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PLoS Computational Biology

Tanmay A Gokhale, Huda Asfour, Shravan Verma, Nenad Bursac, Craig S Henriquez
The incidence of cardiac arrhythmias is known to be associated with tissue heterogeneities including fibrosis. However, the impact of microscopic structural heterogeneities on conduction in excitable tissues remains poorly understood. In this study, we investigated how acellular microheterogeneities affect macroscopic conduction under conditions of normal and reduced excitability by utilizing a novel platform of paired in vitro and in 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...
July 16, 2018: PLoS Computational Biology
Antreas C Kalli, Reinhart A F Reithmeier
The Band 3 (AE1, SLC4A1) membrane protein is found in red blood cells and in kidney where it functions as an electro-neutral chloride/bicarbonate exchanger. 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...
July 16, 2018: PLoS Computational Biology
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 DNA methylation and copy number alteration, inferring context-specific ceRNA interactions accurately is a computationally challenging task...
July 16, 2018: PLoS Computational Biology
Albert Pla, Xiangfu Zhong, Simon Rayner
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to partially complementary regions within the 3'UTR of their target genes. Computational methods play an important role in target prediction and assume that the miRNA "seed region" (nt 2 to 8) is required for functional targeting, but typically only identify ∼80% of known bindings. Recent studies have highlighted a role for the entire miRNA, suggesting that a more flexible methodology is needed. We present a novel approach for miRNA target prediction based on Deep Learning (DL) which, rather than incorporating 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...
July 13, 2018: PLoS Computational Biology
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...
July 12, 2018: PLoS Computational Biology
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 and 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 is the focus on this article...
July 10, 2018: PLoS Computational Biology
Yina Wei, Giri P Krishnan, Maxim Komarov, Maxim Bazhenov
Sleep plays an important role in the consolidation of recent memories. However, the cellular and synaptic mechanisms of consolidation during sleep remain poorly understood. In this study, using a realistic computational model of the thalamocortical network, we tested the role of Non-Rapid Eye Movement (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...
July 9, 2018: PLoS Computational Biology
Joshua H Goldwyn, Bradley R Slabe, Joseph B Travers, David Terman
Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron's output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity...
July 9, 2018: PLoS Computational Biology
Betül 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 worm Caenorhabditis 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...
July 9, 2018: PLoS Computational Biology
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 hardwired, 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 associated with decreased risk-taking in motor decision-making, it is currently unknown whether this is a result of changes in Pavlovian biases, instrumental processes or a combination of both...
July 6, 2018: PLoS Computational Biology
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 ensemble 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...
July 6, 2018: PLoS Computational Biology
Sonja E M Boas, Joao Carvalho, Marloes van den Broek, Ester M Weijers, Marie-José 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 unclear 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 cell migration and fibrin proteolysis by the plasmin system...
July 6, 2018: PLoS Computational Biology
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 circuit function...
July 6, 2018: PLoS Computational Biology
Ankit N Khambhati, John D Medaglia, Elisabeth A Karuza, Sharon L Thompson-Schill, Danielle S Bassett
Brain anatomy and physiology support the human ability to navigate a complex space of perceptions and actions. To maneuver across an ever-changing landscape of mental states, the brain invokes cognitive control-a set of dynamic processes that engage and disengage different groups of brain regions to modulate attention, switch between tasks, and inhibit prepotent responses. Current theory posits that correlated and anticorrelated brain activity may signify cooperative and competitive interactions between brain areas that subserve adaptive behavior...
July 6, 2018: PLoS Computational Biology
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. Signalling 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...
July 5, 2018: PLoS Computational Biology
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 growth. 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 model size and complexity...
July 5, 2018: PLoS Computational Biology
Felix Brinkmann, Moritz Mercker, Thomas Richter, Anna Marciniak-Czochra
Chemical and mechanical pattern formation is fundamental during embryogenesis and tissue development. Yet, the underlying molecular and cellular mechanisms are still elusive in many cases. Most current theories assume that tissue development is driven by chemical processes: either as a sequence of chemical patterns each depending on the previous one, or by patterns spontaneously arising from specific chemical interactions (such as "Turing-patterns"). Within both theories, mechanical patterns are usually regarded as passive by-products of chemical pre-patters...
July 3, 2018: PLoS Computational Biology
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 regulated 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 with two substrates, ATP and P1, the phosphoryl-accepting domain of CheA...
July 2, 2018: PLoS Computational Biology
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 evident 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...
June 28, 2018: PLoS Computational Biology
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 computational models, we identified network mechanisms that may explain differences in spindle properties across cortical structures. First, we report that differences in spindle occurrence between MEG and EEG data may arise from the contrasting properties of the core and matrix thalamocortical systems...
June 27, 2018: PLoS Computational Biology
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