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Background and purposeCerebral small vessel diseases (SVDs) are characterized by early white matter (WM) changes, whose pathological underpinnings are yet poorly understood. CADASIL is a monogenic and archetypal SVD, providing an ideal model for investigating these changes. Here, we used multicompartment microscopic diffusion imaging and relaxometry to elucidate microstructural changes underlying early WM abnormalities in CADASIL.MethodsWe acquired diffusion MRI data with a multiple-shell Q-space sampling strategy, and relaxometry T1 and T2 data, with a 160 and 80-μm isotropic resolution respectively,ex vivo, in CADASIL and control mice. Diffusion datasets were computed with the Neurite Orientation Dispersion and Density Imaging model to extract the neurite density index, the extracellular free water and the orientation dispersion index. Relaxometry datasets were computed with a 3-compartment myelin water imaging model to extract the myelin content. MRI metrics were compared between CADASIL and control mice using voxel and WM tract-based analyses and with electron microscopy analysis.ResultsWM in CADASIL mice displayed a widespread reduction in general fractional anisotropy, a large increase in extracellular free water, a reduction in the myelin content, but no reduction in neurite density. Electron microscopy analysis showed a ∽2-fold increase in the extracellular spaces and an elevation of the g-ratio indicative of myelin sheath thinning in CADASIL WM.ConclusionOur findings suggest that accumulation of interstitial fluid and myelin damage are 2 major factors underlying early WM changes in CADASIL. Advanced diffusion MRI and relaxometry are promising approaches to decipher the underpinnings of WM alterations in SVDs.

résumé de communication dans un congrès; International audience; Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer's disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.

International audience; The literature on the peer-to-peer hospitality market largely assumes that Airbnb hosts are loyal to the platform. However, similar to hoteliers, Airbnb hosts have access to various platforms to diversify their distribution channels. In cases where hosts significantly diversify their distribution channels, they should be considered rather as professional competitors mimicking hoteliers. Proposing an original image-recognition approach to obtain a proxy of the number of platforms used by Airbnb hosts, this paper assesses the probability that a home-sharer practices multichannel distribution. Drawing on a sample of more than 3900 hosts from the region of Corsica in France, we show that a multichannel distribution strategy is commonly adopted. Furthermore, a significant fraction of small hosts uses three or more channels.

International audience

Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies. However, limitations associated with anti-VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled-7 (Fzd7) pathway in a mouse model of oxygen-induced retinopathy (OIR). Using transgenic mice, which enabled endothelium-specific and time-specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso-obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAbFzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/β-catenin and Jagged1 expression to control EC proliferation in extra-retinal neovessels. We identified Fzd7/β-catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies.

International audience

Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-amino-4-imidazole carboxamide ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via the combined effects of both the drug and mutations on G1 cyclins. Our results point to AICAR impacting on Cln3 subcellular localization and at the Cln1 protein level, while the bre1 or set1 deletion affected CLN1 and CLN2 expression. As a consequence, AICAR and bre1/set1 deletions jointly affected all three G1 cyclins (Cln1, Cln2, and Cln3), leading to a condition known to result in synthetic lethality. Significantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Indeed, knock-down of RNF40, ASH2L, and KMT2D/MLL2 induced a highly significant increase in AICAR sensitivity. Given that KMT2D/MLL2 is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.

National audience; Les modèles cellulaires multi-échelles (Cellular Automata Model-CAM) [9, 1, 3, 2] sont souvent utilisés pour déterminer les facteurs-clés qui influencent les variations spatio-temporelles et l'utilisation des sols sur un territoire, notamment leurs déclinaisons de type " syst emes multi-agents d'utilisation et de couverture des sols " (Multi-Agent System models of Land-Use/Cover Change-MAS/LUCC)[4, 5, 10]. Dans ce travail, nous envisageons de développer un CAM de type MAS/LUCC afin d'´ etudier par la simulation informatique la multifonctionnalité du foncier rural en Corse. Nous allons nous intéresser plusparticulì erement a l'approché economique décrivant des usages multiples, en conflit ou complémentaires : tourisme/agriculture, chasse/agriculture, agriculture/environnement, etc. Il s'agit ici de développer un mod ele capable d' expérimenter virtuellement des politiques de projet de territoire, afin que l'on puissé etudier l'impact de l'homme sur la ressourcefoncì ere. Il s'agit notamment de poursuivre les travaux de 2010, en nous inspirant des mod eles décisionnels que nous avons déj a développés dans [7, 6, 8]. Dans ce travail préparatoire , nous discutons précisément de l'opportunité d'initialiser le mod ele MAS/LUCC depuis des données expérimentales provenant d'un SIG 1. En effet, les données SIG ne pouvent pas etre intégrées en l'´ etat dans le mod ele. L'utilisation des données provenant du SIG nécessite un travail de " rasteurisation ". Celui-ci doit permettre de rendre les données digestes par le CAM. Nous pro-posons dans ce travail une méthode d' intégration fondée sur l'analysé econométrique. Pour cela, nous allons utiliser les sciences mathématiques et statistiques afin d'exprimercompì etement les données SIG dans le mod ele MAS/LUCC. Ce traitement d' intégration est illustré sur la figure 1. Nous exprimons rationnellement a l'aide des outils de la science Figure 1 – Traitement d' intégration des données expérimentales SIG.

The main objective of the CLAIM Project is to provide the knowledge base to support an effective CAP policy design in the direction of improved landscape management, particularly providing insights into the ability of landscape to contribute to the production of added value for society in rural areas. The CLAIM knowledge platform (KP) represents the interface between the research findings and policy-making contributing to further knowledge on the cause-effect relationships between landscape policy and management and the appearance of landscape (structure and elements) as well as the related ecosystem functionalities to the actual provision of ecosystem services, values and their application for regional competitiveness and social welfare. The theoretical framework of cause-effect-linkages is substantiated by empirical evidence from 25 individual research studies gathered in 9 different regions in the EU and Turkey. The specific challenge of the CLAIM-KP is the integrated presentation of thematically and methodologically heterogenic knowledge in one knowledge platform to enhance policy support in the field of agri-environmental and landscape management. The main addressee of the CLAIM-KP are: European policy maker in the fields of agri-environmental and landscape management policy and rural development, national and regional decision-makers at programming level as well as regional and local stakeholder and interest groups, who are involved in any kind of governance processes within landscape and rural development. The main output of the CLAIM-KP is qualitative knowledge about theoretical knowledge, but also information on empirical finding, which can be of qualitative and quantitative nature. The CLAIM-KP is accessible online under the following internet address http://project2.zalf.de/claimknowledgeplatform