Multisensory Integration: Flexible Use of General Operations.

Research into the anatomical substrates and "principles" for integrating inputs from separate sensory surfaces has yielded divergent findings. This suggests that multisensory integration is flexible and context dependent and underlines the need for dynamically adaptive neuronal integration mechanisms. We propose that flexible multisensory integration can be explained by a combination of canonical, population-level integrative operations, such as oscillatory phase resetting and divisive normalization. These canonical operations subsume multisensory integration into a fundamental set of principles as to how the brain integrates all sorts of information, and they are being used proactively and adaptively. We illustrate this proposition by unifying recent findings from different research themes such as timing, behavioral goal, and experience-related differences in integration.

Rpe65-Gene Transfer Using an Integration-Deficient Lentiviral Vector

Purpose: We previously demonstrated efficient retinal rescue of RPE65 mouse models (Rpe65-/- (Bemelmans et al, 2006) and Rpe65R91W/R91W mice) using a HIV1-derived lentiviral vector encoding for the mouse RPE65 cDNA. In order to optimize a lentiviral vector as an alternative tool for RPE65-derived Leber Congenital Amaurosis clinical trials, we evaluated the efficiency of an integration-deficient lentiviral vector (IDLV) encoding the human RPE65 cDNA to restore retinal function in the Rpe65R91W/R91W mice. Methods: An HIV-1-derived lentiviral vector expressing either the hrGFPII or the human Rpe65 cDNA under the control of a 0.8 kb fragment of the human Rpe65 promoter (R0.8) was produced by transient transfection of 293T cells. A LQ-integrase mutant was used to generate the IDLV vectors. IDLV-R0.8-hRPE65 or hrGFPII were injected subretinally into 1 month-old Rpe65R91W/R91W mice. Functional rescue was assessed by ERG (1 and 3 months post-injection) and cone survival by immunohistology. Results: An increased light sensitivity was detected by scotopic ERG in animals injected with IDLV-R0.8-hRPE65 compared to hrGFPII-treated animals or untreated mice. However the improvement was delayed compared to integration-proficient LV and observed at 3 months but not 1 month post-injection. Immunolabelling of cone markers showed an increased number of cones in the transduced area compared to control groups. Conclusions: The IDLV-R0.8-hRPE65 vectors allow retinal improvement in the Rpe65R91W/R91W mice. Both rod function and cone survival were demonstrated even if there is a delay in the rescue as assessed by scotopic ERG. Integration-deficient vectors minimize insertional mutagenesis and thus are safer candidates for human application. Further experiments using large animals are now needed to validate correct gene transfer and expression of the RPE65 gene as well as tolerance of the vector after subretinal injection before envisaging a clinical trial application.

Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.

Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.

European Integration Without EU Membership : Models, Experiences, Perspectives

At the beginning of the 1990s, the concept of "European integration" could still be said to be fairly unambiguous. Nowadays, it has become plural and complex almost to the point of unintelligibility. This is due, of course, to the internal differentiation of EU membership, with several Member States pulling out of key integrative projects such as establishing an area without frontiers, the "Schengen" area, and a common currency. But this is also due to the differentiated extension of key integrative projects to European non-EU countries - Schengen is again a case in point. Such processes of "integration without membership", the focus of the present publication, are acquiring an ever-growing topicality both in the political arena and in academia. International relations between the EU and its neighbouring countries are crucial for both, and their development through new agreements features prominently on the continent's political agenda. Over and above this aspect, the dissemination of EU values and standards beyond the Union's borders raises a whole host of theoretical and methodological questions, unsettling in some cases traditional conceptions of the autonomy and separation of national legal orders. This publication brings together the papers presented at the Integration without EU Membership workshop held in May 2008 at the EUI (Max Weber Programme and Department of Law). It aims to compare different models and experiences of integration between the EU, on the one hand, and those European countries that do not currently have an accession perspective on the other hand. In delimiting the geographical scope of the inquiry, so as to scale it down to manageable proportions, the guiding principles have been to include both the "Eastern" and "Western" neighbours of the EU, and to examine both structured frameworks of cooperation, such as the European Neighbourhood Policy and the European Economic Area, and bilateral relations developing on a more ad hoc basis. These principles are reflected in the arrangement of the papers, which consider in turn the positions of Ukraine, Russia, Norway, and Switzerland in European integration - current standing, perspectives for evolution, consequences in terms of the EU-ization of their respective legal orders1. These subjects are examined from several perspectives. We had the privilege of receiving contributions from leading practitioners and scholars from the countries concerned, from EU highranking officials, from prominent specialists in EU external relations law, and from young and talented researchers. We wish to thank them all here for their invaluable insights. We are moreover deeply indebted to Marise Cremona (EUI, Law Department, EUI) for her inspiring advice and encouragement, as well as to Ramon Marimon, Karin Tilmans, Lotte Holm, Alyson Price and Susan Garvin (Max Weber Programme, EUI) for their unflinching support throughout this project. A word is perhaps needed on the propriety and usefulness of the research concept embodied in this publication. Does it make sense to compare the integration models and experiences of countries as different as Norway, Russia, Switzerland, and Ukraine? Needless to say, this list of four evokes a staggering diversity of political, social, cultural, and economic conditions, and at least as great a diversity of approaches to European integration. Still, we would argue that such diversity only makes comparisons more meaningful. Indeed, while the particularities and idiosyncratic elements of each "model" of integration are fully displayed in the present volume, common themes and preoccupations run through the pages of every contribution: the difficulty in conceptualizing the finalité and essence of integration, which is evident in the EU today but which is greatly amplified for non-EU countries; the asymmetries and tradeoffs between integration and autonomy that are inherent in any attempt to participate in European integration from outside; the alteration of deeply seated legal concepts, and concepts about the law, that are already observable in the most integrated of the non-EU countries concerned. These issues are not transient or coincidental: they are inextricably bound up with the integration of non-EU countries in the EU project. By publishing this collection, we make no claim to have dealt with them in an exhaustive, still less in a definitive manner. Our ambition is more modest: to highlight the relevance of these themes, to place them more firmly on the scientific agenda, and to provide a stimulating basis for future research and reflection.

Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.

The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21(WAF1/Cip1) gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-Jkappa protein to the p21 promoter. We show here that Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control.

Processus intégratifs et gouvernance clinique dans la psychiatrie institutionnelle [Integration processes and clinical governance in the psychiatric network]

The Swiss Medical Insurance Act (LAMaL) requires the planning of psychiatric care. This necessitates a coordination between the Department of Public Health and the institutional governance. Given the difficulties to draw comparisons between a wide range of systems in a federal country, the Swiss Conference of the State Directors of Health (CDS) proposed as a first step that each canton present some of the key programs they had developed. In the canton Vaud, the implementation of mobile community treatment teams and of an early intervention program for psychosis was chosen. The main challenges faced were to go past traditional divides within the organisation of the Swiss Health system and to conciliate the requirements of public health with the needs of treating teams, in order to promote early intervention in mental health disorders.

Une étude clinique de l'activité de médecin de premier secours : vers une modélisation d'une profession complexe

Ce travail a pour objectif d'étudier l'évolution du métier de médecin de premier recours à la lumière du réel de son activité. Afin de pallier les lacunes de la littérature, nous proposons d'investiguer les perceptions et les pratiques rapportées de médecins de premier recours, considérant leur activité comme située dans un contexte spécifique. Un cadre théorique multiréférencé, intégrant les apports de Bischoff (2012), de la théorie de l'activité (Engeström et al., 1999), de l'ergonomie (Daniellou, 1996 ; Falzon, 2004a; Leplat, 1997) et de certains courants de la psychologie du travail (Curie et al., 1990 ; Curie, 2000b ; Malrieu, 1989) permet de tenir compte de la complexité du travail des médecins de premier recours. Une méthodologie mixte, alliant une approche qualitative par entretiens semi-structurés (n=20) à une approche quantitative par questionnaire (n=553), a été développée. Les résultats de l'analyse thématique des entretiens mettent en évidence trois thèmes majeurs : l'Evolution du métier (Thème 1), caractérisé par les changements perçus, les demandes des populations qui consultent et les paradoxes et vécus des médecins ; les Ajustements et supports (Thème 2) mis en place par les médecins pour faire face aux changements et aux difficultés de leur métier ; les Perceptions et les attentes par rapport au métier (Thème 3), mettant en avant des écarts perçus entre la formation et la réalité du métier. La partie quantitative permet de répondre aux questionnements générés à partir des résultats qualitatifs et de généraliser certains d'entre eux. Suite à l'intégration des deux volets de l'étude, nous présentons une nouvelle modélisation du métier de médecin de premier recours, soulignant son aspect dynamique et évolutif. Cette modélisation rend possible l'analyse de l'activité réelle des médecins, en tenant compte des contraintes organisationnelles, des paradoxes inhérents au métier et du vécu des médecins de premier recours. L'analyse des limites de cette étude ouvre à de nouvelles perspectives de recherche. A l'issue de ce travail, nous proposons quelques usages pragmatiques, qui pourront être utiles aux médecins de premier recours et aux médecins en formation, non seulement dans la réalisation de leur activité, mais également pour le maintien de leur équilibre et leur épanouissement au sein du métier. - This study aims to investigate the evolution of primary care physicians' work, in the light of the reality of their activity. In order to overcome the limitations of the literature, we propose to focus on primary care physicians' reported perceptions and practices, considering their activity as situated in a specific context. The theoretical framework refers to Bischoff (2012), Activity theory (Engeström et al., 1999), ergonomy (Daniellou, 1996; Falzon, 2004a; Leplat, 1997) and work psychology (Curie et al., 1990 ; Curie, 2000b ; Malrieu, 1989) and enables to take into account the complexity of primary care physicians' work. This mixed methods study proposes semi-structured interviews (n=20) and a questionnaire (n=553). Thematic analysis of interviews points out three major themes : Evolution of work (Theme 1) is characterised by perceived changes, patients' expectations and paradoxes ; Adjustments and supports (Theme 2), that help to face changes and difficulties of work ; Perceptions related to work, including differences between work reality as represented during medical education/training and actual work reality. Quantitative part of the study enables to answer questions generated from qualitative results and to generalise some of them. Integration of qualitative and quantitative results leads to a new modelling of primary care physicians ' work, that is dynamic and evolutionary. This modelling is useful to analyse the primary care physicians' activity, including organisational constraints, paradoxes of work and how primary care physicians are experiencing them. Despite its limitations, this study offers new research perspectives. To conclude, we state pragmatic recommendations that could be helpful to primary care physicians in private practice and junior doctors, in order to realise their activity, to maintain their balance and to sustain their professional fulfilment.