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Alternative splicing makes significant contributions to functional diversity of transcripts and proteins. Many alternatively spliced gene isoforms have been shown to perform specific biological functions under different contexts. In addition to gene-level expression, the advances of high-throughput sequencing offer a chance to estimate isoform-specific exon expression with a high resolution, which is informative for studying splice variants with network analysis. In this study, we propose a novel network-based analysis framework to predict isoform-specific functions from exon-level RNA-Seq data. In particular, based on exon-level expression data, we firstly propose a unified framework, referred to as Iso-Net , to integrate two new mathematical methods (named MINet and RVNet) that infer co-expression networks at different data scenarios. We demonstrate the superior prediction accuracy of Iso-Net over the existing methods for most simulation data, especially in two extreme cases: sample size is very small and exon numbers of two isoforms are quite different. Furthermore, by defining relevant quantitative measures (e.g., Jaccard correlation coefficient) and combining differential co-expression network analysis and GO functional enrichment analysis, a co-expression network analysis framework is developed to predict functions of isoforms and further, to discover their distinct functions within the same gene. We apply Iso-Net to study gene isoforms for several important transcription factors in human myeloid differentiation with the exon-level RNA-Seq data from three different cell lines. Iso-Net is open source and freely available from https://github.com/Dingjie-Wang/Iso-Net. [ABSTRACT FROM AUTHOR]

Abstract: The interferon system provides a powerful and universal intracellular defense mechanism against viruses. As one part of their survival strategies, many viruses have evolved mechanisms to counteract the host type I interferon (IFN-α/β) responses. In this study, we attempt to investigate virus- and double-strand RNA (dsRNA)-triggered type I IFN signaling pathways and understand the inhibition of IFN-α/β induction by viral proteins using mathematical modeling and quantitative analysis. Based on available literature and our experimental data, we develop a mathematical model of virus- and dsRNA-triggered signaling pathways leading to type I IFN gene expression during the primary response, and use the genetic algorithm to optimize all rate constants in the model. The consistency between numerical simulation results and biological experimental data demonstrates that our model is reasonable. Further, we use the model to predict the following phenomena: (1) the dose-dependent inhibition by classical swine fever virus (CSFV) Npro or Erns protein is observed at a low dose and can reach a saturation above a certain dose, not an increase; (2) Erns and Npro have no synergic inhibitory effects on IFN-β induction; (3) the different characters in an important transcription factor, phosphorylated IRF3 (IRF3p), are exhibited because Npro or Erns counteracted dsRNA- and virus-triggered IFN-β induction by targeting the different molecules in the signaling pathways and (4) Npro inhibits the IFN-β expression not only by interacting with IFR3 but also by affecting its complex with MITA. Our approaches help to gain insight into system properties and rational therapy design, as well as to generate hypotheses for further research. [Copyright &y& Elsevier]

Abstract: Cells sense several kinds of stimuli and trigger corresponding responses through signaling pathways. As a result, cells must process and integrate multiple signals in parallel to maintain specificity and avoid erroneous cross-talk. In this study, we focus our theoretical effort on understanding specificity of a model network system in yeast, Saccharomyces cerevisiae, which contains three mitogen-activated protein kinase (MAPK) signal transduction cascades that share multiple signaling components. The cellular response to the pheromone, the filamentous growth and osmotic pressure stimuli in yeast is described and an integrative mathematical model for the three MAPK cascades is developed using available literature and experimental data. The theoretical framework for analyzing the specificity of signaling networks [Bardwell, L., Zou, X.F., Nie, Q., Komarova, N.L., 2007. Mathematical models of specificity in cell signaling. Biophys. J. 92, 3425–3441] is extended to include multiple interacting pathways with shared components. Simulations are also performed with any one stimulus, with any two simultaneous stimuli, and with the simultaneous application of the three stimuli. The interactions between the three pathways are systematically investigated. Moreover, the specificity and fidelity of this model system are calculated using our newly developed concept under different stimuli or with specific mutants. Our simulated and calculated results demonstrate that the yeast MAPK signaling network can achieve specificity and fidelity by filtering out spurious cross-talk between the relevant pathways through different mechanisms, such as scaffolding, cross-inhibiting, and feedback control. Proof that Pbs2 and Hog1 are essential for the maintenance of signaling specificity is presented. Our studies provide novel insights into integration of relevant signaling pathways in a biological system and the mechanisms conferring specificity in cellular signaling networks. [Copyright &y& Elsevier]

Owing to the heterogeneity in the evolution of cancer, distinguishing between diverse growth patterns and predicting long-term outcomes based on short-term measurements poses a great challenge. A novel multiscale framework is proposed to unravel the connections between the population dynamics of cancer growth (i.e., aggressive, bounded, and indolent) and the cellular-subclonal dynamics of cancer evolution. This framework employs the non-negative lasso (NN-LASSO) algorithm to forge a link between an ordinary differential equation (ODE)-based population model and a cellular evolution model. The findings of our current work not only affirm the impact of subclonal composition on growth dynamics but also identify two significant subclones within heterogeneous growth patterns. Moreover, the subclonal compositions at the initial time are able to accurately discriminate diverse growth patterns through a machine learning algorithm. The proposed multiscale framework successfully delineates the intricate landscape of cancer evolution, bridging the gap between long-term growth dynamics and short-term measurements, both in simulated and real-world data. This methodology provides a novel avenue for thorough exploration into the realm of cancer evolution. [Display omitted] • A mathematical framework to link the population dynamics and the subclonal dynamics. • The predicted evolutionary landscape reveals the importance of subclonal composition. • Short-term measurements prove effective in predicting long-term growth patterns. [ABSTRACT FROM AUTHOR]