A new paradigm for improved co-ordination and efficacy of European biomedical research: taking diabetes as a model

Today, European biomedical and health-related research is insufficiently well funded and is fragmented, with no common vision, less-than-optimal sharing of resources, and inadequate support and training in clinical research. Improvements to the competitiveness of European biomedical research will depend on the creation of new infrastructures that must be dynamic and free of bureaucracy, involve all stakeholders and facilitate faster delivery of new discoveries from bench to bedside. Taking diabetes research as the model, a new paradigm for European biomedical research is presented, which offers improved co-ordination and common resources that will benefit both academic and industrial clinical research. This includes the creation of a European Council for Health Research, first proposed by the Alliance for Biomedical Research in Europe, which will bring together and consult with all health stakeholders to develop strategic and multidisciplinary research programmes addressing the full innovation cycle. A European Platform for Clinical Research in Diabetes is proposed by the Alliance for European Diabetes Research (EURADIA) in response to the special challenges and opportunities presented by research across the European region, with the need for common standards and shared expertise and dat

Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia

Summary: Neuropeptide Y in the hypothalamus is a potent physiological stimulator of feeding, and may contribute to the characteristic metabolic defects of obesity when hypothalamic levels remain chronically elevated. Since corticosterone and insulin are important regulators of fuel metabolism, the longitudinal effects of chronic (6 days) intracerebroventricular infusion of neuropeptide Y in normal rats on the hypothalamo-pituitary-adrenal axis and on insulin secretion were studied. Neuropeptide Y-infused rats were either allowed to eat ad libitum, or were pair-fed with normophagic control rats. Neuropeptide Y increased the basal plasma concentrations of adrenocorticotropic hormone and corticosterone during the first 2 days of its intracerebroventricular infusion and increased cold stress-induced plasma adrenocorticotropic hormone concentrations. After 4-6 days of central neuropeptide Y infusion, however, basal plasma adrenocorticotropic hormone and corticosterone concentrations were no different from control values (except in ad libitum-fed rats in which corticosteronaemia remained elevated), they were unaffected by the stress of cold exposure, and the hypothalamic content of corticotropin-releasing factor immunoreactivity was significantly decreased. A state of hyperinsulinaemia was present throughout the 6 days of intracerebroventricular neuropeptide Y infusion, being more marked in the ad libitum-fed than in the pair-fed group. The proportions of insulin, proinsulin, and conversion intermediates in plasma and pancreas were unchanged. Hyperinsulinaemia of the pair-fed neuropeptide Y-infused rats was accompanied by muscle insulin resistance and white adipose tissue insulin hyperresponsiveness, as assessed by the in vivo uptake of 2-deoxyglucose. Finally, bilateral subdiaphragmatic vagotomy prevented both the basal and the marked glucose-induced hyperinsulinaemia of animals chronically infused with neuropeptide Y, demonstrating that central neuropeptide Y-induced hyperinsulinaemia is mediated by the parasympathetic nervous syste

Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription

Aims/hypothesis: The transcription factor Pdx1 is required for the development and differentiation of all pancreatic cells. Beta-cell specific inactivation of Pdx1 in developing or adult mice leads to an increase in glucagon-expressing cells, suggesting that absence of Pdx1could favour glucagon gene expression by a default mechanism. Method: We investigated the inhibitory role of Pdx1 on glucagon gene expression in vitro. The glucagonoma cell line InR1G9 was transduced with a Pdx1-encoding lentiviral vector and insulin and glucagon mRNA levels were analysed by northern blot and real-time PCR. To understand the mechanism by which Pdx1 inhibits glucagon gene expression, we studied its effect on glucagon promoter activity in non-islet cells using transient transfections and gel-shift analysis. Results: In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the α-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. Conclusion/interpretation: Cell-specific expression of the glucagon gene can only occur when Pdx1 expression extinguishes from the early α cell precurso

Theory of decoherence in a matter wave Talbot-Lau interferometer

We present a theoretical framework to describe the effects of decoherence on matter waves in Talbot-Lau interferometry. Using a Wigner description of the stationary beam the loss of interference contrast can be calculated in closed form. The formulation includes both the decohering coupling to the environment and the coherent interaction with the grating walls. It facilitates the quantitative distinction of genuine quantum interference from the expectations of classical mechanics. We provide realistic microscopic descriptions of the experimentally relevant interactions in terms of the bulk properties of the particles and show that the treatment is equivalent to solving the corresponding master equation in paraxial approximation.Comment: 20 pages, 4 figures (minor corrections; now in two-column format