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Understanding disease biology at a cellular level from disease specific tissues is imperative for effective drug development for complex neurodegenerative diseases. We profiled 87,086 nuclei from putamen tissue of healthy controls, Parkinson’s Disease (PD), and Multiple System Atrophy (MSA) subjects to construct a comprehensive single cell atlas. Although both PD and MSA are manifestations of α-synuclein protein aggregation, we observed that both the diseases have distinct cell-type specific changes. We see a possible expansion and activation of microglia and astrocytes in PD compared to MSA and controls. Contrary to PD microglia, we found absence of upregulated unfolded protein response in MSA microglia compared to controls. Differentially expressed genes in major cell types are enriched for genes associated with PD-GWAS loci. We found altered expression of major neurodegeneration associated genes — SNCA, MAPT, LRRK2, and APP — at cell-type resolution. We also identified disease associated gene modules using a network biology approach. Overall, this study creates an interactive atlas from synucleinopathies and provides major cell-type specific disease insights.Link to interactive atlas will be made available at the time of publication.

The role of oligodendrocytes in neurodegenerative diseases remains incompletely understood and largely unexplored at the single cell level. We profiled 87,086 single nuclei from human brain putamen region for healthy control, Parkinson’s Disease (PD), and Multiple System Atrophy (MSA). Oligodendrocyte lineage cells were the dominant cell-type in the putamen with oligodendrocyte subpopulations clustered by transcriptomic variation found to exhibit diverse functional enrichment patterns, and this oligodendrocyte heterogeneity was altered in a disease-specific way. Among profiled oligodendrocyte subpopulations, differences in expression of SNCA, HAPLN2, MAPT, APP, and OPALIN were observed for PD and MSA compared with healthy controls. Intriguingly, greater activation of unfolded protein response pathway gene expression was observed in PD nuclei versus MSA. Using network analysis, we then identified specific PD- and MSA-correlated gene co-expression modules enriched with disease relevant pathways; the PD-correlated module was significantly enriched for Parkinson’s Disease GWAS loci (p = 0.01046). Our analysis provides a broader understanding of oligodendrocyte heterogeneity and reveals distinctive oligodendrocyte pathological alterations associated with PD and MSA which may suggest potential novel therapeutic targets and new strategies for disease modification.

Background Overexpression of human lecithin-cholesterol acyltransferase (LCAT) in transgenic mice results in an increase of the antiatherogenic HDLs. Methods and Results To investigate the potential use of LCAT for gene therapy, a recombinant adenovirus was constructed in which the human LCAT cDNA was expressed under the control of the human cytomegalovirus immediate/early promoter followed by a chimeric intron (AdCMV human LCAT). Human apolipoprotein (apo) A-I transgenic mice infected with AdCMV human LCAT by intravenous injection accumulated reactive LCAT in the plasma. LCAT activity was increased 201-fold in the plasma of mice infected with 1×10 9 pfu AdCMV human LCAT, from 45±2 to 9068±812 nmol·mL −1 ·h −1 , in comparison with basal LCAT activity measured in control mice, 5 days after injection. Plasma HDL cholesterol levels rose from 117±12 to 797±48 mg/dL, and plasma human apo A-I concentrations increased from 247±14 to 616±17 mg/dL, in AdCMV human LCAT–infected mice compared with control mice. HDL particles were larger and had a different electrophoretic mobility. Studies of cholesterol efflux by incubation of serum with cholesterol-loaded Fu5AH cells showed that serum from AdCMV human LCAT–infected mice promoted a significantly higher efflux than did that of the controls. Conclusions These data establish the potential of this approach for treatment of subjects with LCAT gene defects as well as patients with low plasma levels of apo A-I and HDL cholesterol.

[Departement_IRSTEA]Eaux [TR1_IRSTEA]GEUSI; WETwin is a research project supported by the European Commission under the Seventh Framework Program. Its overall objective is to enhance the role of wetlands in basin-scale Integrated Water Resources Management (IWRM), with the aim of improving the community service functions while conserving good ecological status. Decisions about wetland management are made in a complex and dynamic context involving a range of stakeholders with different and sometime competing objectives. The aim of the WETwin project is to provide a rigorous framework for evaluating the effects of alternative development strategies to identify best compromise management solutions that are ecologically sustainable, socially acceptable, and economically sound, taking into account values of different stakeholders. This report describes application of the WETwin decision framework to identify and assess management solutions for each case study. Chapter 1 outlines the theoretical framework used in the analysis and discusses general conclusions and lessons learnt; the remaining chapters describes application of the DSF to each case study site.

WETwin is a research project supported by the European Commission under the Seventh Framework Program. Its overall objective is to enhance the role of wetlands in basin-scale Integrated Water Resources Management (IWRM), with the aim of improving the community service functions while conserving good ecological status. This report addresses formulation of management responses to the drivers, pressures and impacts on wetlands identified in case study sites. Within the WETwin conceptual framework a range of options are identified from which management solutions can be built up. In principle, each option can be carried out alone, but in practice, combinations of several responses are likely to be combined into comprehensive management solutions. Further this document identifies performance indicators used for the evaluation of the management solutions and describes a set of models and expert assessment tools used for this purpose. An overview of generic responses available for wetland management and rehabilitation is presented. Management responses are separated into groups of similar measures targeting specific wetland components. Such a grouping gives a clearer overview of possible measures, and facilitates transfer of these generic groups to other wetlands. A brief overview of the process of identifying, elaborating and combining management options into implementable packages of management solutions is then provided. Site-specific management options and solutions are presented for seven case studies: Ga-Mampa, Inner Niger Delta, Nabajjuzi, Namatala, Abras de Mantequilla, Lobau and Gemenc wetlands.

[Departement_IRSTEA]Eaux [TR1_IRSTEA]GEUSI; WETwin is a research project supported by the European Commission under the Seventh Framework Program. Its overall objective is to enhance the role of wetlands in basin-scale Integrated Water Resources Management (IWRM), with the aim of improving the community service functions while conserving good ecological status. This report addresses formulation of management responses to the drivers, pressures and impacts on wetlands identified in case study sites. Within the WETwin conceptual framework a range of options are identified from which management solutions can be built up. In principle, each option can be carried out alone, but in practice, combinations of several responses are likely to be combined into comprehensive management solutions. Further this document identifies performance indicators used for the evaluation of the management solutions and describes a set of models and expert assessment tools used for this purpose. An overview of generic responses available for wetland management and rehabilitation is presented. Management responses are separated into groups of similar measures targeting specific wetland components. Such a grouping gives a clearer overview of possible measures, and facilitates transfer of these generic groups to other wetlands. A brief overview of the process of identifying, elaborating and combining management options into implementable packages of management solutions is then provided. Site-specific management options and solutions are presented for seven case studies: Ga-Mampa, Inner Niger Delta, Nabajjuzi, Namatala, Abras de Mantequilla, Lobau and Gemenc wetlands.

WETwin is a research project supported by the European Commission under the Seventh Framework Program. Its overall objective is to enhance the role of wetlands in basin-scale Integrated Water Resources Management (IWRM), with the aim of improving the community service functions while conserving good ecological status. Decisions about wetland management are made in a complex and dynamic context involving a range of stakeholders with different and sometime competing objectives. The aim of the WETwin project is to provide a rigorous framework for evaluating the effects of alternative development strategies to identify best compromise management solutions that are ecologically sustainable, socially acceptable, and economically sound, taking into account values of different stakeholders. This report describes application of the WETwin decision framework to identify and assess management solutions for each case study. Chapter 1 outlines the theoretical framework used in the analysis and discusses general conclusions and lessons learnt; the remaining chapters describes application of the DSF to each case study site.

The development of genetically modified adenoviral vectors capable of specifically transducing a given cell population requires the addition and functional presentation of particular tropism determinants within the virus capsid, together with the abrogation of the molecular determinants that dictate their natural tropism in vivo. The human adenovirus serotype 5 (Ad5) first attaches to the cell surface following high-affinity binding of the C-terminal knob of the fiber capsid protein to the coxsackie and adenovirus receptor (CAR). Here we have assessed whether genetic shortening of the fiber shaft (virus BS1), or replacing the Ad5 fiber shaft and knob with their Ad3 counterparts (virus DB6), could cripple this interaction in vitro and in vivo. A 10-fold decrease in the binding of the modified capsids to soluble CAR was evidenced, which correlated with a similar reduction of their ability to transduce CAR-positive cells in vitro. The ability of BS1 to interact with cellular integrins was also impaired, suggesting that the penton base and the short-shafted fiber when embedded in the capsid preclude each other from efficiently interacting with their cognate cell surface receptors (CAR and integrins respectively). BS1 and DB6 intravenous injections in mice further supported a profound impairment of the ability of the capsid-modified viruses to transduce the liver as demonstrated by a 10-fold reduction of intracellular viral DNA and transgene expression. Interestingly enough, the host humoral response was also specifically weakened in BS1- and DB6-inoculated animals. Taken together, these observations indicate that (i) fiber shortening and (ii) pseudo-typing of Ad5-based vectors with the shaft and knob from non-CAR-binding serotypes constitute two promising strategies to successfully attenuate their native tropism in vitro and most importantly in vivo.

La prairie est la première ressource alimentaires des ruminants. Dans les Antilles, les surfaces en herbe offrent une gamme étendue de savanes. De nombreux travaux de l'INRA et du Cemagref ont permis d'identifier les principales espèces fourragères adaptées aux différentes conditions pédo-climatiques rencontrées dans les Antilles. Parmi celles-ci nous pouvons citer : Brachiaria decumbens et humidicola, Cynodon plectostachius, Dichanthium spp, Digitaria decumbens, Panicum maximum, Cultures d'affourragement (Pennisetum purpureum et Tripsacum laxum, Légumineuses (Gliricidia sepium, Cajanus cajan et Desmodium heterocarpum. L'objet de ce document est de présenter, pour chacune des espèces citées préalablement, les informations nécessaires à sa culture : caractéristiques de la plante, conditions écologiques, techniques d'implantation et d'entretien, modes d'exploitation et valeurs alimentaires. Quelques informations concernant les principaux outils (semoir, planteuse de stolons, etc.) et leurs modalités d'utilisation dans le cadre des productions fourragères ont été ajoutées via une fiche supplémentaire spécifique.

Les pratiques maraîchères intensives développées sur les vertisols de la Martinique sont remises en cause car la production se fait au détriment du sol : par rapport aux prairies intensifiées qui permettent la conservation et même la réhabilitation de milieu, les labours des parcelles maraîchères diminuent les teneurs en carbone et augmentent leur érodibilité. Notre objectif est de proposer des pratiques qui préservent les sols et la production tout en restant rentables. Par rapport aux labours, notre étude montre en premier lieu que des préparations plus superficielles limitent la diminution des stocks organiques, facilitent le drainage et préservent mieux l'activité biologique ; en deuxième lieu, ces préparations ne provoquent pas de diminution significative des rendements, troisièmement, elles réduisent le temps de travail, les charges de mécanisation de 26 à 65% et l'investissement en matériel jusqu'à 40%. Les préparations superficielles sont plus rentables et préservent mieux le sol mais les risques de perte en terre persistent. La mise en place de rotations maraîchage/pâturage permettrait le maintien d'une production élevée et une gestion réellement durable du milieu. (Résumé d'auteur)

Les cultures maraîchères intensives apparaissent comme les plus intéressantes dans le contexte économique antillais (nombreux emplois, forte valeur ajoutée à l'ha), mais les techniques culturales actuelles sont très destructrices pour les sols. L'élevage intensif des petits ruminants ou l'embouche de bovins permettent des productions importantes (gains de poids vif de l'ordre de 1 000 à 1 200 kg.ha-1 .an-1 ). Les graminées fourragères utilisées ( en particulier Digitaria decumbens), à enracinement puissant, augmentent les teneurs en MO du sol, améliorent la structure et le comportement hydrique, et pérennisent les systèmes agricoles en les protégeant de l'érosion des sols. La rentabilité intrinsèque de l'élevage et sa faible mobilisation de main d'oeuvre permettent la complémentarité avec les cultures maraîchères dans le cadre d'exploitations familiales de superficie faible ou moyenne, sans accroître de façon significative le besoin global en personnel. Les exploitations de grande taille pratiquant actuellement la monoculture du melon seront aussi amenées à inclure l'élevage et/ou les cultures fourragères et à modifier profondément leurs techniques culturales si elles veulent éviter une dégradation irréversible des sols.

Des études au champ (milieu paysan et station agronomique) sont conduites, pour quatre sols tropicaux des petites Antilles, afin d'établir l'impact des précédents culturaux - jachères/prairies et cultures maraîchères et/ou vivrières - sur la productivité d'une culture de maïs (population du CIMMYT, Eto Amarillo) et sur l'utilisation de l'azote-urée (15N) et de l'azote du sol. Un inventaire agropédologique montre que jachères et prairies conduisent systèmatiquement à une augmentation des stocks organiques de ces sols. Corrélée positivement à ces variations, on note une amélioration générale des propriétés physico-chimiques des sols. Toutefois, l'ensemble de ces modifications a peu d'effet positif sur la productivité et la nutrition azotée (N-urée et N-sol) du maïs en première année. On constate un effet nul, voire négatif, des précédents jachères/prairies sur les rendements et pas d'effet sur l'exportation par la plante de l'azote-urée qui s'élève à 40% lorsque le maïs dépasse le stade de l'épiaison. Dans de telles conditions, le sol fournit plus de la moitié de l'azote total exporté dans la plante, sans que la nature du précédent modifie cette contribution. En comparant toutes les situations agropédologiques, la matière organique des sols n'apparaît pas être un facteur limitant de la fourniture d'azote à la plante

Subgroup C human adenoviruses (Ad2 or Ad5) can transduce a wide array of dividing and quiescent adherent cell types in vitro and in vivo, essentially because their primary receptor (CAR) is widely expressed at the cellular surface. On the other hand, specific target cell types (eg some tumor cells, smooth muscle cells, fibroblasts) display limiting amounts of the CAR receptor so that large viral doses are needed for efficient infection, a constraint which favors vector dissemination in vivo, even after loco-regional injection. Abrogating the native virus-CAR interaction while allowing the virus to use a CAR-independent pathway for entry would thus represent a major milestone in order to better control the vector tropism in vivo. Towards this goal, we first engineered a series of capsid-modified adenoviruses by genetically inserting targeting peptides within protruding loops of the fiber and hexon capsid monomers (Vigne E, et al: J Virol 1999, 73:5156). The most interesting virus – AE43 – displays within the fiber HI loop a vitronectin-derived high affinity peptide for the urokinase-type plasminogen activator (uPAR or CD87), a cell surface receptor upregulated during cellular activation, and which controls cellular migration and invasion. Most interestingly, AE43 could increase transduction of cells normally refractory to adenovirus infection more than 100-fold in vitro. We could also demonstrate that AE43 retained its ability to enter the cell via a CAR-dependent pathway in vitro, and displayed a normal tropism following systemic injection in mice. To cripple the virus-CAR interaction, we then evaluated various strategies, including the introduction of CAR-ablating mutations within the fiber, and the shortening of the fiber shaft. Interestingly, some of these constructs could decrease transduction of CAR-positive cells at least 10-fold in vitro, with a similar reduction in liver transduction following systemic injection in naive mice. We are currently assessing the effect of combining within a single vector the uPAR-binding peptide of AE43 with our best CAR-ablating mutations.

"The empirical study of the cognitive processes at work in various forms of translation makes it possible to leave aside the idealistic postulate of a universal grammar of human culture. The ontological problem, then, no longer refers to the different conceptions of the world expressed in different languages, but to the multiple non-systematic ways of constantly activating different forms of thought [...].