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A fast lasso-based method for inferring higher-order interactions
by Kieran Elmes, Astra Heywood, Zhiyi Huang, Alex Gavryushkin Large-scale genotype-phenotype screens provide a wealth of data for identifying molecular alterations associated with a phenotype. Epistatic effects play an important role in such association studies. For example, siRNA perturbation screens can be used to identify combinatorial gene-silencing effects. In bacteria, epistasis has practical consequences in determining antimicrobial resistance as the genetic background of a strain plays an important role in determining resistance. Recently developed tools scale to human exome-wide screens for pairwise interactions,...
Source: PLoS Computational Biology - December 29, 2022 Category: Biology Authors: Kieran Elmes Source Type: research

Host factor prioritization for pan-viral genetic perturbation screens using random intercept models and network propagation
by Simon Dirmeier, Christopher D ächert, Martijn van Hemert, Ali Tas, Natacha S. Ogando, Frank van Kuppeveld, Ralf Bartenschlager, Lars Kaderali, Marco Binder, Niko Beerenwinkel Genetic perturbation screens using RNA interference (RNAi) have been conducted successfully to identify host factors that are essential for the life cycle of bacteria or viruses. So far, most published studies identified host factors primarily for single pathogens. Furthermore, often only a small subset of genes, e.g., genes encoding kinases, have been targeted. Identification of host factors on a pan-pathogen level, i.e., genes that are crucial ...
Source: PLoS Computational Biology - February 9, 2020 Category: Biology Authors: Simon Dirmeier Source Type: research

Network-based analysis of prostate cancer cell lines reveals novel marker gene candidates associated with radioresistance and patient relapse
by Michael Seifert, Claudia Peitzsch, Ielizaveta Gorodetska, Caroline B örner, Barbara Klink, Anna Dubrovska Radiation therapy is an important and effective treatment option for prostate cancer, but high-risk patients are prone to relapse due to radioresistance of cancer cells. Molecular mechanisms that contribute to radioresistance are not fully understood. Novel computational strategies are needed to i dentify radioresistance driver genes from hundreds of gene copy number alterations. We developed a network-based approach based on lasso regression in combination with network propagation for the analysis of prostate can...
Source: PLoS Computational Biology - November 3, 2019 Category: Biology Authors: Michael Seifert Source Type: research

Dynamic balance between vesicle transport and microtubule growth enables neurite outgrowth
by Arjun Singh Yadaw, Mustafa M. Siddiq, Vera Rabinovich, Rosa Tolentino, Jens Hansen, Ravi Iyengar Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. S...
Source: PLoS Computational Biology - April 30, 2019 Category: Biology Authors: Arjun Singh Yadaw Source Type: research

Bowhead: Bayesian modelling of cell velocity during concerted cell migration
by Mathias Engel, James Longden, Jesper Ferkinghoff-Borg, Xavier Robin, Gaye Sa ğınç, Rune Linding Cell migration is a central biological process that requires fine coordination of molecular events in time and space. A deregulation of the migratory phenotype is also associated with pathological conditions including cancer where cell motility has a causal role in tumor spreading and metastasis f ormation. Thus cell migration is of critical and strategic importance across the complex disease spectrum as well as for the basic understanding of cell phenotype. Experimental studies of the migration of cells in monolayers are...
Source: PLoS Computational Biology - January 8, 2018 Category: Biology Authors: Mathias Engel Source Type: research

LASSIM —A network inference toolbox for genome-wide mechanistic modeling
by Rasmus Magnusson, Guido Pio Mariotti, Mattias K öpsén, William Lövfors, Danuta R. Gawel, Rebecka Jörnsten, Jörg Linde, Torbjörn Nordling, Elin Nyman, Sylvie Schulze, Colm E. Nestor, Huan Zhang, Gunnar Cedersund, Mikael Benson, Andreas Tjärnberg, Mika Gustafsson Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large- scale inference using mechanistically defined ordinary dif...
Source: PLoS Computational Biology - June 22, 2017 Category: Biology Authors: Rasmus Magnusson Source Type: research

The siRNA Non-seed Region and Its Target Sequences Are Auxiliary Determinants of Off-Target Effects
by Piotr J. Kamola, Yuko Nakano, Tomoko Takahashi, Paul A. Wilson, Kumiko Ui-Tei RNA interference (RNAi) is a powerful tool for post-transcriptional gene silencing. However, the siRNA guide strand may bind unintended off-target transcripts via partial sequence complementarity by a mechanism closely mirroring micro RNA (miRNA) silencing. To better understand these off-target effects, we investigated the correlation between sequence features within various subsections of siRNA guide strands, and its corresponding target sequences, with off-target activities. Our results confirm previous reports that strength of base-pairing...
Source: PLoS Computational Biology - December 11, 2015 Category: Biology Authors: Piotr J. Kamola et al. Source Type: research

Quantifying Stochastic Noise in Cultured Circadian Reporter Cells
In this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demon...
Source: PLoS Computational Biology - November 20, 2015 Category: Biology Authors: Peter C. St. John et al. Source Type: research

Characterizing Protein Interactions Employing a Genome-Wide siRNA Cellular Phenotyping Screen
by Apichat Suratanee, Martin H. Schaefer, Matthew J. Betts, Zita Soons, Heiko Mannsperger, Nathalie Harder, Marcus Oswald, Markus Gipp, Ellen Ramminger, Guillermo Marcus, Reinhard Männer, Karl Rohr, Erich W.er, Robert B. Russell, Miguel A. Andrade-Navarro, Roland Eils, Rainer König Characterizing the activating and inhibiting effect of protein-protein interactions (PPI) is fundamental to gain insight into the complex signaling system of a human cell. A plethora of methods has been suggested to infer PPI from data on a large scale, but none of them is able to characterize the effect of this interaction. Here, we present ...
Source: PLoS Computational Biology - September 25, 2014 Category: Biology Authors: Apichat Suratanee et al. Source Type: research

Mathematical Model of a Telomerase Transcriptional Regulatory Network Developed by Cell-Based Screening: Analysis of Inhibitor Effects and Telomerase Expression Mechanisms
In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3â...
Source: PLoS Computational Biology - February 13, 2014 Category: Biology Authors: Alan E. Bilsland et al. Source Type: research

Target Inhibition Networks: Predicting Selective Combinations of Druggable Targets to Block Cancer Survival Pathways
by Jing Tang, Leena Karhinen, Tao Xu, Agnieszka Szwajda, Bhagwan Yadav, Krister Wennerberg, Tero Aittokallio A recent trend in drug development is to identify drug combinations or multi-target agents that effectively modify multiple nodes of disease-associated networks. Such polypharmacological effects may reduce the risk of emerging drug resistance by means of attacking the disease networks through synergistic and synthetic lethal interactions. However, due to the exponentially increasing number of potential drug and target combinations, systematic approaches are needed for prioritizing the most potent multi-target alter...
Source: PLoS Computational Biology - September 12, 2013 Category: Biology Authors: Jing Tang et al. Source Type: research