Distinct CCK-2 Receptor Conformations Associated with β-Arrestin-2 Recruitment or Phospholipase-C Activation Revealed by a Biased Antagonist

Seven-transmembrane receptors (7TMRs), also termed G protein-coupled receptors (GPCRs), form the largest class of cell surface membrane receptors, involving several hundred members in the human genome. Near 30% of marketed pharmacological agents target 7TMRs. 7TMRs adopt multiple conformations upon agonist binding. Biased agonists, in contrast to non-biased agonists, are believed to stabilize conformations preferentially activating either G-protein- or ß-arrestin-dependent signalling pathways. However, proof that cognate conformations of receptors display structural differences within their binding site where biased agonism initiates, are still lacking. Here, we show that a non-biased agonist, cholecystokinin (CCK) induces conformational states of the CCK2R activating Gq-protein-dependent pathway (CCK2RG) or recruiting ß-arrestin2 (CCK2Rß) that are pharmacologically and structurally distinct. Two structurally unrelated antagonists competitively inhibited both pathways. A third ligand (GV150,013X), acted as a high affinity competitive antagonist on CCK2RG but was nearly inefficient as inhibitor of CCK2Rß. Several structural elements on both GV150,013X and in CCK2R binding cavity, which hinder binding of GV150,013X only to the CCK2Rß were identified. At last, proximity between two conserved amino acids from transmembrane helices 3 and 7 interacting through sulphur-aromatic interaction was shown to be crucial for selective stabilization of the CCK2Rß state. These data establish structural evidences for distinct conformations of a 7TMR associated with ß-arrestin-2 recruitment or G-protein coupling and validate relevance of the design of biased ligands able to selectively target each functional conformation of 7TMRs.

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4)

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

After the Critique of Rights: For a Radical Democratic Theory and Practice of Human Rights

The critique of human rights has proliferated in critical legal thinking over recent years, making it clear that we can no longer uncritically approach human rights in their liberal form. In this article I assert that after the critique of rights one way human rights may be productively re-engaged in radical politics is by drawing from the radical democratic tradition. Radical democratic thought provides plausible resources to rework the shortcomings of liberal human rights, and allows human rights to be brought within the purview of a wider political project adopting a critical approach to current relations of power. Building upon previous re-engagements with rights using radical democratic thought, I return to the work of Ernesto Laclau and Chantal Mouffe to explore how human rights may be thought as an antagonistic hegemonic activity within a critical relation to power, a concept which is fundamentally futural, and may emerge as one site for work towards radical and plural democracy. I also assert, via Judith Butler's model of cultural translation, that a radical democratic practice of human rights may be advanced which resonates with and builds upon already existing activism, thereby holding possibilities to persuade those who remain sceptical as to radical re-engagements with rights.

Satellite DNA as a target for TaqMan real-time PCR detection of the pinewood nematode, Bursaphelenchus xylophilus

The pinewood nematode (PWN), Bursaphelenchus xylophilus , is a major pathogen of conifers, which impacts on forest health, natural ecosystem stability and international trade. As a consequence, it has been listed as a quarantine organism in Europe. A real-time PCR approach based on TaqMan chemistry was developed to detect this organism. Specific probe and primers were designed based on the sequence of the Msp I satellite DNA family previously characterized in the genome of the nematode. The method proved to be specific in tests with target DNA from PWN isolates from worldwide origin. From a practical point of view, detection limit was 1 pg of target DNA or one individual nematode. In addition, PWN genomic DNA or single individuals were positively detected in mixed samples in which B. xylophilius was associated with the closely related non-pathogenic species B. mucronatus , up to the limit of 0.01% or 1% of the mixture, respectively. The real-time PCR assay was also used in conjunction with a simple DNA extraction method to detect PWN directly in artificially infested wood samples. These results demonstrate the potential of this assay to provide rapid, accurate and sensitive molecular identification of the PWN in relation to pest risk assessment in the field and quarantine regulation.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

“Should we all be on Marx’s side?” Contributions of post-marxist discourse theory to the historiography of communism

Drawing on post-marxist discourse theory inspired by the writings of Ernesto Laclau and Chantal Mouffe, this article puts the case for a literature on communism situated at the crossroads of critical theory, cultural studies and historiography. Specific illustration is provided by the author's own research on British communism and the Spanish Civil War. However, the scope of the article is much broader and it is intended as a contribution to the theoretical discussion of future possibilities for communist history-writing. The article concludes that discourse should be regarded neither as a flat surface of tightly knit signifiers nor as an impenetrable monolith of meaning systems. Rather, it should be seen as an inherently dynamic phenomenon, with its own condensations and dispersions along the historical continuum. In this lies its significance for historians of communism.

Les Lionel Groulx : la pseudonymie comme stratégie littéraire et jeu institutionnel (1900-1966)

De 1900 à 1966, Lionel Groulx, prêtre, historien, écrivain, conférencier, professeur, a signé 176 textes d'une vingtaine de pseudonymes différents. Le premier chapitre du mémoire résume d'abord les positions théoriques qu'ont adoptées des chercheurs comme Genette, Laugaa et Jeandillou en ce qui concerne la pseudonymie. Le récit de l'aventure pseudonyme de Groulx commence au deuxième chapitre, alors que le jeune professeur du College de Valleyfield, surtout pour éviter les représailles de son évêque, recourra à la pseudonymie pour signer des textes patriotiques. En 1915, Groulx quitte Valleyfield pour Montréal. Dès 1917, il collabore à l'Action française, dont il devient le directeur en 1920. Sans contredit, l'étude de la pseudonymie de Groulx de 1917 a 1929 prouve qu'il est bel et bien "L'Homme à tout faire" de la revue, comme le démontre le troisième chapitre. Le quatrième et dernier chapitre analyse la période 1930 à 1966. [Résumé abrégé par UMI]

L'homosexualité dans la littérature jeunesse québécoise (1988-2003) du paratexte au personnage

Soixante ans après Orage sur mon corps, comment l'homosexualité adolescente est-elle représentée dans la littérature au Québec? Basée sur la presque totalité des romans et nouvelles pour la jeunesse qui ont abordé le thème de l'homosexualité au Québec ces 15 dernières années, cette analyse se veut d'abord et avant tout un tour d'horizon des romans et nouvelles jeunesses québécoises ou éditées dans une collection jeunesse québécoise, qui présentent un ou plusieurs personnages homosexuels"actifs". Il m'apparaît pertinent de voir, dans un premier temps, par qui ces textes ont été écrits, comment ils sont présentés, dans quelles collections et chez quels éditeurs ils ont été publiés, dans quelles circonstances ils ont pris ou non une place enviable dans la production jeunesse et quelles voies ils ont utilisées pour parvenir à leurs fins. Chaque texte est donc soumis à une analyse systématique de ses auteur, éditeur, directeur de collection, collection, titre et couverture (première et quatrième de couverture). Les informations du paratexte éclairent, dans un second temps, les personnages homosexuels qui sont présentés dans les titres retenus. L'examen du personnage s'effectue autour de points spécifiques: description (physique et psychologique), auxiliaires, références à des éléments ou personnages publics homosexuels, sexualité, autonomie et fonctionnalité dans le texte, principe de l'écart minimal, etc., tout en débordant à l'occasion sur certains éléments dignes d'attention. Cette analyse se veut un premier regard sur ces oeuvres, pour comprendre d'où elles sortent, â quoi elles répondent, dans quel courant elles s'inscrivent et comment elles s'y sont prises pour aborder un sujet délicat dans une société où l'on fait une grande place au roman-miroir tout en éprouvant un malaise évident lorsqu'il est question de sexualité adolescente."--Résumé abrégé par UMI.

Théâtre des disparues : Le Premier Jardin

Cette étude du Premier Jardin explore le legs historique et scénique au féminin que s’engage à mettre en lumière Flora, le personnage principal du roman. Flora, qui est comédienne, revendique une création au féminin sans pour autant échapper à un système patriarcal qui dépend de l’effacement du féminin. Cette revendication ambivalente et problématique se déploie par le palimpseste : les divers rôles qu’endosse Flora relèvent de l’Histoire et du récit théâtral.

Cet autre qui me regarde. Phénoménologie de la mémoire et temps eschatologique dans Le Premier Jardin et Oh les beaux jours

Alors que Les fous de Bassan s’attachait à mettre en scène une Amérique métonymique tournée vers sa fin, tout se passe comme si Le premier jardin visait pour sa part à lester cette Amérique incertaine et eschatologique par l’anamnèse de son commencement, qui, chez Anne Hébert, prend le plus souvent la forme d’un re-commencement. Il s’agira ici d’interroger le dispositif temporel mis en fiction dans le roman, notamment par l’entremise d’une lecture de la pièce Oh les beaux jours et de sa temporalité figée d’après-coup. À travers cette analyse de la temporalité, on voudra également mettre en relief l’instrumentalisation de l’histoire collective par le sujet, qui cherche ainsi à se prémunir de sa propre mémoire, constamment mise à distance au sein du roman.

SWOT analysis of a pediatric rehabilitation programme : a participatory evaluation fostering quality improvement

Purpose. To present the results of a strengths, weaknesses, opportunities and threats (SWOT) analysis used as part of a process aimed at reorganising services provided within a pediatric rehabilitation programme (PRP) in Quebec, Canada and to report the perceptions of the planning committee members regarding the usefulness of the SWOT in this process. Method. Thirty-six service providers working in the PRP completed a SWOT questionnaire and reported what they felt worked and what did not work in the existing model of care. Their responses were used by a planning committee over a 12- month period to assist in the development of a new service delivery model. Committee members shared their thoughts about the usefulness of the SWOT. Results. Current programme strengths included favourable organisational climate and interdisciplinary work whereas weaknesses included lack of psychosocial support to families and long waiting times for children. Opportunities included working with community partners, whereas fear of losing professional autonomy with the new service model was a threat. The SWOT results helped the planning committee redefine the programme goals and make decisions to improve service coordination. SWOT analysis was deemed as a very useful tool to help guide service reorganisation. Conclusions. SWOT analysis appears to be an interesting evaluation tool to promote awareness among service providers regarding the current functioning of a rehabilitation programme. It fosters their active participation in the reorganisation of a new service delivery model for pediatric rehabilitation.

Going beyond the identification of change facilitators to effectively implement a new model of services: lessons learned from a case example in paediatric rehabilitation

Purpose: To identify facilitators and barriers to service reorganization, how they evolved and interacted to influence change during the implementation of a new service delivery model of paediatric rehabilitation. Methods: Over 3 years, different stakeholders responded to SWOT questionnaires (n = 139) and participated in focus groups (n = 19) and telephone interviews (n = 13). A framework based on socio constructivist theories made sense of the data. Results: Facilitators related to the programme's structure (e.g. funding), the actors (e.g. willingness to test the new service model) and the change management process (e.g. participative approach). Some initial facilitators became barriers (e.g. leadership lacked at the end), while other barriers emerged (e.g. lack of tools). Understanding factor interactions requires examining the multiple actors’ intentions, actions and consequences and their relations with structural elements. Conclusions: Analysing facilitators and barriers helped better understand the change processes, but this must be followed by concrete actions to successfully implement new paediatric rehabilitation models.

Increasing the use of group interventions in a pediatric rehabilitation program: perceptions of administrators, therapists, and parents

Objectives. To explore perceptions related to increased utilization of group interventions as a part of the service reorganization within a pediatric rehabilitation program. Methods. Individual interviews with program administrators (n=13) and focus groups with therapists (n=19) and parents of children with disabilities (n=5) were conducted. Data were analyzed using a coding grid inspired by the organized action systems theory. Results. Administrators and therapists identified several issues including the need to improve the referral process for groups and the coordination across services. Groups considerably modified practice and required substantial efforts from therapists. Administrators felt groups contributed to increased service accessibility. Although therapists had some doubts about service quality in groups, especially in regard to the reduced attention to individual needs, they reported positive benefits on children’s social participation. Generally, parents were satisfied with group interventions. Conclusion. Groups appear to be a promising method of service delivery, but organizational-related issues should be considered.