Section: New Results

Systems Biology

Systems Biology includes the study of interaction networks such as gene regulatory, metabolic, or signaling networks. It involves both designing the topology of the networks and predicting their dynamic and spatiotemporal aspects. It requires the import of concepts from across various disciplines and crosstalk between theory, benchwork, modelling and simulation.

Topological analysis of metabolic networks

In [73] we have developed a biclustering algorithm for elementary flux modes that is based on the Agglomeration of Common Motifs (ACoM). This allows a drastic diminution of the number of less significant fluxes and a kind of factorization of most important fluxes, yielding an algorithm running in quadratic time in the number of elementary flux modes.

We applied this algorithm to describe the decomposition into elementary flux modes of the central carbon metabolism in Bacillus subtilis and of the yeast mitochondrial energy metabolism. For Bacillus subtilis, a specific inhibition on the second domain of the lipoamide dehydrogenase (pdhD) component of pyruvate dehydrogenase complex that leads to the loss of all fluxes was exhibited [20] . Such a conclusion is not predictable in the classical approach.

Evolution of metabolic networks

A collaboration with Igm on the evolution of metabolic networks is ungoing. We aim at understanding how such networks would emerge over time among the variety of species, and how these changes could be responsible for characteristic life traits. Our methodology to characterize the evolutionary origin of the enzymatic repertoire of different fungal groups relies on machine learning. Preliminary results were presented at Jobim 2013   [35] .

Signaling networks

Our goal is to help the understanding of signaling pathways involving (GPCR) and to provide means to semi-automatically construct the signaling networks. Our method takes into account various kinds of biological experiments and their origin and automatically builds and draws the inferred network. Comparing the automatically deduced network with an already known fragment of the FSHR network allowed us to obtain new interesting hypotheses that are currently experimentally tested by biologists, our collaborators from Inra-Bios in Tours. In the next months, experimental data for some GPCR (FSH, 5HT2 et 5HT4) will be prepared by Bios and Igf (Montpellier), in the context of a GPCRnet ANR project.

Besides, in collaboration with K. Inoue, through the NII International Internship Program, we have studied the System Biology Graphical Notation language, a standard for expressing molecular networks, especially signaling networks, and proposed a translation of SBGN-AF into a logical formalism [31] .

Modelling with Hsim

In a collaboration of P. Amar with microbiologists, the group of Marie-Joëlle Virolle from the Institut de Génétique et de Microbiologie, a first explicative model was proposed for the sigmoidicity of the shape of the survival curve of bacteria (S. lividans) having a antibiotic resistance gene, expressed at different levels, in presence of a constant concentration of antibiotics [24] , [6] , [18] , [41] .

This is particularly important since this method of inclusion of an antibiotics resistance gene to report the activity of its promoter is widely used in the streptomyces community.

Cancer and metabolism

It is shown in M. Behzadi's PhD thesis that most systems have very stable behaviours and that even large variations of their chemical characteristics do not affect the nature of the equilibria. This very general situation has been discovered by simulation but in some cases it is even possible to prove it mathematically.

Our collaborators M. Israël and L. Schwartz have listed more than a hundred tentative such bifurcations that we intend to study systematically. A preliminary study of the mitotic cycle with L. Paulevé has also put in evidence the strong influence of the pH of the cell on its capacity to duplicate. The PhD thesis of E. Bigan, co-directed by S. Daoudi (Univ. Denis Diderot) and J.-M. Steyaert investigates the generic properties of such complex systems and confirms that the ones we have already studied are not exceptions [43] . Some prospective cases are studied in [14] .