Contribution of a mathematical modelling approach to the understanding of the ovarian function

The biological meaning of folliculogenesis is to free fertilisable oocytes at the time of ovulation. We approached the study of the control of follicular development at the level of follicular granulosa cells, on the experimental as well as mathematical modelling grounds. We built a mathematical model allowing for the processes of proliferation, differentiation and apoptosis. State variables correspond to the numbers of cells undergoing these different processes, while control variables correspond to the cellular transition rates. The model results raised the notion of proliferative resources, which leads to consider the optimal management of these resources and has motivated the settling of an experiment investigating the changes in the growth fraction within the granulosa throughout terminal development. We are now investigating the way gonadotrophins, and especially FSH, operate on granulosa cells, in order to account for the hormonal control of the divergent commitment of granulosa cells towards either proliferation, differentiation or apoptosis. We are thus focusing on the dynamics of cAMP production, which appears to be a keypoint in FSH signal transduction.     

An agent-based model of sleeping sickness: simulation trials of a forest focus in southern Cameroon

An agent-based model (AMB) used to simulate the spread of Human African Trypanosomiasis is presented together with the results of simulations of a focus of the disease. This model is a completely spatialized approach taking into account a series of often overlooked parameters such as human behaviour (activity-related movements), the density and mobility of the disease vectors--tsetse flies (Glossina spp.)--and the influence of other tsetse feeding hosts (livestock and wild animal populations). The agents that represent humans and tsetse flies move in a spatially structured environment managed by specialized location agents. Existing compartmental mathematical models governed by differential equations fail to incorporate the spatial dimension of the disease transmission. Furthermore, on a small scale, transmission is unrealistically represented by entities less than one. This ABM was tested with data from one village of the Bipindi sleeping sickness focus (southern Cameroon) and with obtained realistic simulations of stable transmission involving an animal reservoir. In varying different spatial configurations, we observe that the stability of spread is linked to the spatial complexity (number of heterogeneous locations). The prevalence is very sensitive to the human densities and to the number of tsetse flies initially infected in a given location. A relatively low and durable prevalence is obtained with shortening the phase I. In addition, we discuss some upgrading possibilities, in particular the linkage to a Geographical Information System (GIS). The agent-based approach offers new ways to understanding the spread of the disease and a tool to evaluate risk and test control strategies.     

In silico prediction and validation of the importance of the Entner-Doudoroff pathway in poly(3-hydroxybutyrate) production by metabolically engineered Escherichia coli

The metabolic network of Escherichia coli was constructed and was used to simulate the distribution of metabolic fluxes in wild-type E. coli and recombinant E. coli producing poly(3-hydroxybutyrate) [P(3HB)]. The flux of acetyl-CoA into the tricarboxylic acid (TCA) cycle, which competes with the P(3HB) biosynthesis pathway, decreased significantly during P(3HB) production. It was notable to find from in silico analysis that the Entner-Doudoroff (ED) pathway flux increased significantly under P(3HB)-accumulating conditions. To prove the role of ED pathway on P(3HB) production, a mutant E. coli strain, KEDA, which is defective in the activity of 2-keto-3-deoxy-6-phosphogluconate aldolase (Eda), was examined as a host strain for the production of P(3HB) by transforming it with pJC4, a plasmid containing the Alcaligenes latus P(3HB) biosynthesis operon. The P(3HB) content obtained with KEDA (pJC4) was lower than that obtained with its parent strain KS272 (pJC4). The reduced P(3HB) biosynthetic capacity of KEDA (pJC4) could be restored by the co-expression of the E. coli eda gene, which proves the important role of ED pathway on P(3HB) synthesis in recombinant E. coli as predicted by metabolic flux analysis.