Brown, Anmar Khadra Focal adhesions are protein complexes that anchor cells to the extracellular matrix. During migration, the growth and disassembly of these structures are spatiotemporally regulated, with new adhesions forming at the leading edge of the cell and mature adhesions disassembling at the rear. Signallin g proteins and structural cytoskeletal components tightly regulate adhesion dynamics. Paxillin, an adaptor protein within adhesions, is one of these proteins. Its phosphorylation at serine 273 (S273) is crucial for maintaining fast adhesion assembly and disassembly...
Source: PLoS Computational Biology - July 5, 2018 Category: Biology Authors: Kaixi Tang Source Type: research

Post-Turing tissue pattern formation: Advent of mechanochemistry
In this study, we thus focus on the interplay between chemical and mechanical processes during tissue development. On one hand, based on recent exper imental data, we develop new mechanochemical simulation models of evolving tissues, in which the full 3D representation of the tissue appears to be critical for obtaining a realistic mechanochemical behaviour. The presented modelling approach is flexible and numerically studied using state of the ar t finite element methods. Thus, it may serve as a basis to combine simulations with new experimental methods in tissue development. On the other hand, we apply the developed appro...
Source: PLoS Computational Biology - July 3, 2018 Category: Biology Authors: Felix Brinkmann Source Type: research

A dual regulation mechanism of histidine kinase CheA identified by combining network-dynamics modeling and system-level input-output data
by Bernardo A. Mello, Wenlin Pan, Gerald L. Hazelbauer, Yuhai Tu It is challenging to decipher molecular mechanisms in biological systems from system-level input-output data, especially for complex processes that involve interactions among multiple components. We addressed this general problem for the bacterial histidine kinase CheA, the activity of which is re gulated in chemotaxis signaling complexes by bacterial chemoreceptors. We developed a general network model to describe the dynamics of the system, treating the receptor complex with coupling protein CheW and the P3P4P5 domains of kinase CheA as a regulated enzyme ...
Source: PLoS Computational Biology - July 2, 2018 Category: Biology Authors: Bernardo A. Mello Source Type: research

Computation predicts rapidly adapting mechanotransduction currents cannot account for tactile encoding in Merkel cell-neurite complexes
by Gregory J. Gerling, Lingtian Wan, Benjamin U. Hoffman, Yuxiang Wang, Ellen A. Lumpkin Distinct firing properties among touch receptors are influenced by multiple, interworking anatomical structures. Our understanding of the functions and crosstalk of Merkel cells and their associated neurites—the end organs of slowly adapting type I (SAI) afferents—remains incomplete. Piezo2 me chanically activated channels are required both in Merkel cells and in sensory neurons for canonical SAI responses in rodents; however, a central unanswered question is how rapidly inactivating currents give rise to sustained action ...
Source: PLoS Computational Biology - June 29, 2018 Category: Biology Authors: Gregory J. Gerling Source Type: research

Two critical positions in zinc finger domains are heavily mutated in three human cancer types
by Daniel Munro, Dario Ghersi, Mona Singh A major goal of cancer genomics is to identify somatic mutations that play a role in tumor initiation or progression. Somatic mutations within transcription factors are of particular interest, as gene expression dysregulation is widespread in cancers. The substantial gene expression variation evid ent across tumors suggests that numerous regulatory factors are likely to be involved and that somatic mutations within them may not occur at high frequencies across patient cohorts, thereby complicating efforts to uncover which ones are cancer-relevant. Here we analyze somatic mutations...
Source: PLoS Computational Biology - June 28, 2018 Category: Biology Authors: Daniel Munro Source Type: research

Thalamocortical and intracortical laminar connectivity determines sleep spindle properties
by Giri P. Krishnan, Burke Q. Rosen, Jen-Yung Chen, Lyle Muller, Terrence J. Sejnowski, Sydney S. Cash, Eric Halgren, Maxim Bazhenov Sleep spindles are brief oscillatory events during non-rapid eye movement (NREM) sleep. Spindle density and synchronization properties are different in MEG versus EEG recordings in humans and also vary with learning performance, suggesting spindle involvement in memory consolidation. Here, using c omputational models, we identified network mechanisms that may explain differences in spindle properties across cortical structures. First, we report that differences in spindle occurrence between ...
Source: PLoS Computational Biology - June 27, 2018 Category: Biology Authors: Giri P. Krishnan Source Type: research

Age density patterns in patients medical conditions: A clustering approach
by Fahad Alhasoun, Faisal Aleissa, May Alhazzani, Luis G. Moyano, Claudio Pinhanez, Marta C. Gonz ález This paper presents a data analysis framework to uncover relationships between health conditions, age and sex for a large population of patients. We study a massive heterogeneous sample of 1.7 million patients in Brazil, containing 47 million of health records with detailed medical conditions for visits to medical facilities for a period of 17 months. The findings suggest that medical conditions can be grouped into clusters that share very distinctive densities in the ages of the patients. For each cluster, we fur...
Source: PLoS Computational Biology - June 26, 2018 Category: Biology Authors: Fahad Alhasoun Source Type: research

Correction: A Mixture of Delta-Rules Approximation to Bayesian Inference in Change-Point Problems
by Robert C. Wilson, Matthew R. Nassar, Gaia Tavoni, Joshua I. Gold (Source: PLoS Computational Biology)
Source: PLoS Computational Biology - June 26, 2018 Category: Biology Authors: Robert C. Wilson Source Type: research

The impact of temporal sampling resolution on parameter inference for biological transport models
by Jonathan U. Harrison, Ruth E. Baker Imaging data has become an essential tool to explore key biological questions at various scales, for example the motile behaviour of bacteria or the transport of mRNA, and it has the potential to transform our understanding of important transport mechanisms. Often these imaging studies require us to compare biological species or mutants, and to do this we need to quantitatively characterise their behaviour. Mathematical models offer a quantitative description of a system that enables us to perform this comparison, but to relate mechanistic mathematical models to imaging data, we need...
Source: PLoS Computational Biology - June 25, 2018 Category: Biology Authors: Jonathan U. Harrison Source Type: research

Exploring the single-cell RNA-seq analysis landscape with the scRNA-tools database
by Luke Zappia, Belinda Phipson, Alicia Oshlack As single-cell RNA-sequencing (scRNA-seq) datasets have become more widespread the number of tools designed to analyse these data has dramatically increased. Navigating the vast sea of tools now available is becoming increasingly challenging for researchers. In order to better facilitate selection of appropriate analysis tools we have created the scRNA-tools database (www.scRNA-tools.org) to catalogue and curate analysis tools as they become available. Our database collects a range of information on each scRNA-seq analysis tool and categorises them according to the analysis ...
Source: PLoS Computational Biology - June 25, 2018 Category: Biology Authors: Luke Zappia Source Type: research

Removing contaminants from databases of draft genomes
by Jennifer Lu, Steven L. Salzberg Metagenomic sequencing of patient samples is a very promising method for the diagnosis of human infections. Sequencing has the ability to capture all the DNA or RNA from pathogenic organisms in a human sample. However, complete and accurate characterization of the sequence, including identificatio n of any pathogens, depends on the availability and quality of genomes for comparison. Thousands of genomes are now available, and as these numbers grow, the power of metagenomic sequencing for diagnosis should increase. However, recent studies have exposed the presence of contamination in publ...
Source: PLoS Computational Biology - June 25, 2018 Category: Biology Authors: Jennifer Lu Source Type: research

Lipidated apolipoprotein E4 structure and its receptor binding mechanism determined by a combined cross-linking coupled to mass spectrometry and molecular dynamics approach
by Nicolas Henry, Eva-Maria Krammer, Florian Stengel, Quentin Adams, Fran çois Van Liefferinge, Ellen Hubin, Rui Chaves, Rouslan Efremov, Ruedi Aebersold, Guy Vandenbussche, Martine Prévost, Vincent Raussens, Stéphanie Deroo Apolipoprotein E (apoE) is a forefront actor in the transport of lipids and the maintenance of cholesterol homeostasis, and is also strongly implicated in Alzheimer’s disease. Upon lipid-binding apoE adopts a conformational state that mediates the receptor-induced internalization of lipoproteins . Due to its inherent structural dynamics and the presence of lipids, the struct...
Source: PLoS Computational Biology - June 22, 2018 Category: Biology Authors: Nicolas Henry Source Type: research

Transmission of temporally correlated spike trains through synapses with short-term depression
by Alex D. Bird, Magnus J. E. Richardson Short-term synaptic depression, caused by depletion of releasable neurotransmitter, modulates the strength of neuronal connections in a history-dependent manner. Quantifying the statistics of synaptic transmission requires stochastic models that link probabilistic neurotransmitter release with pre synaptic spike-train statistics. Common approaches are to model the presynaptic spike train as either regular or a memory-less Poisson process: few analytical results are available that describe depressing synapses when the afferent spike train has more complex, temporally correlated stat...
Source: PLoS Computational Biology - June 22, 2018 Category: Biology Authors: Alex D. Bird Source Type: research

Solving the RNA design problem with reinforcement learning
by Peter Eastman, Jade Shi, Bharath Ramsundar, Vijay S. Pande We use reinforcement learning to train an agent for computational RNA design: given a target secondary structure, design a sequence that folds to that structurein silico. Our agent uses a novel graph convolutional architecture allowing a single model to be applied to arbitrary target structures of any length. After training it on randomly generated targets, we test it on the Eterna100 benchmark and find it outperforms all previous algorithms. Analysis of its solutions shows it has successfully learned some advanced strategies identified by players of the game E...
Source: PLoS Computational Biology - June 21, 2018 Category: Biology Authors: Peter Eastman Source Type: research

Community interactions and spatial structure shape selection on antibiotic resistant lineages
by Sylvie Estrela, Sam P. Brown Polymicrobial interactions play an important role in shaping the outcome of antibiotic treatment, yet how multispecies communities respond to antibiotic assault is still little understood. Here we use an individual-based simulation model of microbial biofilms to investigate how competitive and mut ualistic interactions between an antibiotic-resistant and a susceptible strain (or species) influence the two-lineage community response to antibiotic exposure. Our model predicts that while increasing competition and antibiotics leads to increasing competitive release of the antibiotic-resistant ...
Source: PLoS Computational Biology - June 21, 2018 Category: Biology Authors: Sylvie Estrela Source Type: research

Control of neurite growth and guidance by an inhibitory cell-body signal
by Brendan A. Bicknell, Zac Pujic, Peter Dayan, Geoffrey J. Goodhill The development of a functional nervous system requires tight control of neurite growth and guidance by extracellular chemical cues. Neurite growth is astonishingly sensitive to shallow concentration gradients, but a widely observed feature of both growth and guidance regulation, with important co nsequences for development and regeneration, is that both are only elicited over the same relatively narrow range of concentrations. Here we show that all these phenomena can be explained within one theoretical framework. We first test long-standing explanation...
Source: PLoS Computational Biology - June 21, 2018 Category: Biology Authors: Brendan A. Bicknell Source Type: research

Systems modelling of the EGFR-PYK2-c-Met interaction network predicts and prioritizes synergistic drug combinations for triple-negative breast cancer
by Sung-Young Shin, Anna-Katharina M üller, Nandini Verma, Sima Lev, Lan K. Nguyen Prediction of drug combinations that effectively target cancer cells is a critical challenge for cancer therapy, in particular for triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype with no effective targeted treatment. As signalling pathway networks critically control cancer cell behaviour, analysis of signalling network activity and crosstalk can help predict potent drug combinations and rational stratification of patients, thus bringing therapeutic and prognostic values. We have previously showed that th...
Source: PLoS Computational Biology - June 19, 2018 Category: Biology Authors: Sung-Young Shin Source Type: research

Evolutionary dynamics of paroxysmal nocturnal hemoglobinuria
by Nathaniel Mon P ère, Tom Lenaerts, Jorge M. Pacheco, David Dingli Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A ge ne within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A muta...
Source: PLoS Computational Biology - June 18, 2018 Category: Biology Authors: Nathaniel Mon P ère Source Type: research

Modeling the functions of condensin in chromosome shaping and segregation
by Yuji Sakai, Atsushi Mochizuki, Kazuhisa Kinoshita, Tatsuya Hirano, Masashi Tachikawa The mechanistic details underlying the assembly of rod-shaped chromosomes during mitosis and how they segregate from each other to act as individually mobile units remain largely unknown. Here, we construct a coarse-grained physical model of chromosomal DNA and condensins, a class of large protein complexes that plays key roles in these processes. We assume that condensins have two molecular activities: consecutive loop formation in DNA and inter-condensin attractions. Our simulation demonstrates that both of these activities and their...
Source: PLoS Computational Biology - June 18, 2018 Category: Biology Authors: Yuji Sakai Source Type: research

Stochastic shielding and edge importance for Markov chains with timescale separation
by Deena R. Schmidt, Roberto F. Gal án, Peter J. Thomas Nerve cells produce electrical impulses (“spikes”) through the coordinated opening and closing of ion channels. Markov processes with voltage-dependent transition rates capture the stochasticity of spike generation at the cost of complex, time-consuming simulations. Schmandt and Galán introdu ced a novel method, based on the stochastic shielding approximation, as a fast, accurate method for generating approximate sample paths with excellent first and second moment agreement to exact stochastic simulations. We previously analyzed the mathemat...
Source: PLoS Computational Biology - June 18, 2018 Category: Biology Authors: Deena R. Schmidt Source Type: research

Evolution of chemokine receptors is driven by mutations in the sodium binding site
This study indicates that the three mutations crucial for the evolution of the chemokine receptors dramatically altered the sodium binding mode. In CXCR4, the sodium ion is tightly bound by four protein atoms and one water molecule. In CCR5, the sodium ion is mobil e within the binding pocket and moves between different sites involving from one to three protein atoms and two to five water molecules. Analysis of chemokine receptor evolution reveals that a highly constrained sodium binding site characterized most ancient receptors, and that the constraints were subsequently loosened during the divergence of this receptor fam...
Source: PLoS Computational Biology - June 18, 2018 Category: Biology Authors: Bruck Taddese Source Type: research

Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response
by Wei-Ven Tee, Enrico Guarnera, Igor N. Berezovsky The omnipresence of allosteric regulation together with the fundamental role of structural dynamics in this phenomenon have initiated a great interest to the detection of regulatory exosites and design of corresponding effectors. However, despite a general consensus on the key role of dynamics mos t of the earlier efforts on the prediction of allosteric sites are heavily crippled by the static nature of the underlying methods, which are either structure-based approaches seeking for deep surface pockets typical for “traditional” orthosteric drugs or sequence-b...
Source: PLoS Computational Biology - June 18, 2018 Category: Biology Authors: Wei-Ven Tee Source Type: research

Nonmechanistic forecasts of seasonal influenza with iterative one-week-ahead distributions
This article describes two main contributions we made recently toward this goal: a novel approach to probabilistic modeling of sur veillance time series based on “delta densities”, and an optimization scheme for combining output from multiple forecasting methods into an adaptively weighted ensemble. Delta densities describe the probability distribution of the change between one observation and the next, conditioned on avail able data; chaining together nonparametric estimates of these distributions yields a model for an entire trajectory. Corresponding distributional forecasts cover more observed events than al...
Source: PLoS Computational Biology - June 15, 2018 Category: Biology Authors: Logan C. Brooks Source Type: research

Tellurium notebooks —An environment for reproducible dynamical modeling in systems biology
by J. Kyle Medley, Kiri Choi, Matthias K önig, Lucian Smith, Stanley Gu, Joseph Hellerstein, Stuart C. Sealfon, Herbert M. Sauro The considerable difficulty encountered in reproducing the results of published dynamical models limits validation, exploration and reuse of this increasingly large biomedical research resource. To address this problem, we have developed Tellurium Notebook, a software system for model authoring, s imulation, and teaching that facilitates building reproducible dynamical models and reusing models by 1) providing a notebook environment which allows models, Python code, and narrative to be inte...
Source: PLoS Computational Biology - June 15, 2018 Category: Biology Authors: J. Kyle Medley Source Type: research

Classification of red blood cell shapes in flow using outlier tolerant machine learning
by Alexander Kihm, Lars Kaestner, Christian Wagner, Stephan Quint The manual evaluation, classification and counting of biological objects demands for an enormous expenditure of time and subjective human input may be a source of error. Investigating the shape of red blood cells (RBCs) in microcapillary Poiseuille flow, we overcome this drawback by introducing a convolutional neural regression network for an automatic, outlier tolerant shape classification. From our experiments we expect two stable geometries: the so-called ‘slipper’ and ‘croissant’ shapes depending on the prevailing flow conditions...
Source: PLoS Computational Biology - June 15, 2018 Category: Biology Authors: Alexander Kihm Source Type: research

Cloud computing applications for biomedical science: A perspective
by Vivek Navale, Philip E. Bourne Biomedical research has become a digital data–intensive endeavor, relying on secure and scalable computing, storage, and network infrastructure, which has traditionally been purchased, supported, and maintained locally. For certain types of biomedical applications, cloud computing has emerged as an alternative to locally maintained traditional computing approaches. Cloud computing offers users pay-as-you-go access to services such as hardware infrastructure, platforms, and software for solving common biomedical computational problems. Cloud computing services offer secure on-demand ...
Source: PLoS Computational Biology - June 14, 2018 Category: Biology Authors: Vivek Navale Source Type: research

Hybrid stochastic framework predicts efficacy of prophylaxis against HIV: An example with different dolutegravir prophylaxis schemes
by Sulav Duwal, Laura Dickinson, Saye Khoo, Max von Kleist To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the ‘five pillars’ to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for P rEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated. However, pre-clinical testing may not guide...
Source: PLoS Computational Biology - June 14, 2018 Category: Biology Authors: Sulav Duwal Source Type: research

Mechanical evolution of DNA double-strand breaks in the nucleosome
by Fabrizio Cleri, Fabio Landuzzi, Ralf Blossey Double strand breaks (DSB) in the DNA backbone are the most lethal type of defect induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the outcomes of damage in nucleosomal DNA, and on its effects on damage repair. We performed microsecond-long molecular dynamics computer simulations of nucleosomes including a DSB at various sites, to characterize the early stages of the evolution of this DNA lesion. The damaged structures are studied by the essential dynamics of DNA and histones, and compared to the intact nucleosome, th...
Source: PLoS Computational Biology - June 14, 2018 Category: Biology Authors: Fabrizio Cleri Source Type: research

Identifying functional groups among the diverse, recombining antigenic < i > var < /i > genes of the malaria parasite < i > Plasmodium falciparum < /i > from a local community in Ghana
by Mary M. Rorick, Edward B. Baskerville, Thomas S. Rask, Karen P. Day, Mercedes Pascual A challenge in studying diverse multi-copy gene families is deciphering distinct functional types within immense sequence variation. Functional changes can in some cases be tracked through the evolutionary history of a gene family; however phylogenetic approaches are not possible in cases where ge ne families diversify primarily by recombination. We take a network theoretical approach to functionally classify the highly recombiningvar antigenic gene family of the malaria parasitePlasmodium falciparum. We samplevar DBL α sequence...
Source: PLoS Computational Biology - June 13, 2018 Category: Biology Authors: Mary M. Rorick Source Type: research

3D morphology-based clustering and simulation of human pyramidal cell dendritic spines
by Sergio Luengo-Sanchez, Isabel Fernaud-Espinosa, Concha Bielza, Ruth Benavides-Piccione, Pedro Larra ñaga, Javier DeFelipe The dendritic spines of pyramidal neurons are the targets of most excitatory synapses in the cerebral cortex. They have a wide variety of morphologies, and their morphology appears to be critical from the functional point of view. To further characterize dendritic spine geometry, we used in this p aper over 7,000 individually 3D reconstructed dendritic spines from human cortical pyramidal neurons to group dendritic spines using model-based clustering. This approach uncovered six separate grou...
Source: PLoS Computational Biology - June 13, 2018 Category: Biology Authors: Sergio Luengo-Sanchez Source Type: research