La trisomie 21 (T21) résulte de la présence d’une extra-copie du chromosome 21 (Chr21). Parmi les gènes candidats impliqués dans les déficits cognitifs liés à la T21, DYRK1A est un des plus pertinents. Des études ont montré une corrélation entre l’augmentation de son activité kinase avec les déficits mnésiques observés dans les modèles murins de T21. Afin de comprendre les mécanismes sous-jacents aux altérations cognitives causées par son surdosage, nous avons utilisé des modèles murins sur-exprimant DYRK1A seule ou en plus d’autres gènes orthologues au Chr21, ainsi que des inhibiteurs spécifiques de DYRK1A (Leucettines) synthétisés par ManRos Therapeutics. Ici sont présentées les conséquences d’un traitement chronique avec ces Leucettines sur la cognition de ces animaux. Des analyses du phosphoprotéome de ces souris traitées ou non avec une des Leucettines, la L41, a mis en lumière des cibles et mécanismes biologiques impliqués dans les perturbations mnésiques de ces animaux. Enfin, ce projet a surtout permis de mettre en évidence un nouvel inhibiteur plus sélectif pour DYRK1A comme candidat-médicament pour l’amélioration des fonctions cognitives des porteurs de la T21. / Down Syndrome (DS), is due to the presence of an extra copy of chromosome 21 (Ch21). Among the candidates implicated in DS intellectual disabilities, DYRK1A is one of the most relevant. Several studies have shown a correlation between an increase of its kinase activity and the intellectual defects observed in DS models. In order to understand the mechanisms underlying the impact of DYRK1A overdosage on cognitive alterations, we used several trisomic mouse models expressing DYRK1A alone or with additional Hsa21 orthologous genes and specific DYRK1A inhibitors (Leucettines) from ManRos Therapeutics. We will present here the consequence of the Leucettines treatment following repetitive administration to several DS mouse models on the behavior and cognition. Further analysis of the phosphoproteome of DS mouse models treated or not with one of the Leucettine, the L41, unravels a few targets and pathways which are involved in the cognitive alterations observed in these trisomic mice. These results support the potential of more selective DYRK1A inhibitor as a therapeutic approach to improve cognitive functions in DS patients.

The existing theoretical and empirical literature to investigate the existence of local market power is typically based on spatial competition models in the tradition of Hotelling's (1929) linear city and Salop's (1979) circular city. In models of this kind, strong assumptions are made that lead to a spatial homogeneity (symmetry) of firms in a highly stylized one-dimensional market space. However, some of these assumptions are hardly satisfied in many (retail) markets. The present thesis builds on a recent model by Chen and Riordan (2007), in which the market is characterized by a star-shaped graph with a central intersection. In an extension of Chen and Riordan, I distinguish between firms close to the center and firms in the periphery of a spatial market. This spatial heterogeneity leads to an asymmetric competition between firms. A central firm directly competes with a larger number of firms than remote firms do. The implications of the theoretical model are tested in two empirical applications to the retail gasoline market of Vienna and Austria. Using station level data on diesel prices, I estimate price reaction functions for gasoline stations in two different approaches. In the first approach the Austrian retail gasoline market is divided into numerous highly localized and delimited markets. The second approach analyzes the metropolitan area of Vienna and treats the whole market as one big network of gasoline stations, which are connected through the road network. In both approaches I apply econometric spatial autoregressive (SAR) models. The estimated parameters of the slopes of the reaction functions are used to evaluate the impact of individual gasoline stations on equilibrium market prices depending on their location within the market (network). All results obtained provide evidence for (more) central suppliers serving as a stronger reference in pricing than (rather) remote suppliers. Thus, the assumption of a symmetry in spatial competition which is usually implied by spatial competition models in theoretical and applied research, is rejected. (author's abstract)

The empirical literature on mergers, market power and collusion in differentiated markets has mainly focused on methods relying on output and/or panel data. In contrast to this literature we suggest a novel approach that allows for the detection of collusive behavior among a group of firms making use of information on the spatial structure of horizontally differentiated products. By estimating best response functions using a spatial econometrics approach, we focus on differences in the strategic interaction in pricing between different groups of firms as well as on differences in price levels. We apply our method to the market for ski lift tickets using a unique data set on ticket prices and detailed resort-specific characteristics covering all ski resorts in Austria. (authors' abstract) / Series: Department of Economics Working Paper Series

This paper looks at the effects of different forms of wholesale and retail regulation on retail competition in fixed network telephony markets. We explicitly model two asymmetries between the incumbent operator and two entrants: (i) While the incumbent has zero marginal costs, the entrant has the wholesale access charge as (positive) marginal costs; (ii) While the incumbent is setting a two-part tariff at the retail level (fixed fee and calls price), the entrant can only set a linear price for calls. We model the product of the incumbent as horizontally differentiated from the products of the entrants who are homogenous and do not have any market power. Competition from other infrastructures such as mobile telephony or cable is modelled as an "outside opportunity" for consumers. We find that entrants without market power might be subject to a margin squeeze if the wholesale access price is set at average costs and competitive pressure from other infrastructures increases. Product differentiation, however, prevents market foreclosure. We argue that a wholesale price regulation at average costs is not optimal in such a situation and discuss retail-minus and deregulation as potential alternatives. (author's abstract) / Series: Working Papers / Research Institute for Regulatory Economics