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NPJ Systems Biology and Applications

Daniel Domingo-Fernández, Charles Tapley Hoyt, Carlos Bobis-Álvarez, Josep Marín-Llaó, Martin Hofmann-Apitius
Although pathways are widely used for the analysis and representation of biological systems, their lack of clear boundaries, their dispersion across numerous databases, and the lack of interoperability impedes the evaluation of the coverage, agreements, and discrepancies between them. Here, we present ComPath, an ecosystem that supports curation of pathway mappings between databases and fosters the exploration of pathway knowledge through several novel visualizations. We have curated mappings between three of the major pathway databases and present a case study focusing on Parkinson's disease that illustrates how ComPath can generate new biological insights by identifying pathway modules, clusters, and cross-talks with these mappings...
2019: NPJ Systems Biology and Applications
Hari Shankar Mahato, Christine Ahlstrom, Rasmus Jansson-Löfmark, Ulrika Johansson, Gabriel Helmlinger, K Melissa Hallow
Many preclinically promising therapies for diabetic kidney disease fail to provide efficacy in humans, reflecting limited quantitative translational understanding between rodent models and human disease. To quantitatively bridge interspecies differences, we adapted a mathematical model of renal function from human to mice, and incorporated adaptive and pathological mechanisms of diabetes and nephrectomy to describe experimentally observed changes in glomerular filtration rate (GFR) and proteinuria in db/db and db/db UNX (uninephrectomy) mouse models...
2019: NPJ Systems Biology and Applications
Fabian Fröhlich, Anita Reiser, Laura Fink, Daniel Woschée, Thomas Ligon, Fabian Joachim Theis, Joachim Oskar Rädler, Jan Hasenauer
Single-cell time-lapse studies have advanced the quantitative understanding of cellular pathways and their inherent cell-to-cell variability. However, parameters retrieved from individual experiments are model dependent and their estimation is limited, if based on solely one kind of experiment. Hence, methods to integrate data collected under different conditions are expected to improve model validation and information content. Here we present a multi-experiment nonlinear mixed effect modeling approach for mechanistic pathway models, which allows the integration of multiple single-cell perturbation experiments...
2019: NPJ Systems Biology and Applications
Vivek Kohar, Mingyang Lu
Stochasticity in gene expression impacts the dynamics and functions of gene regulatory circuits. Intrinsic noises, including those that are caused by low copy number of molecules and transcriptional bursting, are usually studied by stochastic simulations. However, the role of extrinsic factors, such as cell-to-cell variability and heterogeneity in the microenvironment, is still elusive. To evaluate the effects of both the intrinsic and extrinsic noises, we develop a method, named sRACIPE, by integrating stochastic analysis with random circuit perturbation (RACIPE) method...
2018: NPJ Systems Biology and Applications
Greta Del Mistro, Philippe Lucarelli, Ines Müller, Sébastien De Landtsheer, Anna Zinoveva, Meike Hutt, Martin Siegemund, Roland E Kontermann, Stefan Beissert, Thomas Sauter, Dagmar Kulms
Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mut BRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network...
2018: NPJ Systems Biology and Applications
Anqi Jing, Frederick S Vizeacoumar, Sreejit Parameswaran, Bjorn Haave, Chelsea E Cunningham, Yuliang Wu, Roland Arnold, Keith Bonham, Andrew Freywald, Jie Han, Franco J Vizeacoumar
Can transcriptomic alterations drive the evolution of tumors? We asked if changes in gene expression found in all patients arise earlier in tumor development and can be relevant to tumor progression. Our analyses of non-mutated genes from the non-amplified regions of the genome of 158 triple-negative breast cancer (TNBC) cases identified 219 exclusively expression-altered (EEA) genes that may play important role in TNBC. Phylogenetic analyses of these genes predict a "punctuated burst" of multiple gene upregulation events occurring at early stages of tumor development, followed by minimal subsequent changes later in tumor progression...
2018: NPJ Systems Biology and Applications
Simone Rizzetto, Petros Moyseos, Bianca Baldacci, Corrado Priami, Attila Csikász-Nagy
Most cellular processes are regulated by groups of proteins interacting together to form protein complexes. Protein compositions vary between different tissues or disease conditions enabling or preventing certain protein-protein interactions and resulting in variations in the complexome. Quantitative and qualitative characterization of context-specific protein complexes will help to better understand context-dependent variations in the physiological behavior of cells. Here, we present SiComPre 1.0, a computational tool that predicts context-specific protein complexes by integrating multi-omics sources...
2018: NPJ Systems Biology and Applications
Jérémy Gruel, Julia Deichmann, Benoit Landrein, Thomas Hitchcock, Henrik Jönsson
The plant shoot apical meristem holds a stem cell niche from which all aerial organs originate. Using a computational approach we show that a mixture of monomers and heterodimers of the transcription factors WUSCHEL and HAIRY MERISTEM is sufficient to pattern the stem cell niche, and predict that immobile heterodimers form a regulatory "pocket" surrounding the stem cells. The model achieves to reproduce an array of perturbations, including mutants and tissue size modifications. We also show its ability to reproduce the recently observed dynamical shift of the stem cell niche during the development of an axillary meristem...
2018: NPJ Systems Biology and Applications
Bharat Mishra, Yali Sun, T C Howton, Nilesh Kumar, M Shahid Mukhtar
Age-dependent senescence is a multifaceted and highly coordinated developmental phase in the life of plants that is manifested with genetic, biochemical and phenotypic continuum. Thus, elucidating the dynamic network modeling and simulation of molecular events, in particular gene regulatory network during the onset of senescence is essential. Here, we constructed a computational pipeline that integrates senescence-related co-expression networks with transcription factor (TF)-promoter relationships and microRNA (miR)-target interactions...
2018: NPJ Systems Biology and Applications
Elif Tekin, Cynthia White, Tina Manzhu Kang, Nina Singh, Mauricio Cruz-Loya, Robert Damoiseaux, Van M Savage, Pamela J Yeh
Interactions and emergent processes are essential for research on complex systems involving many components. Most studies focus solely on pairwise interactions and ignore higher-order interactions among three or more components. To gain deeper insights into higher-order interactions and complex environments, we study antibiotic combinations applied to pathogenic Escherichia coli and obtain unprecedented amounts of detailed data (251 two-drug combinations, 1512 three-drug combinations, 5670 four-drug combinations, and 13608 five-drug combinations)...
2018: NPJ Systems Biology and Applications
Stephen M Rappaport
Etiological studies of human exposures to environmental factors typically rely on low-throughput methods that target only a few hundred chemicals or mixtures. In this Perspectives article, I outline how environmental exposure can be defined by the blood exposome-the totality of chemicals circulating in blood. The blood exposome consists of chemicals derived from both endogenous and exogenous sources. Endogenous chemicals are represented by the human proteome and metabolome, which establish homeostatic networks of functional molecules...
2018: NPJ Systems Biology and Applications
Chunhe Li, Gabor Balazsi
The epithelial-mesenchymal transition (EMT) is a basic developmental process that converts epithelial cells to mesenchymal cells. Although EMT might promote cancer metastasis, the molecular mechanisms for it remain to be fully clarified. To address this issue, we constructed an EMT-metastasis gene regulatory network model and quantified the potential landscape of cancer metastasis-promoting system computationally. We identified four steady-state attractors on the landscape, which separately characterize anti-metastatic (A), metastatic (M), and two other intermediate (I1 and I2) cell states...
2018: NPJ Systems Biology and Applications
Elaina M Maldonado, Ciarán P Fisher, Dawn J Mazzatti, Amy L Barber, Marcus J Tindall, Nicholas J Plant, Andrzej M Kierzek, J Bernadette Moore
Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism...
2018: NPJ Systems Biology and Applications
Mariano Beguerisse-Díaz, Gabriel Bosque, Diego Oyarzún, Jesús Picó, Mauricio Barahona
Cells adapt their metabolic fluxes in response to changes in the environment. We present a framework for the systematic construction of flux-based graphs derived from organism-wide metabolic networks. Our graphs encode the directionality of metabolic flows via edges that represent the flow of metabolites from source to target reactions. The methodology can be applied in the absence of a specific biological context by modelling fluxes probabilistically, or can be tailored to different environmental conditions by incorporating flux distributions computed through constraint-based approaches such as Flux Balance Analysis...
2018: NPJ Systems Biology and Applications
Pierre-Etienne Cholley, Julien Moehlin, Alexia Rohmer, Vincent Zilliox, Samuel Nicaise, Hinrich Gronemeyer, Marco Antonio Mendoza-Parra
Complex organisms originate from and are maintained by the information encoded in the genome. A major challenge of systems biology is to develop algorithms that describe the dynamic regulation of genome functions from large omics datasets. Here, we describe TETRAMER, which reconstructs gene-regulatory networks from temporal transcriptome data during cell fate transitions to predict "master" regulators by simulating cascades of temporal transcription-regulatory events.
2018: NPJ Systems Biology and Applications
Christoph Thiel, Ines Smit, Vanessa Baier, Henrik Cordes, Brigida Fabry, Lars Mathias Blank, Lars Kuepfer
A quantitative analysis of dose-response relationships is essential in preclinical and clinical drug development in order to optimize drug efficacy and safety, respectively. However, there is a lack of quantitative understanding about the dynamics of pharmacological drug-target interactions in biological systems. In this study, a quantitative systems pharmacology (QSP) approach is applied to quantify the drug efficacy of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by coupling physiologically based pharmacokinetic models, at the whole-body level, with affected biological networks, at the cellular scale...
2018: NPJ Systems Biology and Applications
Eugen Bauer, Ines Thiele
Crohn's disease (CD) is associated with an ecological imbalance of the intestinal microbiota, consisting of hundreds of species. The underlying complexity as well as individual differences between patients contributes to the difficulty to define a standardized treatment. Computational modeling can systematically investigate metabolic interactions between gut microbes to unravel mechanistic insights. In this study, we integrated metagenomic data of CD patients and healthy controls with genome-scale metabolic models into personalized in silico microbiotas...
2018: NPJ Systems Biology and Applications
H Alexander Ebhardt, Alex Root, Yansheng Liu, Nicholas Paul Gauthier, Chris Sander, Ruedi Aebersold
In the United States alone one in five newly diagnosed cancers in men are prostate carcinomas (PCa). Androgen receptor (AR) status and the PI3K-AKT-mTOR signal transduction pathway are critical in PCa. After initial response to single drugs targeting these pathways resistance often emerges, indicating the need for combination therapy. Here, we address the question of efficacy of drug combinations and development of resistance mechanisms to targeted therapy by a systems pharmacology approach. We combine targeted perturbation with detailed observation of the molecular response by mass spectrometry...
2018: NPJ Systems Biology and Applications
Amitabh Sharma, Arda Halu, Julius L Decano, Megha Padi, Yang-Yu Liu, Rashmi B Prasad, Joao Fadista, Marc Santolini, Jörg Menche, Scott T Weiss, Marc Vidal, Edwin K Silverman, Masanori Aikawa, Albert-László Barabási, Leif Groop, Joseph Loscalzo
Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS p -values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study...
2018: NPJ Systems Biology and Applications
Stephen Wilson, Fabian Volker Filipp
Coordinated experiments focused on transcriptional responses and chromatin states are well-equipped to capture different epigenomic and transcriptomic levels governing the circuitry of a regulatory network. We propose a workflow for the genome-wide identification of epigenomic and transcriptional cooperation to elucidate transcriptional networks in cancer. Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators...
2018: NPJ Systems Biology and Applications
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