In implantology, biointegration of the implant is known to be a major issue for the long term clinical success. This biointegration is conditioned by different kinds or parameters such as the chemical nature and the mechanical compatibility of the material regarding the bone/implant interface. Currently, osseointegrated implants are made of Cr-Co alloys, Stainless steel (316L), pure Titanium or conventional TA6V titanium alloys.Titanium and its alloys have emerged as the most promising candidates for the realization of highly bio-compatible and high performance implant materials. However, it is recognized, that in the long-term effect of these implants may be associated with adverse local and remote tissue reactivities (inflammatory reactions) since the use of alloying elements such as Aluminium or Vanadium is still highly questionable. As a consequence there is an increasing need for improved materials displaying: - Superior chemical biocompatibility to ensure the long term inertness of the osseointegrated implant - High specific resistance associated with reduced elastic mismatch between the implant and the surrounding bone, to trigger the load transfer regime at the bone implant/ interface and avoid the so called 'stress shielding' phenomenon. In the frame of this project, it is proposed to develop a new set of beta metastable titanium alloys, composed of biocompatible chemical elements such as Ti, Zr, Ta and Nb, and displaying an improved mechanical compatibility with tissues. (i) Chemical formulation of the (Ti-Ta-Nb-Zr) alloys should result in materials with reduced intrinsic (enthalpic) elastic modulus and well adapted to implantology field. (ii) Additional compositional modifications based on the Morigana prediction model will give possibilities to provide alloys displaying mechanical instability and superelastic properties. This will lead to possible Ni-free alternatives to Ni-Ti alloys for medical application such as stents or orthodontic wires. The originality and the novelty of the project are to take advantage of a double effect. The (Ti-Ta-Nb-Zr) based alloys have already been shown to display a unique combination of low intrinsic modulus keeping mechanical resistance at a high level compared to pure titanium. Careful adjustment of the chemical composition will provide an additional benefit since, in this particular class of materials, the beta matrix can display a mechanical instability leading to a reversible stress induced phase transformation alpha ''. This reversible phase transformation results in a remarkable superelestic effect leading to a drastic decrease of the apparent Young modulus. As a consequence, it will be possible to reduce the elastic mismatch between the implant and the surrounding tissues using the remarkable elastic properties of these alloys. The work will deal with alloys formulation, synthesis, structural characterization and optimization of the associated mechanical properties regarding superelastic properties. The project will provide well defined protocols concerning the elaboration way and the subsequent thermomechanical treatments as a technological input for industrial development in the field of medical devices. This project has been organised on the basis of the complementary expertise of 4 academic partners and is supported by 2 industrials partners to ensure a technological transfer of the developed systems in the growing field of medical devices. It is an ideal way to provide a internationally competitive consortium, gathering complementary forces of metallurgists and increasing involvement of two French companies in the biomedical field.

In Southern Africa, the predicted increase in aridity will increase uncertainty of resource availability in space and time (surface water and forage), as well as decrease primary production. The land use mosaic should evolve towards more pastoralism and the role of protected areas could be crucial as one of the land-use options. Understanding the responses of the key component of these savanna systems to the increasing variability of rainfall in time and space is of primary importance to anticipate biome shifts, and the loss of identity of the biodiversity based savanna socio-ecological systems. The project will thus address the management of protected areas and their adequacy to sustainably meet their original biodiversity conservation objectives in the face of climate change as well as the role of protected areas as ecosystem services providers for their broader socio-ecological system. Studying the effects of climate change on biotic interactions is necessary to understand the response of ecosystem functions and their associated services. Our general objective here is to predict possible trajectories of a biodiversity-based socio-ecological system (protected area and its periphery) through understanding the functional relationships between the key biotic drivers of semi-arid African savannas (plants, large herbivores and humans) in response to variability and uncertainty in rainfall and surface water. Although the decrease in resource and increase in uncertainty may lead to increase in conflict locally, we hypothesise that the new constraints imposed on the various production systems may create the conditions for promoting a new integrated land-use system based on sustainable wildlife utilisation and biodiversity valuation. The study will be carried out within the Hwange LTER (Zone Atelier Hwange), thus benefiting from existing long-term data, field experiment facilities, as well as strong collaborations between researchers, managers and the rural communities. The consortium gathered for this project is pluri-disciplinary and international, has common past research experience and a long working experience in African savanna. These attributes thus offer a good feasibility and a high international visibility for this project.

A human body performs about 10,000 trillion cell divisions in a lifetime. Deciphering how is precisely controlled the “decision” to enter into mitosis during each cell cycle is a major challenge in cell biology that will create new therapeutic perspectives. Irreversible entry into mitosis is under the control of checkpoint mechanisms; a G2 DNA damage checkpoint that will arrest cells in G2 phase in the presence of DNA lesions and an antephase checkpoint sensing stress conditions up to early prophase. These control mechanisms delay Cyclin B1-Cdk1 activation, the master kinase orchestrating entry into mitosis, and prevent genetic instability as a consequence of chromosome separation with unreplicated or damaged DNA. Experiments performed in yeast to human showed that deregulation of Cyclin B-Cdk1 activity or overexpression of its activator(s) can trigger entry into mitosis of S phase cells still containing unreplicated DNA, enlightening the importance of the tight control of entry into mitosis for genomic stability. When the checkpoint mechanisms are satisfied, Cyclin B1-Cdk1 activation takes place and trigger entry into mitosis. We previously developed a FRET (Förster Resonance Energy Transfer)-based specific CyclinB1-Cdk1 activity biosensor to demonstrate that its initial activation is taking place at a very reproducible set time in each individual living cell. What are the immediate upstream mechanisms that reproductively trigger its initial activation during each G2 phase is still a fundamental unanswered question. More generally, the core molecular machinery taking place after the completion of DNA replication during a normal G2 phase progression and ultimately leading to Cyclin B1-Cdk1 activation is poorly understood. In the present project, we aim to investigate the spatio-temporal regulation and roles of ERK (Extracellular Regulated Kinases) 1&2 and Plk1 (Polo-like kinase 1) in the cell cycle progression from early G2 to mitosis. Recent reports suggest that ERK1&2 activities regulate a gene expression program in early G2 specifically in epithelial versus fibroblast cells. Because temporal and intensity-modulated ERK1&2 activities strongly affect their ability to activate downstream events, we will analyze in real time their activation signature during G2 progression using our recently developed FRET-based specific activity reporter. We will next combine the use of this biosensor with ERK inhibitor(s) to visualize in each individual living cell the extent of ERK1&2 inhibition and the consequences for G2 phase progression and/or mitotic entry in cells from different tissue origins. We thus expect to clarify their involvement in the regulation of G2/M progression. Plk1 is known to participate in the regulation of entry into mitosis in mammals but the underlying mechanisms are not fully understood. We identified a main target, among the Cyclin B1-Cdk1 regulators, and observed that its phosphorylation is taking place from late G2 cells, mostly at centrosomes. We will determine if a burst of Plk1 kinase activity is taking place just before entry into mitosis during each cell cycle and if Plk1 dependent phosphorylation of the Cyclin B1-Cdk1 regulator triggers entry into mitosis. We will evaluate if the centrosome is a "platform" facilitating the initial activation of CyclinB1-Cdk1 and entry into mitosis using optogenetic inducible recruitment of this regulator. Finally, an ambitious aim of this project will be to analyze the conservation of our findings concerning the regulation and roles of ERK1&2 and Plk1 during G2 to mitosis progression in Xenopus embryonic epithelial tissues as a model of cell proliferation in vertebrate tissues using our corresponding FRET-based activity reporters and implemented frequency domain FLIM FRET microscopy approaches. We thus expect to significantly improve our knowledge of the successive molecular steps taking place during G2 to mitosis progression and which are potential therapeutic targets.