Inherited retinal degenerative diseases constitute a major cause of vision loss in humans. Retinitis pigmentosa and macular degeneration (MD) are the two main classes of retinal diseases. They are characterized by the loss of rod and cone photoreceptor (PR) cells leading to progressive blindness. Most monogenic forms of retinitis pigmentosa and MD are associated with genes expressed in PR or retinal pigment epithelial (RPE) cells where they encode proteins that are critical for PR structure, function and survival. Specific cellular processes and biochemical pathways implicated in retinopathies include: phototransduction, visual cycle, PR development, morphogenesis, cellular metabolism, protein folding, among others. Lipid metabolism is of major importance for retina integrity and its dysregulation can lead to retinopathies. Lipid disorders have been implicated in macular degeneration such as the Age-Related Macular Degeneration (AMD) and Stargardt disease. Partner 1 has found that loss of function mutation in fatp (fatty acid transport protein) gene leads to PR loss in Drosophila and partner 2 has identified FATP1 as a potential regulatory component of the visual cycle in mammals. In the following four specific tasks, we propose to 1) Coordinate the project; use mouse FATP and Drosophila fatp mutants to study in 2) the roles of Fatp genes in PR function and survival, 3) examine the roles of Fatp genes in the visual cycle, and 4) investigate the role of Fatp genes in lipid metabolism in the retina (Partners 1, 2 and 3). All together our proposal will help elucidating the mechanisms by which a lipid dysregulation leads to PR degeneration and retinal pathology.

The use of renewable resources is essential for a sustainable society. Developing clean catalytic processes to produce value-added chemicals from renewable materials such as wood or plants has become a major goal for chemists. The bio-feedstocks issued from lignocellulose after either enzymatic fermentation or acidic deconstruction consist mainly of water-soluble molecules containing many oxygenated groups ((di)acids, alcohols, ethers), which must be subsequently transformed to find applications as monomers, solvents, etc. For this purpose, the design of new water-stable catalysts able to withstand rather harsh reaction conditions in term of pH, temperature and pressure is required. The NHYSCAB project aims at the synthesis of hydrothermally stable promoted metallic catalysts, based on a supported noble metal (e.g. Pd, Ru) modified with an oxophilic promoter (Re or Mo). They will be used for catalytic hydrogenation/hydrogenolysis of biosourced molecules in aqueous phase, at temperatures in the range 100 to 200°C and hydrogen pressure in the range 50 to 150 bar, at acidic to neutral pH. This project is based on the collaboration between two complementary public partners, IRCELYON (coordinator) and ICGM Montpellier, which are internationally recognized for their expertise in the fields of biomass catalytic upgrading and of non-hydrolytic sol-gel (NHSG) synthesis of mixed oxides, respectively. The first part of the project consists in the design of advanced mesoporous catalyst supports using the NHSG process which offers powerful synthetic routes to hydrothermally stable mesoporous oxides (TiO2, ZrO2) and mixed oxides incorporating the promoter species (Re-Ti, Mo-Ti), which after an appropriate thermal treatment are dispersed at the surface of the oxide. The hydrothermal stability of these supports will be assessed under the reaction conditions. Noble metal will be deposited on the stable supports with well-defined compositions and structures in order to prepare efficient promoted metallic catalysts. The second part concerns the evaluation of the synthesized catalysts in the reference reaction of aqueous-phase hydrogenation of biosourced acids (succinic acid and levulinic acid) to the corresponding diols (1,4-butane- and 1,4-pentane- diols). The catalysts will also be evaluated in the challenging hydrogenolysis of tetrahydrofurfuryl alcohol from the furfural platform into the corresponding 1,2- or 1,5- pentanediols. The expected products can find many applications, including as monomers. The design of well-defined, thoroughly characterized solids is essential to optimize the selective synthesis of targeted chemicals. Therefore, extensive characterization of the solids (supports and catalysts) will be performed at different stages (oxides, mixed oxides, supported metallic catalysts, before and after reaction) and their stability will be investigated under the reaction conditions. These will allow us to determine the texture/structure/composition of the solids, to validate their stability and to correlate the characteristics of the catalysts and their performance. To reach the highest activity or selectivity, the study will focus not only on the catalyst design but also on the optimization of reaction conditions. After screening of catalyst compositions using a batch reactor, the catalytic reaction will be conducted in a continuous trickle-bed reactor to further study the stability of the selected catalytic systems.

Eukaryotic organisms exhibit strikingly complex gene and genome architectures whose origin remains largely debated. In 2003, Michael Lynch proposed that this complexity emerged thanks to non-adaptive forces. Under this hypothesis, many genomic traits would be controlled by the balance between the emergence of slightly deleterious variants and their fixation rate, which ultimately depends on the effective population size (Ne). Although appealing because it is based on universal principles of population genetics, Lynch's theory has rarely been tested empirically. Here, we will compare the genome architecture of closely related species with contrasted Ne in five different groups of animals. We will first evaluate the influence of Ne on the evolution of genome size and on the dynamics of transposable elements. Then, we will test if Ne has an influence on the gene structure (number and size of introns) and transcription complexity (number and frequency of alternative transcripts). In parallel, we will use modeling and simulations to understand the reasons for a possible lack of applicability and to ultimately redefine or refine the contours of Lynch’s theory.

This project is devoted to design robust and efficient catalysts for performing challenging reactions under clean and mild conditions yet unavailable in chemical industry. We will develop an approach inspired by Nature which performs under physiological conditions difficult processes (e.g. methane oxidation, sMMO) or highly selective ones (e.g. hydroxylations by cytochromes P450 and halogenations by non-heme iron enzymes. Cytochromes P450 are able also to catalyze nitrene transfers, reactions conceptually analogous to hydroxylations. We have recently developed a novel concept based on combining the structures of the two most efficient enzymes in oxidation by assembling two iron atoms (as in sMMO) within macrocycling ligands (as in P450). This concept was validated by our discovery of remarkable catalytic properties of N-bridged diiron phthalocyanine and porphyrin complexes (PFeIII(µ-N)FeIVP) for the mild oxidation of methane C-H bond by H2O2 in water with turnover numbers up to 500. Aromatic C-F bonds can also be activated in oxidative conditions provided by these diiron complexes and H2O2, enabling high defluorination of a wide range of poly- and perfluorinated aromatics which are among the most stable organic molecules. Oxidative defluorination thus appears as a fundamentally new type of the activation of C-F bonds. The Fe(µN)Fe structural feature is essential for this outstanding reactivity. Non-heme diiron complexes have been less studied and their potential has not yet been fully revealed. Indeed, we recently showed that non-heme diiron sites show remarkable activity in nitrene transfer reactions which are of utmost importance for the synthesis of biologically and pharmacologically active amines. Nitrene transfer can be activated by oxo transfer reagents, which opens the way to catalyze the transfer reactions of different groups. The common feature of these catalysts is the presence of diiron sites supported by macrocyclic (phthalocyanine, porphyrin) or non-heme ligands which form catalytically active high-valent diiron species. They have been evidenced by advanced spectroscopic methods and characterized by DFT calculations by project partners. We have shown the superiority of the diiron systems over their mononuclear counterparts in catalysis. However, many bottlenecks still remain (reaction scope and selectivity, catalysts life span, operating conditions, ...). In-depth investigation of these systems is thus necessary to get a deeper insight into the reactions and further improvements of the catalysts for challenging reactions: oxidation of methane, transformation of fluorinated aromatic compounds in oxidative conditions, selective halogenations of organic compounds, preparation of nitrogen compounds by transformation of C-H bonds to C-N bonds. Novel heme and non-heme diiron catalysts will be developed on the basis of our present knowledge of oxygen and nitrene transfer to C-H bonds. Improving the efficiency of these reactions in mild and green conditions is the objective. For halogenation and dehalogenation reactions we will pursue the search for efficient catalysts and operation conditions. (ii) A new generation of catalysts will be designed by using a nitrido bridge to team up mixed assemblies of iron porphyrin-like macrocycles and non-heme iron systems. Benefiting from the robustness of the former and the versatility of the latter, such systems are likely to provide interesting advances and improvements. The optimization of the catalytic systems and the development of practical applications will be based on new fundamental knowledge of the mechanisms using state-of-the-art spectroscopic and computational studies. Consequently, we believe that successful project development will provide new fundamental insights in this highly competitive field and the scientific basis for innovative chemistry to lead to efficient and energy saving industrial processes based on iron, a cheap, non toxic and earth-abundant metal.

Aquaculture is an important source for food, nutrition, income and livelihoods for millions of people around the globe. Intensive fish farming is often associated with pathogen outbreaks and therefore high amounts of veterinary drugs are used worldwide. As in many other environments, mostly application of antimicrobials triggers the development of (multi)resistant microbiota. This process might be fostered by co-selection as a consequence of the additional use of antiparasitics. Usage of antimicrobials in aquaculture does not only affect the cultured fish species, but - to a so far unknown extent - also aquatic ecosystems connected to fish farms including microbiota from water and sediment as well as its eukaryotes. Effects include increases in the number of (multi)resistant microbes, as well as complete shifts in microbial community structure and function. This dysbiosis might have pronounced consequences for the functioning of aquatic ecosystems. Thus in the frame of this project we want to study consequences of antimicrobial/-parastic application in aquaculture for the cultured fish species as well as for the aquatic environments. To consider the variability of aquaculture practices worldwide four showcases representing typical systems from the tropics, the Mediterranean and the temperate zone will be studied including freshwater and marine environments. For one showcase a targeted mitigation approach to reduce the impact on aquatic ecosystems will be tested.