The problem: Heart failure (HF) is one of the most relevant diseases affecting >15 Mio Europeans with an average 5-year mortality of 50% and an increasing economic burden for our society. Arterial hypertension and diabetes are important causes for cardiac hypertrophy and HF, especially for diastolic HF (DHF) making up 50% of all HF patients. While disturbed Ca and Na homeostasis was shown to be a main cause for systolic HF (SHF), the mechanisms involved in DHF are unclear, especially in the progression from diastolic dysfunction to DHF. In contrast to SHF, no specific evidence-based and pathophysiologically founded therapy exists for DHF resulting in a tremendous clinical unmet need in addition to the huge socioeconomic relevance. Current knowledge: We previously showed that CaMKIIdC overexpression in mice causes end-stage HF due to disturbed Ca homeostasis. In addition to systolic dysfunction, these animals also develop diastolic dysfunction. We discovered in these mice a novel CaMKII-dependent Na channel regulation with an increased persistent (or late) Na current (late INa) leading to intracellular Na overload. Late INa with subsequent Ca influx via Na/Ca-exchanger (NCX) can also lead to intracellular Ca overload. While there are hints that this compromises diastolic function, these pathomechanisms have not been investigated in DHF so far. However, our small placebo-controlled proof-of-concept study (RALI-DHF) showed that inhibition of late INa improves diastolic function in DHF patients suggesting that targeting diastolic Ca overload (i.e. by late INa inhibition) could provide a path to urgently needed therapies in DHF. Unfortunately, it is unclear which patients with compensated cardiac hypertrophy and diastolic dysfunction progress to end-stage DHF. Yet, the goal must be to understand the mechanisms involved in DHF and to identify patients early enough who would benefit from a specific inhibition of late INa, and/or CaMKII. Proposal: We propose that altered Na handling consecutively leading to Ca overload due to CaMKII activation is involved in the development of DHF. The results of the proposed project will lead to innovative differential therapeutic approaches for diastolic dysfunction and DHF going beyond the current state of the art. We will test what role late INa and CaMKII activation play in DHF and in what stage of the disease. We believe that the work will provide important insights into novel mechanisms for DHF beyond the state of the art, which is needed for patients that are currently not adequately treated but hopefully in the near future.

The GHaNA project aims to explore and characterize a new marine bioresource, for blue biotechnology applications in aquaculture, cosmetics and possibly food and health industry. The project will determine the biological and chemical diversity of Haslea diatoms to develop mass-scale production for viable industrial applications by maximising biomass production and associated high-value compound production, including terpenoids, marennine-like pigments, lipids and silica skeletons. The genus Haslea species type H. ostrearia, produces marennine, a water-soluble blue pigment used for greening oysters in Western France, which is also a bioactive molecule. Haslea diatoms have thus a high potential for use in (1) existing oyster farming, (2) production of pigments and bioactive compounds with natural antibacterial properties, (3) application as a colouring agent within industry, and (4) use of silica skeletons as inorganic “biocharges” in the formulation of new elastomeric materials. This will be achieved through fundamental and applied-oriented research to isolate fast- growing strains of Haslea, optimising their growth environment to increase marennine and other high-value compound productivity; to develop blue biotechnology specifically applied to benthic microalgae (biorefinery approach, processes); and to develop industrial exploitation of colouring and bioactive compounds through commercial activities of aquaculture, food, cosmetics and health.

Additive manufacturing processes have opened the doors for the conception of high temperature energy systems (volumetric solar receivers, gas-to-gas heat exchangers, radiant tube inserts) based on highly porous ceramics with 3D tailored geometries. New architectures are now accessible (triply periodic minimal surfaces, hierarchical structures) but their thermal and mechanical performances remain questionable especially when they are used under harsh environment (T>1300 K, high-temperature gradient ? 500 K, high heat flux ? MW/m2). The fine control of the 3D spatial distribution of both radiative heat and fluid flows is crucial here to push back the current limitations. To make a decisive breakthrough in this topic, ORCHESTRA will gather a multidisciplinary consortium (LTeN, GeM, IFPEN, IRCER) whose objective will be to print SiC-based ceramics whose 3D architectures will be settled through advanced topology optimisation approaches, taking into account radiative transfers and all the coupled physics. A fast 3D numerical image-based pore-scale methodology under HPC environment based on voxel finite element methods will be then developed in order to finely reproduce the thermo-mechanical behaviours of the 3D architectures up to failure at high temperatures. Then the selected architectures will be elaborated by coupling the robocasting process and the polymer-derived ceramics route. In addition, new experimental (energy conversion, thermal shocks) facilities will be also implemented to determine both the thermal efficiencies and mechanical performances of the as-grown architectures. Finely, the confrontation of the numerical results with those obtained through the experimental part of OCHESTRA will allow us to define a robust methodology to design improved high temperature energy systems.

Rotaviruses (RVAs) are the most common cause of acute gastroenteritis in children. The disease frequently requires hospitalization and annually causes the death of several hundred thousands children in low-income countries. Two live vaccines have been developed and both show remarkable efficacy in high-income countries, but unfortunately and for unknown reasons they prove much less efficient in several regions of lower income. Nonetheless, recent data on the glycan-binding properties of human RVAs unexpectedly offered a potential clue to understanding of this limitation. RVAs are known to interact with glycans of the host cell membrane through their VP4 spikes, more specifically by the VP8* outermost domain. Until recently it was considered that, depending on the strains P-genotype characterized by genetic variation of the VP4 protein, interacting glycans contained sialic acid motifs, either sensitive or resistant to sialidase treatment. The new data indicate that human RVA strains additionally bind to neutral fucosylated glycans of the histo-blood group type (HBGAs). These carbohydrate antigens are located at the termini of either O-linked or N-linked glycan chains of proteins and of lipids and are expressed mainly on epithelial cells. They are characterized by an extensive genetic variation caused by common polymorphisms at the ABO, FUT2 and FUT3 loci. These genes encode glycosyltransferases that contribute in concert to the synthesis of the ABH and Lewis antigens that define the ABO, secretor and Lewis phenotypes. The VP8* of some strains appears to recognize the Leb difucosylated motif, whilst others bind to the A blood group antigen. Based on a limited number of cases, we and others observed that individuals lacking a functional FUT2 enzyme (nonsecretors) were never found among children with severe rotavirus gastroenteritis, suggesting resistance to infection by the common P[8] strains. This is consistent with the requirement of a functional FUT2 enzyme in the synthesis of the Leb ligand. Others additionally observed that children infected with P[6] strains were found among Lewis positive (FUT3+) only, suggesting that different strains may have different HBGAs specificities and may recognize distinct subgroups of the population. The vaccine strains contain a VP8* of the P[8] type and may not infect FUT2- or FUT3-null children. Since the frequencies of HBGAs polymorphisms greatly vary across geographical locations such refractory individuals may represent up to 50% of the population in some areas. We hypothesize that the lack of vaccine efficacy in many children of those areas could be due to an absence of HBGA ligand and that due to the higher diversity of circulating virus strains in tropical areas, the vaccine refractory children may remain susceptible to strains other than those of the common P[8] type. The aim of our project is to document this hypothesis through the combination of a prospective genetic study, analyses of the glycan specificity of the VP8* from clinical and vaccine strains and of in vitro experiments aimed at characterizing the role of HBGAs binding in the infection process. The prospective study will be carried both on a western European population in Nantes and a population from a tropical area at Cayenne (French Guyana). RVA infected children admitted at the pediatric emergency units at both locations will be enrolled alongside non-infected control groups. Virus genotypes as well as patients and controls HBGAs subtypes will be determined in order to uncover a relationship between them. Glycan specificity of the VP8* of strains of diverse P-genotypes will be determined using glycan microarrays and saliva mucins of diverse HBGA phenotypes in order to control for a match with the infection data. HBGA involvement in the infection process will be assessed using cultivable strains through manipulation of the glycan expression of susceptible cells lines under conditions mimicking in vivo infection.

Performances achievable through the use of continuous reinforced composites are today typically acquired and demonstrated. Among these composite materials, it is generally accepted that the use of thermoplastic matrices represents a major advantage because of their low environmental impact (no solvents and no VOCs) and their good behaviour in crash stress (intrinsic ductility). However, the inability to produce parts of complex geometry at controlled cost prevents the use of composite materials for applications in medium to large series. The Project objective is to develop new materials / new processing ways for the production of composite parts based on thermoplastic polymer for the automotive market, in order to meet the demand about lighter structures which become necessary because of new environmental regulations and energy dependence problems. This weight reduction requires the development of high performances parts or component modules, compatible with the requirements of cost and mass production rate. Composite fiber thermoplastics (CFRT) is a technological response to this need, but several problems have to be solved in order to consider the use of such materials. Thus, there are currently no available materials that meet the requirements of processability / performance / cost. Among the different manufacturing processes of composite structures, the consolidation in mold at low pressure (Liquid Composite Molding) present a major interest in the production of parts with complex geometry (non-developable surfaces) with the possibility of integrated functions. The recent development of new thermoplastic polymers with low melt viscosity (based on polyamide chemistry) enables access to these new processing routes, but a number of drawbacks about both the consolidated material and the final part have to be solved. This is the case of thermal transfer, the impregnation at high rate of a given reinforcing structure (deformable perform, with variable permeability), and the control of the polymer crystallization and induced residual stresses (thermal and crystallization volumic variation). The objective of the Project is fully consistent with this approach, and its complexity and character of technological breakthrough requires the use of close collaboration between industrial skills (major Groups and SMEs) and academic experts in their field. We will focus together to : - develop base materials (compatible polymers and reinforcements, polymer viscosity, wettability, crystallinity ...); - optimize the processing conditions (LCM) at lab via an instrumented mold of simple geometry (plate) in a first time; - develop a database modeling and simulation; - validate the models on a real functional piece (3D geometry) to be simulated and processed using a LCM system design; - optimize the technical and economic performance of the developed processing way (positive cost, life cycle analysis, recycling aspect ...). The complementarity of the partners in this consortium must help to realize the breaking science and technology needed to strengthen the position of France in the field of composites by opening the way to medium / large series market.