Systems Genetics of Metabolism: The Use of the BXD Murine Reference Panel for Multiscalar Integration of Traits.

Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders.

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.

Social inequalities of functioning and perceived health in Switzerland: a representative cross-sectional analysis.

Many people worldwide live with a disability, i.e. limitations in functioning. The prevalence is expected to increase due to demographic change and the growing importance of non-communicable disease and injury. To date, many epidemiological studies have used simple dichotomous measures of disability, even though the WHO's International Classification of Functioning, Disability, and Health (ICF) provides a multi-dimensional framework of functioning. We aimed to examine associations of socio-economic status (SES) and social integration in 3 core domains of functioning (impairment, pain, limitations in activity and participation) and perceived health. We conducted a secondary analysis of representative cross-sectional data of the Swiss Health Survey 2007 including 10,336 female and 8,424 male Swiss residents aged 15 or more. Guided by a theoretical ICF-based model, 4 mixed effects Poisson regressions were fitted in order to explain functioning and perceived health by indicators of SES and social integration. Analyses were stratified by age groups (15-30, 31-54, ≥55 years). In all age groups, SES and social integration were significantly associated with functional and perceived health. Among the functional domains, impairment and pain were closely related, and both were associated with limitations in activity and participation. SES, social integration and functioning were related to perceived health. We found pronounced social inequalities in functioning and perceived health, supporting our theoretical model. Social factors play a significant role in the experience of health, even in a wealthy country such as Switzerland. These findings await confirmation in other, particularly lower resourced settings.

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.