Fas (CD95/Apo-1) is a major apoptosis regulator that, in some cellular context, can also signal proliferation and survival pathways. Thus the control of Fas signalling plasticity is central to the balance of life and death decision of the cell, and understanding this issue is crucial for the development of cancer treatment strategies. In colorectal cancer (CRC), the malignant cells frequently coexpress Fas and its ligand (FasL) but often have a markedly reduced susceptibility to FasL-induced, Fas-mediated apoptosis and Fas-induced signalling by FasL can activate proteins that promote survival and proliferative functions in CRC cells that are resistant to Fas-induced cell death. Thus far the mechanisms of the resistance to Fas-mediated apoptosis and the contribution of Fas-mediated survival pathway in CRC remain unclear. Increasing evidence has suggested role of posttranslational modifications and membrane dynamics of Fas in the control of its signalling mode and cancer etiology. We hypothesize that the membrane dynamics and posttranslational modifications of Fas (Palmitoylation/nitrosylation and glycosylation/phosphorylation) are key factors in determining its life/death signalling balance in CRC, and thus the therapeutic responses. We will study the integrated mechanisms of Fas membrane dynamics and posttranslational modifications in the control of its signaling in CRC, with respect to the response to the neoadjuvant and/or first line radiotherapy (RT) -/+ chemotherapy (CT) regimen to ultimately identify potential targets, predictive factors, and physiopathologic markers that will aid the design of well-targeted therapeutic strategies. Specifically we will: ?Assessing the Fas non cell death pathways in CRC cells (Task 1) ?Dissecting the molecular events (constitutive and FasL-induced) involved in Fas early signalling with two mains axis: the regulation of membrane dynamics and the post translational modifications (Task 2), with a special interest to the intracellular proximal membrane region (Task3) The studies will be carried out using CRC cell lines, primary cells, biopsy tissues. We will employ various approaches in cellular and molecular biology, biophysics, biochemistry, and genetics to elucidate the integrated mechanisms of Fas membrane dynamics and posttranslational modifications in the control of its signaling in CRC. Studying the roles of Fas membrane dynamics, phosphorylation, glycosylation, palmitoylation/nitrosylation and the actors involved, we expect a clear picture of the relationship among Fas modifications that explains its behaviour, signalling events, and cellular responses. This will provide more targets in Fas signalling pathway for the design of therapeutic strategies. Studying the posttranslational modifications in biopsy tissues will allow the identification of modification sites and patterns. This may lead to the use of these modifications as predictive/physiopathologic markers for treatments and delineate the pathways involved that will allow the identification of targets for development of treatments with improved specificity. And by investigating genetic alterations in CRC tissues, we expect to identify genetic components of Fas membrane dynamics and posttranslational modifications and to obtain pharmacogenetics information of Fas as predictive and/or physiopathologic markers for the treatments of CRC

Among materials that have been exploited over time, natural substances are probably the most challenging to study. Issued from organic biomaterials such as resins, beeswax, animal fats or vegetal oils, they are preserved at low amount as amorphous organic residues and are often difficult to detect at the archaeological field. They give evidence for the use of animal, plant and fossil products that were of great importance for various aspects of human life, including diet, medicine, funerary rituals, economic and technical activities. Because they lack recognisable morphological attributes, the only way to determine their nature and origin relies on the development of analytical strategies that allow elucidation of their chemical composition. This proposal is focused on the study of the exploitation of fresh and fossil plant exsudates and tars. All these substances share common features in the field of archaeology and chemistry: they are made of complex molecular mixtures, they contain terpenoid components, they are often preserved at low amount and they were used for common purposes (hafting lithic and bone tools; mending, decorating or waterproofing ceramic vessels, etc.). In some cases, these materials were mixed with various adjuvants such as beeswax, vegetal oils, animal fats, clay, ochre, …, that will also be considered in this project. Surprisingly, despite the first interest of researchers for bitumen, vegetal resins and tars as early as the 19th century, no systematic study was carried out on such materials. While these substances are of prime importance in ancient societies due to their role in subsistence strategies, medicine and rituals, only partial and occasional data are thus available. This is why we decided to develop the present interdisciplinary research programme based upon complementary approaches including archaeology, analytical chemistry and archaeobotany. At this stage of the research, it would be a non-sense to focus on a narrow chronological and / or geographic area. Indeed, the study of such remains is still quite young and before developing detailed research on specific points, we first need to gain an overview of the sites in which plant amorphous remains are preserved and, of the diversity of materials exploited. We will first proceed to the inventory of samples issued from a large geo-chronological zone, from western Europe to eastern mediterranean region, from Neolithic to recent periods, and we will then focus on geo-chronological windows for which numerous series of samples are available and specific archaeological questions have to be addressed. Our purpose is to better understand the socio-economic systems of production, from acquisition to utilisations, of fresh and fossil plant exudates / tars and their evolution over time. The putative causes of this evolution will also be considered (climatic changes, cultural evolution, change of trade/exchange networks, etc.), as well as strategies of plant management. The most striking aspect of this project is the development of a multi-sided methodology that allows overcoming the physico-chemical characterisation of the materials studied to reach socio-economic information on the systems of exploitation of plant substances over time, by combining chemical and archaeobotanical data. At the end of this project, we hope that we could pass from a fragmentary knowledge to an extended overview of plant exudates and tars exploitation. The choice of diachronic study will highlight the continuity and discontinuity of use of the materials identified and the evolution of their modes of production.

SCIENTIFIC DESCRIPTION OF THE PROJECT STATFLOW 1 Introduction The description of the large-scale structures of turbulent flows is of wide practical and fundamental interest, in many domains of fluid mechanics. For instance, the knowledge of the evolution of the large-scale atmosphere and ocean, is both a fascinating scientific issue and a very important problem for understanding climate change. A statistical description of the large-scale organization of conservative two-dimensionnal and geophysical flows has been described by the equilibrium Robert-Sommeria-Miller (RSM) theory [Miller-90, Robert-Sommeria-91]. This theory does not consider any forcing. However, when a weak forcing and dissipation is added, a situation relevant for any physical applications, the forcing is known to select the large-scale structures. The aim of this project is to consider a probabilistic description of the large scales for the 2-D Navier-Stokes with weak forcing. In particular, we want to systematically relate the forcing to the observed large-scale structures, and the possible links with the RSM equilibria. Ideally, one would like to obtain a probabilistic description of the flow, starting from the equations of fluid mechanics. This represents one of the most complex and fascinating unsolved problem faced by science, and it still appears out of reach in general. For instance, the description of the velocity increments statistics in 3-D turbulent flows is one of the greatest problem of physics [Frisch], still to be understood theoretically. For simpler problems in turbulence, progress have been achieved, in the direction of a probabilistic description, starting from the fluid equation, for instance using the Kraichnan model [Gawedski] of a passive scalar advected by a delta-correlated velocity. Another example is the computation of the energy spectrum of waves when nonlinear interactions are weak. In this last example, a kinetic theory is indeed possible thanks to the separation between the time scale associated with the linear wave dynamics and the typical time scale for nonlinear wave interactions. This provides a decisive simplification, allowing a natural closure for the probability distribution functions [Zakharov, Newell]. Our main point is that 2-D turbulence, in the limit of weak forcing and dissipation, should be another instance where a kinetic theory approach, to a probabilistic description of the large-scale dynamics, is possible. Our first argument is that the statistical mechanics of conservative dynamics is well understood, it is the Robert-Sommeria-Miller theory. The second argument is that, when both forcing and dissipation vanish (the Eulerian limit) the 2-D Navier-Stokes equation is well behaved. The small parameter necessary to obtain a relevant kinetic description is then the small parameter characterizing the amplitude of the forcing and the dissipation. The possibility to use kinetic theory in order to predict the statistics of the large scales in 2-D Navier-Stokes flows has never been considered before. We will derive the prediction of kinetic theory and analyze its physical implications. By contrast with the spectral behavior of the inertial scales, we do not expect some universal behavior for the large scales. Their behavior will be (strongly) dependent on the boundary conditions, on the type of forcing as well as the dissipation mechanisms. Because we do not underestimate the difficulty of the theoretical problem, our approach will also rely on very precise numerical computations. For instance, we will assess the range of validity for the kinetic approach hypothesis, and we will test its predictions using intensive numerical simulations. Kinetic theory describes the evolution of the macroscopic dynamics (the large scale flow) on time scale which are much longer than the time scale typical of the microscopic dynamics (the small-scale turbulence