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author:("Zou, jiufeng")
1.  The linear interplay of intrinsic and extrinsic noises ensures a high accuracy of cell fate selection in budding yeast 
Scientific Reports  2014;4:5764.
To gain insights into the mechanisms of cell fate decision in a noisy environment, the effects of intrinsic and extrinsic noises on cell fate are explored at the single cell level. Specifically, we theoretically define the impulse of Cln1/2 as an indication of cell fates. The strong dependence between the impulse of Cln1/2 and cell fates is exhibited. Based on the simulation results, we illustrate that increasing intrinsic fluctuations causes the parallel shift of the separation ratio of Whi5P but that increasing extrinsic fluctuations leads to the mixture of different cell fates. Our quantitative study also suggests that the strengths of intrinsic and extrinsic noises around an approximate linear model can ensure a high accuracy of cell fate selection. Furthermore, this study demonstrates that the selection of cell fates is an entropy-decreasing process. In addition, we reveal that cell fates are significantly correlated with the range of entropy decreases.
PMCID: PMC4104398  PMID: 25042292
2.  Characterizing and controlling the inflammatory network during influenza A virus infection 
Scientific Reports  2014;4:3799.
To gain insights into the pathogenesis of influenza A virus (IAV) infections, this study focused on characterizing the inflammatory network and identifying key proteins by combining high-throughput data and computational techniques. We constructed the cell-specific normal and inflammatory networks for H5N1 and H1N1 infections through integrating high-throughput data. We demonstrated that better discrimination between normal and inflammatory networks by network entropy than by other topological metrics. Moreover, we identified different dynamical interactions among TLR2, IL-1β, IL10 and NFκB between normal and inflammatory networks using optimization algorithm. In particular, good robustness and multistability of inflammatory sub-networks were discovered. Furthermore, we identified a complex, TNFSF10/HDAC4/HDAC5, which may play important roles in controlling inflammation, and demonstrated that changes in network entropy of this complex negatively correlated to those of three proteins: TNFα, NFκB and COX-2. These findings provide significant hypotheses for further exploring the molecular mechanisms of infectious diseases and developing control strategies.
PMCID: PMC3896911  PMID: 24445954
3.  Construction of the influenza A virus infection-induced cell-specific inflammatory regulatory network based on mutual information and optimization 
BMC Systems Biology  2013;7:105.
Influenza A virus (IAV) infection-induced inflammatory regulatory networks (IRNs) are extremely complex and dynamic. Specific biological experiments for investigating the interactions between individual inflammatory factors cannot provide a detailed and insightful multidimensional view of IRNs. Recently, data from high-throughput technologies have permitted system-level analyses. The construction of large and cell-specific IRNs from high-throughput data is essential to understanding the pathogenesis of IAV infection.
In this study, we proposed a computational method, which combines nonlinear ordinary differential equation (ODE)-based optimization with mutual information, to construct a cell-specific optimized IRN during IAV infection by integrating gene expression data with a prior knowledge of network topology. Moreover, we used the average relative error and sensitivity analysis to evaluate the effectiveness of our proposed approach. Furthermore, from the optimized IRN, we confirmed 45 interactions between proteins in biological experiments and identified 37 new regulatory interactions and 8 false positive interactions, including the following interactions: IL1β regulates TLR3, TLR3 regulates IFN-β and TNF regulates IL6. Most of these regulatory interactions are statistically significant by Z-statistic. The functional annotations of the optimized IRN demonstrated clearly that the defense response, immune response, response to wounding and regulation of cytokine production are the pivotal processes of IAV-induced inflammatory response. The pathway analysis results from the Kyoto Encyclopaedia of Genes and Genomes (KEGG) showed that 8 pathways are enriched significantly. The 5 pathways were validated by experiments, and 3 other pathways, including the intestinal immune network for IgA production, the cytosolic DNA-sensing pathway and the allograft rejection pathway, are the predicted novel pathways involved in the inflammatory response.
Integration of knowledge-driven and data-driven methods allows us to construct an effective IRN during IAV infection. Based on the constructed network, we have identified new interactions among inflammatory factors and biological pathways. These findings provide new insight into our understanding of the molecular mechanisms in the inflammatory network in response to IAV infection. Further characterization and experimental validation of the interaction mechanisms identified from this study may lead to a novel therapeutic strategy for the control of infections and inflammatory responses.
PMCID: PMC4016583  PMID: 24138989
4.  Modeling and Dynamical Analysis of Virus-Triggered Innate Immune Signaling Pathways 
PLoS ONE  2012;7(10):e48114.
The investigation of the dynamics and regulation of virus-triggered innate immune signaling pathways at a system level will enable comprehensive analysis of the complex interactions that maintain the delicate balance between resistance to infection and viral disease. In this study, we developed a delayed mathematical model to describe the virus-induced interferon (IFN) signaling process by considering several key players in the innate immune response. Using dynamic analysis and numerical simulation, we evaluated the following predictions regarding the antiviral responses: (1) When the replication ratio of virus is less than 1, the infectious virus will be eliminated by the immune system’s defenses regardless of how the time delays are changed. (2) The IFN positive feedback regulation enhances the stability of the innate immune response and causes the immune system to present the bistability phenomenon. (3) The appropriate duration of viral replication and IFN feedback processes stabilizes the innate immune response. The predictions from the model were confirmed by monitoring the virus titer and IFN expression in infected cells. The results suggest that the balance between viral replication and IFN-induced feedback regulation coordinates the dynamical behavior of virus-triggered signaling and antiviral responses. This work will help clarify the mechanisms of the virus-induced innate immune response at a system level and provide instruction for further biological experiments.
PMCID: PMC3484162  PMID: 23118935
5.  Synchronization ability of coupled cell-cycle oscillators in changing environments 
BMC Systems Biology  2012;6(Suppl 1):S13.
The biochemical oscillator that controls periodic events during the Xenopus embryonic cell cycle is centered on the activity of CDKs, and the cell cycle is driven by a protein circuit that is centered on the cyclin-dependent protein kinase CDK1 and the anaphase-promoting complex (APC). Many studies have been conducted to confirm that the interactions in the cell cycle can produce oscillations and predict behaviors such as synchronization, but much less is known about how the various elaborations and collective behavior of the basic oscillators can affect the robustness of the system. Therefore, in this study, we investigate and model a multi-cell system of the Xenopus embryonic cell cycle oscillators that are coupled through a common complex protein, and then analyze their synchronization ability under four different external stimuli, including a constant input signal, a square-wave periodic signal, a sinusoidal signal and a noise signal.
Through bifurcation analysis and numerical simulations, we obtain synchronization intervals of the sensitive parameters in the individual oscillator and the coupling parameters in the coupled oscillators. Then, we analyze the effects of these parameters on the synchronization period and amplitude, and find interesting phenomena, e.g., there are two synchronization intervals with activation coefficient in the Hill function of the activated CDK1 that activates the Plk1, and different synchronization intervals have distinct influences on the synchronization period and amplitude. To quantify the speediness and robustness of the synchronization, we use two quantities, the synchronization time and the robustness index, to evaluate the synchronization ability. More interestingly, we find that the coupled system has an optimal signal strength that maximizes the synchronization index under different external stimuli. Simulation results also show that the ability and robustness of the synchronization for the square-wave periodic signal of cyclin synthesis is strongest in comparison to the other three different signals.
These results suggest that the reaction process in which the activated cyclin-CDK1 activates the Plk1 has a very important influence on the synchronization ability of the coupled system, and the square-wave periodic signal of cyclin synthesis is more conducive to the synchronization and robustness of the coupled cell-cycle oscillators. Our study provides insight into the internal mechanisms of the cell cycle system and helps to generate hypotheses for further research.
PMCID: PMC3403058  PMID: 23046815
6.  A theoretical framework for specificity in cell signaling 
Molecular Systems Biology  2005;1:2005.0023.
Different cellular signal transduction pathways are often interconnected, so that the potential for undesirable crosstalk between pathways exists. Nevertheless, signaling networks have evolved that maintain specificity from signal to cellular response. Here, we develop a framework for the analysis of networks containing two or more interconnected signaling pathways. We define two properties, specificity and fidelity, that all pathways in a network must possess in order to avoid paradoxical situations where one pathway activates another pathway's output, or responds to another pathway's input, more than its own. In unembellished networks that share components, it is impossible for all pathways to have both mutual specificity and mutual fidelity. However, inclusion of either of two related insulating mechanisms—compartmentalization or the action of a scaffold protein—allows both properties to be achieved, provided deactivation rates are fast compared to exchange rates.
PMCID: PMC1681467  PMID: 16729058
protein kinase; mathematical model; network; scaffold; signal transduction

Results 1-6 (6)