Mountain social-ecological systems contribute critically to ecosystem services at local, regional and global scales. Yet they are critically vulnerable to climate, political and economic changes which compound with natural climate harshness and variability and with natural risks. Therefore co-designing with mountain stakeholders future adaptation pathways towards sustainability is critical. Specific sustainability and global change adaptation issues in the Alps regard the development of a local economy that is resilient to both climate and broader-scale political and economic context, builds on local natural and social assets and benefits from societal demands for mountain ecosystem services. The objective of MtnPATHS is to develop such adaptation pathways by considering ecosystem services and climate adaptation services for the participatory construction of visions for sustainable futures in the Swiss Central Valais and the southern French Alps (Lautaret, Haute-Romanche) and by implementing these visions through participatory modelling. Our transdisciplinary approach will include three interlinked work packages. First an integrated understanding of the social-ecological systems, including key driving variables and interactions, the critical actors and the supply, demand and flow of ecosystem services will be co-constructed with local stakeholders and regional experts, culminating in the formulation of future visions. Based on these visions participants will identify change scenarios leading to desired futures and push back scenarios leading to unwanted outcomes. Second, these scenarios and the visions will be explored using agent-based modelling, with the support of the CRAFTY framework. The three original aspects of this modelling process will be the development of agent functional types relevant across our two alpine regions, the implementation of common trait-based and process-based ecosystem service supply functions and the novel incorporation of climate adaptation services, i.e. those ecosystem properties that support social adaptation to climate change by buffering climate impacts, offering novel ecosystem services and transforming. The model will be run under different climate and socio-economic scenarios and policy options to evaluate changes in ecosystem services provision and demand. To address the challenges of adaptation, diverse management practices and land users’ behavior strategies will be incorporated. The time courses for socio-economic output variables, the state of the biophysical system and its translation into the amount of delivered ecosystem services or into adaptation services will characterize alternative adaptation pathways to visions and provide quantitative information for pathway design, the final and third stage of the research. For the simulated pathways to be implemented requires that their acceptability and social and institutional feasibility are evaluated, and potential barriers or facilitating factors identified. Also future implementation will depend on the empowerment of stakeholders and larger-scale experts, and their ability to communicate their objectives to larger-scale institutions and to urban-based citizens. Workpackage 3 aims to facilitate this process through a participatory evaluation of adaptation pathways and of their associated value-knowledge-rules constraints, and by co-developing a dissemination strategy towards decision makers and the public.

Detergents are key components in the field of structural biology and biochemistry of membranes proteins. They are required for maintaining them in solution for crystallography, ligand screening, antibody production, immunization and other applications. Unfortunately, they tend to unfold these proteins as, contrarily to lipids, they are in fast-exchange equilibrium with micelles (Israelachvili 1977), weakening the compactness of the membrane region and leading to a partial-to-severe loss of functionality. The field of detergent design is thus quite active as membrane proteins account for 30% of proteins (Wallin 1998; von Heijne 2006) and 60 % of drug targets (Overington 2006). The hydrophobic nature of these proteins makes difficult their crystallization and further steps to a 3D-structure resolution, hampering structure-based drug design approaches. As a consequence, membranes proteins account for less than 1% of the 3D-structures resolved (White 2009). The vast majority of membranes proteins share a net enrichment in basic residues at the interface between membrane and cytoplasm, a property known as the positive-inside rule (von Heijne 1986). We propose to conceive a new class of detergents based on this feature, which, in addition to their capacity to interact with membranes proteins through hydrophobic interactions, will have the additional capacity to generate a network of salt bridges around the membrane region with these basic residues. We expect this synergy obtained by both actions will compensate the lack of lipids much more efficiently than with classical detergents, which mainly interact through hydrophobic interactions, and will preserve the compactness of the membrane part. Following this concept, we propose to generate a family of molecular clamps bearing in their hydrophilic moiety 2 mild-acid groups (carboxylates) to generate the salt-bridges network. The length of the arms bearing each carboxylate will be optimized to promote the formation of salt bridges. The hydrophilic head will also include a maltoside and their hydrophobic moiety will be made of one or two aliphatic tails. Trials of syntheses carried out by partner 2 since november 2011 and leading to the first set of compounds demonstrate the feasibility of such project. As a first proof of concept, we propose to test this new family of compounds on membranes proteins belonging to the multidrug ABC efflux pumps family, studied by partner 1 together with the International partner, Pr. Geoffrey Chang. Multidrug ABC efflux pumps are recruited to reduce the intracellular concentration of endogenous or exogenous cytotoxic compounds, such as anticancer, antifungal or antiinfectious drugs, by coupling the drug efflux to ATP hydrolysis. Several structures have been resolved (Dawson 2006; Ward 2007; Aller 2009; Liu 2012) after extraction, but with a deep impact on the ATPase activity which is lowered (Matar 2011), together with on drug affinity which is reduced 100 to 4000 times after detergent extraction (Liu 2012). As a consequence, no 3D-structure has been yet obtained with transported drugs. We expect from these detergents a better preservation of the full ATPase activity and drug affinity, and get the corresponding truly-functional 3D structure(s). This interdisciplinary project involves two french teams and an international partner. Chemistry will be achieved by Pr. Ahcène Boumendjel’s team (UJF Grenoble, partner 2). Biochemistry and crystallography will be carried out by Dr. Pierre Falson’s team (BMSSI / IBCP, Lyon, partner 1), in collaboration with Pr. Geoffrey Chang’s team (UCSD, Ca USA) who has resolved the structure of the prokaryotic ABC transporter MsbA (Ward 2007) and more recently that of the mouse P-glycoprotein (P-gp) (Aller 2009). The three teams are working together regularly on ABC transporters: (Arnaud 2011), (Boumendjel 2011); Pierre Falson and Geoffrey Chang are collaborating since 2 years on the function of the mouse P-gp.