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PLoS Computational Biology

Méziane Aite, Marie Chevallier, Clémence Frioux, Camille Trottier, Jeanne Got, María Paz Cortés, Sebastián N Mendoza, Grégory Carrier, Olivier Dameron, Nicolas Guillaudeux, Mauricio Latorre, Nicolás Loira, Gabriel V Markov, Alejandro Maass, Anne Siegel
Genome-scale metabolic models have become the tool of choice for the global analysis of microorganism metabolism, and their reconstruction has attained high standards of quality and reliability. Improvements in this area have been accompanied by the development of some major platforms and databases, and an explosion of individual bioinformatics methods. Consequently, many recent models result from "à la carte" pipelines, combining the use of platforms, individual tools and biological expertise to enhance the quality of the reconstruction...
May 23, 2018: PLoS Computational Biology
Yun Tao, Katriona Shea, Matthew Ferrari
Dynamic models in disease ecology have historically evaluated vaccination strategies under the assumption that they are implemented homogeneously in space and time. However, this approach fails to formally account for operational and logistical constraints inherent in the distribution of vaccination to the population at risk. Thus, feedback between the dynamic processes of vaccine distribution and transmission might be overlooked. Here, we present a spatially explicit, stochastic Susceptible-Infected-Recovered-Vaccinated model that highlights the density-dependence and spatial constraints of various diffusive strategies of vaccination during an outbreak...
May 23, 2018: PLoS Computational Biology
Linda Dib, Nicolas Salamin, David Gfeller
Major histocompatibility complex class I (MHC-I) molecules are critical to adaptive immune defence mechanisms in vertebrate species and are encoded by highly polymorphic genes. Polymorphic sites are located close to the ligand-binding groove and entail MHC-I alleles with distinct binding specificities. Some efforts have been made to investigate the relationship between polymorphism and protein stability. However, less is known about the relationship between polymorphism and MHC-I co-evolutionary constraints...
May 21, 2018: PLoS Computational Biology
Philipp Berens, Jeremy Freeman, Thomas Deneux, Nicolay Chenkov, Thomas McColgan, Artur Speiser, Jakob H Macke, Srinivas C Turaga, Patrick Mineault, Peter Rupprecht, Stephan Gerhard, Rainer W Friedrich, Johannes Friedrich, Liam Paninski, Marius Pachitariu, Kenneth D Harris, Ben Bolte, Timothy A Machado, Dario Ringach, Jasmine Stone, Luke E Rogerson, Nicolas J Sofroniew, Jacob Reimer, Emmanouil Froudarakis, Thomas Euler, Miroslav Román Rosón, Lucas Theis, Andreas S Tolias, Matthias Bethge
In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing...
May 21, 2018: PLoS Computational Biology
Andrew D Rouillard, Mark R Hurle, Pankaj Agarwal
Target selection is the first and pivotal step in drug discovery. An incorrect choice may not manifest itself for many years after hundreds of millions of research dollars have been spent. We collected a set of 332 targets that succeeded or failed in phase III clinical trials, and explored whether Omic features describing the target genes could predict clinical success. We obtained features from the recently published comprehensive resource: Harmonizome. Nineteen features appeared to be significantly correlated with phase III clinical trial outcomes, but only 4 passed validation schemes that used bootstrapping or modified permutation tests to assess feature robustness and generalizability while accounting for target class selection bias...
May 21, 2018: PLoS Computational Biology
Ji Hyun Bak, Seogjoo J Jang, Changbong Hyeon
Binding of odorants to olfactory receptors (ORs) elicits downstream chemical and neural signals, which are further processed to odor perception in the brain. Recently, Mainland and colleagues have measured more than 500 pairs of odorant-OR interaction by a high-throughput screening assay method, opening a new avenue to understanding the principles of human odor coding. Here, using a recently developed minimal model for OR activation kinetics, we characterize the statistics of OR activation by odorants in terms of three empirical parameters: the half-maximum effective concentration EC50, the efficacy, and the basal activity...
May 21, 2018: PLoS Computational Biology
Carlos Espinosa-Soto
Modularity is a widespread property in biological systems. It implies that interactions occur mainly within groups of system elements. A modular arrangement facilitates adjustment of one module without perturbing the rest of the system. Therefore, modularity of developmental mechanisms is a major factor for evolvability, the potential to produce beneficial variation from random genetic change. Understanding how modularity evolves in gene regulatory networks, that create the distinct gene activity patterns that characterize different parts of an organism, is key to developmental and evolutionary biology...
May 18, 2018: PLoS Computational Biology
Kevin Breslin, John Joseph Wade, KongFatt Wong-Lin, Jim Harkin, Bronac Flanagan, Harm Van Zalinge, Steve Hall, Matthew Walker, Alexei Verkhratsky, Liam McDaid
A biophysical model that captures molecular homeostatic control of ions at the perisynaptic cradle (PsC) is of fundamental importance for understanding the interplay between astroglial and neuronal compartments. In this paper, we develop a multi-compartmental mathematical model which proposes a novel mechanism whereby the flow of cations in thin processes is restricted due to negatively charged membrane lipids which result in the formation of deep potential wells near the dipole heads. These wells restrict the flow of cations to "hopping" between adjacent wells as they transverse the process, and this surface retention of cations will be shown to give rise to the formation of potassium (K+) and sodium (Na+) microdomains at the PsC...
May 18, 2018: PLoS Computational Biology
Jagannath Mondal, Navjeet Ahalawat, Subhendu Pandit, Lewis E Kay, Pramodh Vallurupalli
Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound T4L L99A are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive...
May 18, 2018: PLoS Computational Biology
Andreas Petrides, Glenn Vinnicombe
This paper is concerned with the potential multistability of protein concentrations in the cell. That is, situations where one, or a family of, proteins may sit at one of two or more different steady state concentrations in otherwise identical cells, and in spite of them being in the same environment. For models of multisite protein phosphorylation for example, in the presence of excess substrate, it has been shown that the achievable number of stable steady states can increase linearly with the number of phosphosites available...
May 17, 2018: PLoS Computational Biology
Milad Hobbi Mobarhan, Geir Halnes, Pablo Martínez-Cañada, Torkel Hafting, Marianne Fyhn, Gaute T Einevoll
Visually evoked signals in the retina pass through the dorsal geniculate nucleus (dLGN) on the way to the visual cortex. This is however not a simple feedforward flow of information: there is a significant feedback from cortical cells back to both relay cells and interneurons in the dLGN. Despite four decades of experimental and theoretical studies, the functional role of this feedback is still debated. Here we use a firing-rate model, the extended difference-of-Gaussians (eDOG) model, to explore cortical feedback effects on visual responses of dLGN relay cells...
May 17, 2018: PLoS Computational Biology
Damiano Pasetto, Flavio Finger, Anton Camacho, Francesco Grandesso, Sandra Cohuet, Joseph C Lemaitre, Andrew S Azman, Francisco J Luquero, Enrico Bertuzzo, Andrea Rinaldo
Computational models of cholera transmission can provide objective insights into the course of an ongoing epidemic and aid decision making on allocation of health care resources. However, models are typically designed, calibrated and interpreted post-hoc. Here, we report the efforts of a team from academia, field research and humanitarian organizations to model in near real-time the Haitian cholera outbreak after Hurricane Matthew in October 2016, to assess risk and to quantitatively estimate the efficacy of a then ongoing vaccination campaign...
May 16, 2018: PLoS Computational Biology
Aaditya V Rangan, Caroline C McGrouther, John Kelsoe, Nicholas Schork, Eli Stahl, Qian Zhu, Arjun Krishnan, Vicky Yao, Olga Troyanskaya, Seda Bilaloglu, Preeti Raghavan, Sarah Bergen, Anders Jureus, Mikael Landen
A common goal in data-analysis is to sift through a large data-matrix and detect any significant submatrices (i.e., biclusters) that have a low numerical rank. We present a simple algorithm for tackling this biclustering problem. Our algorithm accumulates information about 2-by-2 submatrices (i.e., 'loops') within the data-matrix, and focuses on rows and columns of the data-matrix that participate in an abundance of low-rank loops. We demonstrate, through analysis and numerical-experiments, that this loop-counting method performs well in a variety of scenarios, outperforming simple spectral methods in many situations of interest...
May 14, 2018: PLoS Computational Biology
Tim van Mourik, Lukas Snoek, Tomas Knapen, David G Norris
The field of neuroimaging is rapidly adopting a more reproducible approach to data acquisition and analysis. Data structures and formats are being standardised and data analyses are getting more automated. However, as data analysis becomes more complicated, researchers often have to write longer analysis scripts, spanning different tools across multiple programming languages. This makes it more difficult to share or recreate code, reducing the reproducibility of the analysis. We present a tool, Porcupine, that constructs one's analysis visually and automatically produces analysis code...
May 10, 2018: PLoS Computational Biology
Thanos Manos, Magteld Zeitler, Peter A Tass
Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies...
May 10, 2018: PLoS Computational Biology
Gonçalo M Marques, Starrlight Augustine, Konstadia Lika, Laure Pecquerie, Tiago Domingos, Sebastiaan A L M Kooijman
We developed new methods for parameter estimation-in-context and, with the help of 125 authors, built the AmP (Add-my-Pet) database of Dynamic Energy Budget (DEB) models, parameters and referenced underlying data for animals, where each species constitutes one database entry. The combination of DEB parameters covers all aspects of energetics throughout the full organism's life cycle, from the start of embryo development to death by aging. The species-specific parameter values capture biodiversity and can now, for the first time, be compared between animals species...
May 9, 2018: PLoS Computational Biology
Nathanaël Hozé, Sebastian Bonhoeffer, Roland Regoes
Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure on the pathogen it has been hypothesised to be "evolution-proof". However, the primary public health goal is to reduce the incidence and mortality associated with a disease. From this perspective, tolerance-based treatment bears the risk of increasing the prevalence of the disease, which may lead to increased mortality...
May 4, 2018: PLoS Computational Biology
Florian Aspart, Michiel W H Remme, Klaus Obermayer
The rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS...
May 4, 2018: PLoS Computational Biology
Joseph B Dechery, Jason N MacLean
Visual stimuli evoke activity in visual cortical neuronal populations. Neuronal activity can be selectively modulated by particular visual stimulus parameters, such as the direction of a moving bar of light, resulting in well-defined trial averaged tuning properties. However, given any single stimulus parameter, a large number of neurons in visual cortex remain unmodulated, and the role of this untuned population is not well understood. Here, we use two-photon calcium imaging to record, in an unbiased manner, from large populations of layer 2/3 excitatory neurons in mouse primary visual cortex to describe co-varying activity on single trials in neuronal populations consisting of both tuned and untuned neurons...
May 4, 2018: PLoS Computational Biology
Aaron T L Lun, Hervé Pagès, Mike L Smith
Biological experiments involving genomics or other high-throughput assays typically yield a data matrix that can be explored and analyzed using the R programming language with packages from the Bioconductor project. Improvements in the throughput of these assays have resulted in an explosion of data even from routine experiments, which poses a challenge to the existing computational infrastructure for statistical data analysis. For example, single-cell RNA sequencing (scRNA-seq) experiments frequently generate large matrices containing expression values for each gene in each cell, requiring sparse or file-backed representations for memory-efficient manipulation in R...
May 3, 2018: PLoS Computational Biology
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