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Section: New Results

Time-series and asymptotic dynamics

Participants : Anne Siegel, Jérémie Bourdon, Jeanne Cambefort, Damien Eveillard, Vincent Picard, Nathalie Théret, Santiago Videla.

Reasoning on the response of logical signaling networks with boolean models A series of papers and a PhD thesis focused on modeling the response of logical signaling networks by means of automated reasoning using ASP. In this context, a crucial issue is automatic learning of logical networks from partial observations of input/output behaviours, in order to achieve unbiased and robust discoveries. Experiments showed that many networks can be compatible with a given set of experimental observations. In a review chapter, we first discuss how ASP can be used to exhaustively enumerate all these logical networks. Next, in order to gain control over the system, we look for intervention strategies that force a set of target species into a desired steady state. Finally, we discuss the usage of ASP for solving the aforementioned problems and the novelty of our approach with respect to existing methods. [S. Videla, A. Siegel, J. Nicolas] [23] , [38] , [12] [Online publication]

Integrative modeling framework for signaling networks based on guarded transitions models We develop a new non-ambiguous formal interpretation of signaling pathways as discrete dynamic models. The resulting language, Computer-Aided Design for BIOlogical Models (CADBIOM), is based on a simplified version of guarded transitions in which we introduced temporal parameters for each transition to manage competition and cooperation between parts of the models . Tools for simulation and model checking analyses using the formal Cadbiom language have been developed (http://cadbiom.genouest.org). Using CADBIOM, we built the first discrete model of TGF-β signaling networks by automatically integrating the 137 human signaling maps from the Pathway Interaction Database into a single unified dynamic model. Temporal property-checking analyses of 15934 trajectories that regulate 145 TGF-beta target genes reveal the association of specific pathways with distinct biological processes. [G Andrieux, M Le Borgne, N. Théret] [15] [Online publication]

Exploring metabolism flexibility in complex organisms through quantitative study of precursor sets for system outputs We extended a Flux-Balanced-Analysis approach to quantify the precursor composition of each system output and to discuss the biological relevance of a set of flux in a given metabolic network. The composition is called contribution of inputs over outputs [AIO]. In order to further investigate metabolic network flexibility, we have proposed an efficient local search algorithm computing the extremal values of AIO coefficients. This approach enables to discriminate diets without making any assumption on the internal behaviour of the system. [O. Abdou-Arbi, J. Bourdon, A. Siegel] [14] [Online publication]

Multivariate Normal Approximation for the Stochastic Simulation Algorithm: limit theorem and applications We prove a central limit theorem on the asymptotic stochastic dynamical behavior of the outputs of a reaction network under certain steady-state assumptions. We present multiple applications including a constraints-based approach to verify asymptotic properties on the output moments without prior knowledge about the kinetic parameters. [V. Picard, A. Siegel, J. Bourdon] [33] [Online publication]

Numeric model for initiation of translation in sea-urchin We use a numeric-based modeling approach to study the regulation of protein synthesis following fertilization in sea urchin. This approach based on parcimonious modelling evidenced that two processes are required to explain experimental data: a destabilization of eIF4E:4E-BP complex and a great stimulation of the 4E-BP-degradation mechanism, both rapamycin-sensitive [A. Siegel, J. Bourdon] [21] [Online publication]