Redirecting splicing with bifunctional oligonucleotides

Abstract: Ectopic modulators of alternative splicing are important tools to study the function of splice variants and for correcting mis-splicing events that cause human diseases. Such modulators can be bifunctional oligonucleotides made of an antisense portion that determines target specificity, and a nonhybridizing tail that recruits proteins or RNA/protein complexes that affect splice site selection (TOSS and TOES, respectively, for targeted oligonucleotide silencer of splicing and targeted oligonucleotide enhancer of splicing). The use of TOSS and TOES has been restricted to a handful of targets. To generalize the applicability and demonstrate the robustness of TOSS, we have tested this approach on more than 50 alternative splicing events. Moreover, we have developed an algorithm that can design active TOSS with a success rate of 80%. To produce bifunctional oligonucleotides capable of stimulating splicing, we built on the observation that binding sites for TDP-43 can stimulate splicing and improve U1 snRNP binding when inserted downstream from 50 splice sites. A TOES designed to recruit TDP-43 improved exon 7 inclusion in SMN2. Overall, our study shows that bifunctional oligonucleotides can redirect splicing on a variety of genes, justifying their inclusion in the molecular arsenal that aims to alter the production of splice variants

Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study

Background: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults.Methods: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users.Results: The majority of the 50 selected articles report results of cross-sectional studies (29; 58 %), mainly conducted in the US (24; 48 %) or Canada (15; 30 %). Studies mostly focused on neighborhood environment associations with mobility (39; 78 %), social participation (19; 38 %), and occasionally both (11; 22 %). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74 %), but also 'Natural and human- made changes' (27; 54 %) and 'Support and relationships' (21; 42 %). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'.Conclusion: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User-friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults

Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study

ABSTRACT: Background: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults.Methods: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users.Results: The majority of the 50 selected articles report results of cross-sectional studies (29; 58 %), mainly conducted in the US (24; 48 %) or Canada (15; 30 %). Studies mostly focused on neighborhood environment associations with mobility (39; 78 %), social participation (19; 38 %), and occasionally both (11; 22 %). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74 %), but also 'Natural and human- made changes' (27; 54 %) and 'Support and relationships' (21; 42 %). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'.Conclusion: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User-friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults

Parallélisme et communications dans les applications scientifiques (fortran)

Ce mémoire de recherche présente une méthode d'évaluation du potentiel de concurrence contenu dans des applications scientifiques programmées en FORTRAN et ayant été écrites en vue d'une exécution séquentielle sur un ordinateur conventionnel. Cette évaluation cherche à déterminer l'impact des coûts de communication ainsi que le nombre maximal de processeurs à utiliser afin d'exécuter le plus rapidement possible une application scientifique sur un système parallèle ayant une architecture donnée. Trois classes d'architectures multi-ordinateurs ont fait l'objet d'une étude particulière, à savoir: les architectures hypercubes, en grille et à bus simple. Un logiciel s'inspirant des techniques d'insertion de moniteurs utilisées pour obtenir des statistiques concernant les programmes exécutés sur des ordinateurs conventionnels, a été élaboré. Celui-ci permet d'établir, durant l'exécution de ces programmes, le parallélisme maximal pouvant être obtenu avec ou sans contraintes, telles que le nombre de processeurs et le coût d'une communication, et ce, en fonction de l'architecture choisie. Cet outil s'appelle OSASMO, qui est l'acronyme de: Outil de Simulation Architecturale pour Systèmes Multi-Ordinateurs permet donc l'analyse automatique de n'importe quelle application écrite en FORTRAN standard. Dix applications scientifiques connues ont été analysées à l'aide de l'outil logiciel. Plus de 700 simulations ont été exécutées afin d'obtenir une vue d'ensemble de tous les facteurs intervenant dans l'exécution d'un programme parallèle. Plusieurs simulations confirment certains résultats expérimentaux observés par d'autres chercheurs. De plus, plusieurs autres résultats d'importance pour les utilisateurs et les concepteurs de systèmes parallèles sont présentés. La conclusion la plus intéressante de ce travail est que, généralement, peu de processeurs sont nécessaires pour réaliser l'exécution parallèle optimale d'applications scientifiques

Activités ioniques et protonation dans des solutions mixtes d’électrolytes et de polybase faible I. par dialyses d’équilibre et par mesures de ddp entre électrodes réversibles

On obtient les coefficients d’activité des électrolytes, le degré de neutralisation, ou de protonation théorique ([math]), et le degré de protonation réel (α) d’une polybase très faible (polyvinyl-2 pyridine) en présence d’un excès d’électrolyte, par trois méthodes. 1° En équilibre de dialyse avec une solution mixte diluée d'électrolytes NaCl-HCl (même ion compensateur); les valeurs thermodynamiques d’activités s’accordent avec les valeurs des coefficients d’activités ioniques calculées par le traitement de Manning d'un côté et Debye-Huckel de l’autre. Les situations en absence de Na s’obtiennent par extrapolation linéaire expérimentale et par le calcul. 2° La d.d.p. entre électrodes réversibles identiques devient nulle en équilibre de dialyse : on peut s'en servir comme indicateur dans des « dialyses-titrages ». 3° La d.d.p. entre électrodes réversibles différentes (H+ et LL) conduisent aux mêmes valeurs d’activités ioniques que les autres méthodes. Ceci est applicable à d’autres polyélectrolytes

Activités ioniques et protonation dans des solutions mixtes d’électrolytes et de polybase faible

Nous comparons les solutions de poly(vinyl-2 pyridine) partiellement protonée par HCl ou HNO3. En présence de nitrates le degré de protonation α est plus grand et le coefficient d'activité de l’électrolyte plus petit. La détermination de α est précise et ses valeurs permettent d’accéder au ρΚαapp. de la polybase, de tester la relation entre le coefficient d’extinction molaire ε et le degré de protonation α (spectrophotométrie), d’évaluer la contribution du polyion à la conductivité de la solution. Enfin avec les mélanges chlorures-nitrates la sélectivité est en faveur des chlorures quand α 0,35 (condensation des ions compensateurs)

Particle dynamics at the onset of the granular gas-liquid transition

Granular gases are composed by a large amount of mobile solid particles. Unlike molecular gases, they are characterized by inelastic collisions leading to an ongoing loss of kinetic energy over time. In order to avoid such cooling of the system, mechanical energy should be injected in the granular gas..

Pierre Boulle

Pierre Boulle est l’un des rares exemples d’auteur français ayant publié à la fois de la littérature générale et des récits de science-fiction. Ses récits de science-fiction doivent-ils être interprétés à l’aune de sa production « blanche », ou peut-on s’autoriser la proposition inverse ? La pensée de la science-fiction informe-t-elle, ou insémine-t-elle, l’ensemble de la production de Pierre Boulle

Threshold of gas-like to clustering transition in driven granular media in low-gravity environment

Strongly driven granular media are known to undergo a transition from a gas-like to a cluster regime when the density of particles is increased. However, the main mechanism triggering this transition is not fully understood so far. Here, we investigate experimentally this transition within a 3D cell filled with beads that are driven by two face-to-face vibrating pistons in low gravity during parabolic flight campaigns. By varying large ranges of parameters, we obtain the full phase diagram of the dynamical regimes reached by the out-of-equilibrium system: gas, cluster or bouncing aggregate. The images of the cell recorded by two perpendicular cameras are processed to obtain the profiles of particle density along the vibration axis of the cell. A statistical test is then performed on these distributions to determinate which regime is reached by the system. The experimental results are found in very good agreement with theoretical models for the gas-cluster transition and for the emergence of the bouncing state. The transition is shown to occur when the typical propagation time needed to transmit the kinetic energy from one piston to the other is of the order of the relaxation time due to dissipative collisions.ESA Topical Team No. 400010346