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NPJ Systems Biology and Applications

Kazuhiro Maeda, Hans V Westerhoff, Hiroyuki Kurata, Fred C Boogerd
The complex ammonium transport and assimilation network of E. coli involves the ammonium transporter AmtB, the regulatory proteins GlnK and GlnB, and the central N-assimilating enzymes together with their highly complex interactions. The engineering and modelling of such a complex network seem impossible because functioning depends critically on a gamut of data known at patchy accuracy. We developed a way out of this predicament, which employs: (i) a constrained optimization-based technology for the simultaneous fitting of models to heterogeneous experimental data sets gathered through diverse experimental set-ups, (ii) a 'rubber band method' to deal with different degrees of uncertainty, both in experimentally determined or estimated parameter values and in measured transient or steady-state variables (training data sets), (iii) integration of human expertise to decide on accuracies of both parameters and variables, (iv) massive computation employing a fast algorithm and a supercomputer, (v) an objective way of quantifying the plausibility of models, which makes it possible to decide which model is the best and how much better that model is than the others...
2019: NPJ Systems Biology and Applications
Matthew A Care, David R Westhead, Reuben M Tooze
Cancers converge onto shared patterns that arise from constraints placed by the biology of the originating cell lineage and microenvironment on programs driven by oncogenic events. Here we define consistent expression modules reflecting this structure in colon and breast cancer by exploiting expression data resources and a new computationally efficient approach that we validate against other comparable methods. This approach, Parsimonious Gene Correlation Network Analysis (PGCNA), allows comparison of network structures between these cancer types identifying shared modules of gene co-expression reflecting: cancer hallmarks, functional and structural gene batteries, copy number variation and biology of originating lineage...
2019: NPJ Systems Biology and Applications
Renana Sabi, Tamir Tuller
The ability to dynamically control mRNA translation has a great impact on many intracellular processes. Whereas it is believed that translational control in eukaryotes occurs mainly at initiation, the condition-specific changes at the elongation level and their potential regulatory role remain unclear. Using computational approaches applied to ribosome profiling data, we show that elongation rate is dynamic and can change considerably during the yeast meiosis to facilitate the selective translation of stage-specific transcripts...
2019: NPJ Systems Biology and Applications
Fabian Fröhlich, Anita Reiser, Laura Fink, Daniel Woschée, Thomas Ligon, Fabian Joachim Theis, Joachim Oskar Rädler, Jan Hasenauer
[This corrects the article DOI: 10.1038/s41540-018-0079-7.].
2019: NPJ Systems Biology and Applications
Daniel Domingo-Fernández, Charles Tapley Hoyt, Carlos Bobis-Álvarez, Josep Marín-Llaó, Martin Hofmann-Apitius
[This corrects the article DOI: 10.1038/s41540-018-0078-8.].
2019: NPJ Systems Biology and Applications
Hari Shankar Mahato, Christine Ahlstrom, Rasmus Jansson-Löfmark, Ulrika Johansson, Gabriel Helmlinger, K Melissa Hallow
[This corrects the article DOI: 10.1038/s41540-018-0077-9.].
2019: NPJ Systems Biology and Applications
Matteo Manica, Joris Cadow, Roland Mathis, María Rodríguez Martínez
Reliable identification of molecular biomarkers is essential for accurate patient stratification. While state-of-the-art machine learning approaches for sample classification continue to push boundaries in terms of performance, most of these methods are not able to integrate different data types and lack generalization power, limiting their application in a clinical setting. Furthermore, many methods behave as black boxes, and we have very little understanding about the mechanisms that lead to the prediction...
2019: NPJ Systems Biology and Applications
Cankut Çubuk, Marta R Hidalgo, Alicia Amadoz, Kinza Rian, Francisco Salavert, Miguel A Pujana, Francesca Mateo, Carmen Herranz, Jose Carbonell-Caballero, Joaquín Dopazo
In spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA)...
2019: NPJ Systems Biology and Applications
Kelly E Regan-Fendt, Jielin Xu, Mallory DiVincenzo, Megan C Duggan, Reena Shakya, Ryejung Na, William E Carson, Philip R O Payne, Fuhai Li
Systems biology perspectives are crucial for understanding the pathophysiology of complex diseases, and therefore hold great promise for the discovery of novel treatment strategies. Drug combinations have been shown to improve durability and reduce resistance to available first-line therapies in a variety of cancers; however, traditional drug discovery approaches are prohibitively cost and labor-intensive to evaluate large-scale matrices of potential drug combinations. Computational methods are needed to efficiently model complex interactions of drug target pathways and identify mechanisms underlying drug combination synergy...
2019: NPJ Systems Biology and Applications
William Deveaux, Kentaro Hayashi, Kumar Selvarajoo
Owing to their self-organizing evolutionary plasticity, cancers remain evasive to modern treatment strategies. Previously, for sensitizing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant human fibrosarcoma (HT1080), we developed and validated a dynamic computational model that showed the inhibition of protein kinase (PK)C, using bisindolylmaleimide (BIS) I, enhances apoptosis with 95% cell death. Although promising, the long-term effect of remaining ~ 5% cells is a mystery. Will they remain unchanged or are they able to proliferate? To address this question, here we adopted a discrete spatiotemporal cellular automata model utilizing simple rules modified from the famous "Conway's game of life"...
2019: NPJ Systems Biology and Applications
Lisa Küstner, Thomas Nägele, Arnd G Heyer
We developed a mathematical model to simulate dynamics of central carbon metabolism over complete diurnal cycles for leaves of Arabidopsis thaliana exposed to either normal (120 µmol m-2  s-1 ) or high light intensities (1200 µmol m- 2  s-1 ). The main objective was to obtain a high-resolution time series for metabolite dynamics as well as for shoot structural carbon formation (compounds with long residence time) and assimilate export of aerial organs to the sink tissue. Model development comprised a stepwise increment of complexity to finally approach the in vivo situation...
2019: 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
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