Section: Research Program

Stochastic modeling for complex and biological systems

Participants: R. Azaïs, T. Bastogne, C. Lacaux, A. Muller-Gueudin, S. Tindel, P. Vallois, S. Wantz-Mézières

In most biological contexts, mathematics turn out to be useful in producing accurate models with dual objectives: they should be simple enough and meaningful for the biologist on the one hand, and they should provide some insight on the biological phenomenon at stake on the other hand. We have focused on this kind of issue in various contexts that we shall summarize below.

Photodynamic Therapy: Photodynamic therapy induces a huge demand of interconnected mathematical systems, among which we have studied recently the following ones:

$•$ The tumor growth model is of crucial importance in order to understand the behavior of the whole therapy. We have considered the tumor growth as a stochastic equation, for which we have handled the problem uncertainties on the measure times [27] as well as mixed effects for parameter estimation.

$•$ Another important aspect to quantify for photodynamic therapy calibration is the response to radiotherapy treatments. There are several valid mathematical ways to describe this process, among which we distinguish the so-called hit model. This model assumes that whenever a group of sensitive targets (chromosomes, membrane) in the cell are reached by a sufficient number of radiations, then the cell is inactivated and dies. We have elaborated on this scheme in order to take into account two additional facts: (i) The reduction of the cell situation to a two-state model might be an oversimplification. (ii) Several doses of radiations are inoculated as time passes. These observations have lead us to introduce a new model based on multi-state Markov chains arguments (Keinj & al, 2012), in which cell proliferation can be incorporated.

Bacteriophage therapy: Let us mention a starting collaboration between BIGS and the Genetics and Microbiology department at the Universitat Autònoma de Barcelona, on the modeling of bacteriophage therapies. The main objective here is to describe how a certain family of benign viruses is able to weaken a bacterium induced disease, which naturally leads to the introduction of a noisy predator-prey system of equations. It should be mentioned that some similar problems have been treated (in a rather informal way, invoking a linearization procedure) by Carletti in [34] . These tools cannot be applied directly to our system, and our methods are based on concentration and large deviations techniques (on which we already had an expertise [57] , [60] ) in order to combine convergence to equilibrium for the deterministic system and deviations of the stochastic system. Notice that A. Muller-Gueudin is also working with A. Debussche and O. Radulescu on a related topic  [37] , namely the convergence of a model of cellular biochemical reactions.

Gaussian signals: Nature provides us with many examples of systems such that the observed signal has a given Hölder regularity, which does not correspond to the one we might expect from a system driven by ordinary Brownian motion. This situation is commonly handled by noisy equations driven by Gaussian processes such as fractional Brownian motion or (in higher dimensions of the parameter) fractional fields.

The basic aspects of differential equations driven by a fractional Brownian motion (fBm) and other Gaussian processes are now well understood, mainly thanks to the so-called rough paths tools [52] , but also invoking the Russo-Vallois integration techniques [59] . The specific issue of Volterra equations driven by fBm, which is central for the subdiffusion within proteins problem, is addressed in [38] .

Fractional fields are very often used to model irregular phenomena which exhibit a scale invariance property, fractional Brownian motion being the historical fractional model. Nevertheless, its isotropy property is a serious drawback for instance in hydrology or in medecine (see [33] ). Moreover, the fractional Brownian motion cannot be used to model some phenomena for which the regularity varies with time. Hence, many generalizations (Gaussian or not) of this model have been recently proposed, see for instance [28] for some Gaussian locally self-similar fields, [46] for some non-Gaussian models, [31] for anisotropic models.

Our team has thus contributed [36] , [47] , [46] , [48] , [58] and still contributes [30] , [32] , [31] , [49] , [44] to this theoretical study: Hölder continuity, fractal dimensions, existence and uniqueness results for differential equations, study of the laws to quote a few examples. As we shall see below, this line of investigation also has some impact in terms of applications: we shall discuss how we plan to apply our results to osteoporosis on the one hand and to fluctuations within protein molecules on the other hand.