Venous thrombosis (VT) is the third leading cause of cardiovascular death in industrialized countries. Using a genome wide association study (GWAS) approach we have recently identified SLC44A2 as a new susceptibility gene for VT, the Arg154 isoform being associated with an increased risk. The SLC44A2 gene does not belong to the coagulation/fibrinolytic cascades and encodes choline transporter-like protein 2 (CTL2). Little is known about the function of CTL2. It has been associated with transfusion-related acute lung injury (TRALI), a process which involves activated neutrophils in a CTL2 isoform-dependent manner. In TRALI, alloantibodies react with the Arg154 (also called HNA-3a antigen), but not with the Gln154 (HNA-3b antigen). The direct binding of HNA-3a antibodies to HNA-3a+ neutrophils results in neutrophil activation and subsequent neutrophil-mediated destruction of pulmonary endothelial cells. The TRALI model, thought being different from VT physiopathology, paves the way to understand why SLCC44A2 plays a role in VT and why Arg154 isoform carriers have an increased risk of VT. The aim of the current project is to characterize the role of SLC44A2 in the physiopathology of VT using in-depth molecular functional studies. Given the increasing evidence of neutrophil involvement in VT physiopathology, we speculate that Arg154 isoform favors neutrophil adhesion and activation which in turn provides the initiating stimulus for VT development. To explain why the HNA-3a antigen associated with TRALI is also linked to an increased risk of VT, we made several assumptions based on 1) the receptor properties of CTL2 and 2) on the presence of CTL2 antibodies in blood circulation. We will characterize the interaction between CTL2 and von Willebrand factor (VWF), and how the polymorphism modulates this interaction. We will define the domain of interaction of VWF to CTL2 and elaborate potent modulating tools. For this, we will use human embryonic kidney cells (HEK-293 cell line) transfected to over-express either the CTL2/HNA-3a or the CTL2/HNA-3b isoform, in static and flow-based cell recruitment assays. Screening for anti-CTL2 autoantibodies will be performed in a large sample of individuals with VT from the EDITH case/control study. If present, antibodies from patients will be purified and they will be characterized. We will investigate the effects of the Arg154Gln polymorphism in vivo through work on SLC44A2 knock-out mice and the generation of knock-in mutant-mice. These humanized mice will be submitted to the most clinically relevant model of VT which consists in the partial ligation of the inferior vena cava. The development of the thrombus, the capacity of neutrophils to adhere to the venous endothelium and to become activated will be compared in the mice carrying either the CTL2/HNA-3a or CTL2/HNA-3b isoform. The capacity of NET release by activated neutrophils will also be compared. The present translational project is the transformation of omics data, obtained through the largest investigation to date of the influence of common genetic variations on VT risk by meta-analyzing 12 VT GWAS, into new ways of understanding, prediction (by identification and validation of new biomarkers) and treatment of patients with VT.

In a fusion plasma, ions escape from the plasma core and hit the reactor's walls where they remain implanted. During operation, the walls are hot (~900 K) and while absorbing hydrogen isotopes and helium they also release them. This implantation/degassing process is called recycling. The recycling process affects mainly the tungsten divertor which receives the highest power fluxes (up to 40 MW/m²). The interaction of intense particle fluxes with walls can induce changes in the surface condition and thermo-mechanical properties of plasma facing components and thus affecting the proper functioning of the reactor. For these reasons, in the framework of the LETHE project, we will experimentally study changes in the recycling process induced by He/wall and light/wall interactions. Such studies are necessary to predict how the walls will behave during plasma operation in tokamaks. The experiments will be carried out using an ultra-high vacuum device allowing to characterize the atomic composition of sample surfaces, to implant helium with ion beams or plasma, and to quantify the species trapped in the volume of the materials by using the temperature-programmed desorption technique. Three are the main objectives of the LETHE project: 1. Understanding the physical mechanisms underlying the degradation of materials (e.g. blister formation) and the change in their physico-chemical properties after He implantation/thermo-desorption cycles. Moreover, an in situ spectroscopic ellipsometer, installed in the framework of the LETHE project, will allow to probe the degradation of the surface of materials during ion-surface interaction. 2. The study of the influence of thermal loads in the recycling process and, consequently, on the parameters of the edge plasma. Thermal loads, simulated by a high-power laser, reaching pre-implanted samples, will induce sudden desorption of trapped species which, consequently, will perturb the plasma. The properties of the plasma (e.g. temperature and density) will be measured by a Langmuir probe. 3. Development of an optical method to prevent surface degradation, e.g. blistering, which can lead to plasma disruption.

A major question in molecular biology is to understand how precise regulation of gene expression during normal development and cell differentiation is achieved by the combined action of proximal (promoters) and distal (enhancers) cis-regulatory elements. A breakthrough discovery of our team reported that a subset of promoters, termed Epromoters, works also as enhancers to regulate distal genes. This new paradigm opens novel questions regarding the complexity of our genome and raises the intriguing possibility that genetic variants lying within Epromoters might have pleiotropic effects on various physiological and pathological traits by differentially impacting multiple proximal and distal genes. The general goal of the present project is to understand the molecular determinants that drive enhancer and promoter activity at Epromoters. Building on our interdisciplinary expertise, we will leverage high-throughput reporter assays, synthetic biology and deep learning approaches in a back-and-forth strategy to disentangle the cis- and trans-factors determinants of enhancer and promoter activity of Epromoters. First, we will develop a dual-reporter assay allowing us to quantify enhancer and promoter activity in a quantitative and high-throughput way. Wild-type and mutated Epromoters will be systematically tested along with typical promoters and enhancers. These data will be implemented in deep learning models to infer the DNA sequence determinants that drive enhancer and promoter functions. Subsequently, dual-reporter assays will be performed with loss and gain of function mutations and synthetic DNA sequences to validate and refine the deep learning models. Second, we will develop an integrative reporter strategy to study Epromoter function in a more physiological and chromatinized context. Third, we will perform CRISPR screening to identify transcription factors that are specifically required for either the enhancer or promoter function of Epromoters. Fourth, we will assess the impact of genetic variants on the enhancer and promoter activity of Epromoters and investigate the relevance of enhancer/promoter switch in disease and physiological traits. In particular, we will assess whether Epromoter variants have a pleiotropic or synergistic effect on human diseases by impacting the expression of proximal and distal genes at the same time. In fine, by dissecting the regulatory code of Epromoters, we aim for providing a unifying model of how cis-regulatory elements function to better predict how their dysregulation by genetic variants or other genomic alterations might impact human health.

Point defects in crystals occur when an atom is missing or is in an irregular position. After an initial skepticism, they spiked interest because of their possible applications as qubits in quantum computers. A strong and stable photoluminescence at room temperature (RT) and a single photon emission are the needed requirements. Point defects in hexagonal Boron Nitride(hBN) have been experimentally identified as RT stable single photon sources. In the photoluminescence spectrum of hBN there are different emission lines at transition energies ranging over the visible and the UV spectrum, and well-resolved phonon replica at lower energies. Whereas a considerable effort has been made so far and several color centers candidate have already been suggested, their exact nature remains uncertain. This project aims to solve some controversies related to the interpretation of defect related emission lines, with a special care for the study of the local vibrations at the origin of phonon replica.

To develop sustainable cities, urban mitigation policies reduced pollutant emissions and increased the number of vegetated areas to reduce urban heat islands, counteract carbon emissions, and improve air quality. But the impact of green infrastructures on secondary pollutants (formed in the air) remains poorly understood. Urban vegetated areas are a source of Biogenic Volatile Organic Compounds (BVOCs) that can react with the atmospheric oxidants, leading to the formation of Secondary Organic Aerosols (SOAs), one of the dominant fractions of atmospheric aerosols (particles suspended in air), that induce adverse health effects on human health. Currently, the impact of green infrastructures on SOAs is highly uncertain, because of the lack of knowledge regarding BVOC emissions from urban vegetated areas and the processes at the origin of SOA formation (in particular when mixed with anthropogenic emissions), pointing to urgent need for new studies on this topic. The general aim of VesPA (impact of Vegetated areas on Secondary Pollutants levels in urban Air) is to assess the contribution of vegetated urban areas to SOA levels in cities. This project will thus focus on SOA generated by BVOC emissions in urban areas through two main research tasks. The first one will characterize BVOC emissions from plant scale up to the district scale. The second task will investigate the reactivity and the potential SOA formation of these BVOC emissions, especially when they are mixed with anthropogenic VOCs. This original approach combines field and laboratory experiments, and will be developed in Marseilles, which gathers many advantages for the project. VeSPA will ultimately provide new knowledge to help developing future sustainable cities, in terms of urban air quality in the context of climate change.