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NPJ Systems Biology and Applications

Megha Padi, John Quackenbush
Complex traits and diseases like human height or cancer are often not caused by a single mutation or genetic variant, but instead arise from functional changes in the underlying molecular network. Biological networks are known to be highly modular and contain dense "communities" of genes that carry out cellular processes, but these structures change between tissues, during development, and in disease. While many methods exist for inferring networks and analyzing their topologies separately, there is a lack of robust methods for quantifying differences in network structure...
2018: NPJ Systems Biology and Applications
Martin Hoffmann, Jörg Galle
Kinetic models are at the heart of system identification. A priori chosen rate functions may, however, be unfitting or too restrictive for complex or previously unanticipated regulation. We applied general purpose piecewise linear functions for stochastic system identification in one dimension using published flow cytometry data on E.coli and report on identification results for equilibrium state and dynamic time series. In metabolic labelling experiments during yeast osmotic stress response, we find mRNA production and degradation to be strongly co-regulated...
2018: NPJ Systems Biology and Applications
Kaoru Ohashi, Masashi Fujii, Shinsuke Uda, Hiroyuki Kubota, Hisako Komada, Kazuhiko Sakaguchi, Wataru Ogawa, Shinya Kuroda
Insulin plays a central role in glucose homeostasis, and impairment of insulin action causes glucose intolerance and leads to type 2 diabetes mellitus (T2DM). A decrease in the transient peak and sustained increase of circulating insulin following an infusion of glucose accompany T2DM pathogenesis. However, the mechanism underlying this abnormal temporal pattern of circulating insulin concentration remains unknown. Here we show that changes in opposite direction of hepatic and peripheral insulin clearance characterize this abnormal temporal pattern of circulating insulin concentration observed in T2DM...
2018: NPJ Systems Biology and Applications
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning...
2018: NPJ Systems Biology and Applications
Marc Santolini, Milagros C Romay, Clara L Yukhtman, Christoph D Rau, Shuxun Ren, Jeffrey J Saucerman, Jessica J Wang, James N Weiss, Yibin Wang, Aldons J Lusis, Alain Karma
A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP)...
2018: NPJ Systems Biology and Applications
Jingqi Q X Gong, Eric A Sobie
Quantitative mismatches between human physiology and experimental models can be problematic for the development of effective therapeutics. When the effects of drugs on human adult cardiac electrophysiology are of interest, phenotypic differences with animal cells, and more recently stem cell-derived models, can present serious limitations. We addressed this issue through a combination of mechanistic mathematical modeling and statistical analyses. Physiological metrics were simulated in heterogeneous populations of models describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs)...
2018: NPJ Systems Biology and Applications
Henrik Cordes, Christoph Thiel, Vanessa Baier, Lars M Blank, Lars Kuepfer
Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism...
2018: NPJ Systems Biology and Applications
Sylvie Delhalle, Sebastian F N Bode, Rudi Balling, Markus Ollert, Feng Q He
Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics" data have been made especially in personalized oncology. However, immune cells relative to tumor cells show a much higher degree of complexity in heterogeneity, dynamics, memory-capability, plasticity and "social" interactions. There is still a long way ahead on translating our capability to identify potentially targetable personalized biomarkers into effective personalized therapy in immune-centralized diseases...
2018: NPJ Systems Biology and Applications
Friederike Langhauser, Ana I Casas, Vu-Thao-Vi Dao, Emre Guney, Jörg Menche, Eva Geuss, Pamela W M Kleikers, Manuela G López, Albert-L Barabási, Christoph Kleinschnitz, Harald H H W Schmidt
Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease-disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology...
2018: NPJ Systems Biology and Applications
Jorge Júlvez, Duygu Dikicioglu, Stephen G Oliver
Mathematical models that combine predictive accuracy with explanatory power are central to the progress of systems and synthetic biology, but the heterogeneity and incompleteness of biological data impede our ability to construct such models. Furthermore, the robustness displayed by many biological systems means that they have the flexibility to operate under a range of physiological conditions and this is difficult for many modeling formalisms to handle. Flexible nets (FNs) address these challenges and represent a paradigm shift in model-based analysis of biological systems...
2018: NPJ Systems Biology and Applications
Tyler Quarton, Kristina Ehrhardt, James Lee, Srijaa Kannan, Yi Li, Lan Ma, Leonidas Bleris
MicroRNAs are a class of short, noncoding RNAs that are ubiquitous modulators of gene expression, with roles in development, homeostasis, and disease. Engineered microRNAs are now frequently used as regulatory modules in synthetic biology. Moreover, synthetic gene circuits equipped with engineered microRNA targets with perfect complementarity to endogenous microRNAs establish an interface with the endogenous milieu at the single-cell level. The function of engineered microRNAs and sensor systems is typically optimized through extensive trial-and-error...
2018: NPJ Systems Biology and Applications
Maria Rita Fumagalli, Stefano Zapperi, Caterina A M La Porta
While almost all animals are able to at least partially replace some lost parts, regeneration abilities vary considerably across species. Here we study gene expression patterns in distantly related species to investigate conserved regeneration strategies. To this end, we collect from the literature transcriptomic data obtained during the regeneration of three species ( Hydra magnipapillata, Schmidtea mediterranea, and Apostichopus japonicus ), and compare them with gene expression during regeneration in vertebrates and mammals...
2018: NPJ Systems Biology and Applications
Ishan Ajmera, Jing Shi, Jitender Giri, Ping Wu, Dov J Stekel, Chungui Lu, T Charlie Hodgman
Phosphorus is a growth-limiting nutrient for plants. The growing scarcity of phosphate stocks threatens global food security. Phosphate-uptake regulation is so complex and incompletely known that attempts to improve phosphorus use efficiency have had extremely limited success. This study improves our understanding of the molecular mechanisms underlying phosphate uptake by investigating the transcriptional dynamics of two regulators: the Ubiquitin ligase PHO2 and the long non-coding RNA IPS1. Temporal measurements of RNA levels have been integrated into mechanistic mathematical models using advanced statistical techniques...
2018: NPJ Systems Biology and Applications
Guoshou Teo, Yun Bin Zhang, Christine Vogel, Hyungwon Choi
Simultaneous dynamic profiling of mRNA and protein expression is increasingly popular, and there is a critical need for algorithms to identify regulatory layers and time dependency of gene expression. A group of scientists from United States and Singapore present PECAplus, a comprehensive set of statistical analysis tools to address this challenge. Protein expression control analysis (PECA) computes the probability scores for change in mRNA and protein-level regulatory parameters at each time point, deconvoluting gene expression regulation in the presence of measurement noise...
2018: NPJ Systems Biology and Applications
Laura Cantini, Laurence Calzone, Loredana Martignetti, Mattias Rydenfelt, Nils Blüthgen, Emmanuel Barillot, Andrei Zinovyev
Gene signatures are more and more used to interpret results of omics data analyses but suffer from compositional (large overlap) and functional (correlated read-outs) redundancy. Moreover, many gene signatures rarely come out as significant in statistical tests. Based on pan-cancer data analysis, we construct a restricted set of 962 signatures defined as informative and demonstrate that they have a higher probability to appear enriched in comparative cancer studies. We show that the majority of informative signatures conserve their weights for the genes composing the signature (eigengenes) from one cancer type to another...
2018: NPJ Systems Biology and Applications
Jared C Weddell, Si Chen, P I Imoukhuede
The ability to control vascular endothelial growth factor (VEGF) signaling offers promising therapeutic potential for vascular diseases and cancer. Despite this promise, VEGF-targeted therapies are not clinically effective for many pathologies, such as breast cancer. VEGFR1 has recently emerged as a predictive biomarker for anti-VEGF efficacy, implying a functional VEGFR1 role beyond its classically defined decoy receptor status. Here we introduce a computational approach that accurately predicts cellular responses elicited via VEGFR1 signaling...
2018: NPJ Systems Biology and Applications
Dezső Módos, Krishna C Bulusu, Dávid Fazekas, János Kubisch, Johanne Brooks, István Marczell, Péter M Szabó, Tibor Vellai, Péter Csermely, Katalin Lenti, Andreas Bender, Tamás Korcsmáros
Even targeted chemotherapies against solid cancers show a moderate success increasing the need to novel targeting strategies. To address this problem, we designed a systems-level approach investigating the neighbourhood of mutated or differentially expressed cancer-related proteins in four major solid cancers (colon, breast, liver and lung). Using signalling and protein-protein interaction network resources integrated with mutational and expression datasets, we analysed the properties of the direct and indirect interactors (first and second neighbours) of cancer-related proteins, not found previously related to the given cancer type...
January 24, 2017: NPJ Systems Biology and Applications
Adriana Lucía-Sanz, Susanna Manrubia
Multipartitism counts amongst the weirdest lifestyles found in the virosphere. Multipartite viruses have genomes segmented in pieces enclosed in different capsids that are independently transmitted. Since all segments have to meet in the host for complementation and completion of the viral cycle, multipartite viruses are bound to fight the loss of genomic information. While this is an obvious disadvantage of this strategy, no consensus on its actual advantages has been reached. In this review we present an exhaustive summary of all multipartite viruses described to date...
2017: NPJ Systems Biology and Applications
Christian V Forst, Bin Zhou, Minghui Wang, Tsui-Wen Chou, Guy Mason, Won-Min Song, Eric Schadt, Elodie Ghedin, Bin Zhang
Influenza A virus, with the limited coding capacity of 10-14 proteins, requires the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only reveals molecular pathways exploited by the virus or triggered by the immune system, but also provides further targets for antiviral drug development. To uncover novel pathways and key targets of influenza infection, we assembled a large amount of data from 12 cell-based gene-expression studies of influenza infection for an integrative network analysis...
2017: NPJ Systems Biology and Applications
Anirikh Chakrabarti, Mathieu Membrez, Delphine Morin-Rivron, Jay Siddharth, Chieh Jason Chou, Hugues Henry, Stephen Bruce, Sylviane Metairon, Frederic Raymond, Bertrand Betrisey, Carole Loyer, Scott J Parkinson, Mojgan Masoodi
The gut microbiome and lipid metabolism are both recognized as essential components in the maintenance of metabolic health. The mechanisms involved are multifactorial and (especially for microbiome) poorly defined. A strategic approach to investigate the complexity of the microbial influence on lipid metabolism would facilitate determination of relevant molecular mechanisms for microbiome-targeted therapeutics. E. coli is associated with obesity and metabolic syndrome and we used this association in conjunction with gnotobiotic models to investigate the impact of E...
2017: NPJ Systems Biology and Applications
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