Effects of the novel (Pro(3))GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

AIMS/HYPOTHESIS: This study examined the biological effects of the GIP receptor antagonist, (Pro3)GIP and the GLP-1 receptor antagonist, exendin(9-39)amide.

METHODS: Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic ( ob/ ob) mice.

RESULTS: In GIP receptor-transfected fibroblasts, (Pro(3))GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0+/-3.5% and 73.5+/-3.2% at 10(-6) mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60+/-0.7% at 10(-6) mol/l, whereas (Pro(3))GIP had no effect. (Pro(3))GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro(3))GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro3)GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small.

CONCLUSIONS/INTERPRETATION: These data show that (Pro(3))GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release.

Emotional speech: towards a new generation of databases

Research on speech and emotion is moving from a period of exploratory research into one where there is a prospect of substantial applications, notably in human-computer interaction. Progress in the area relies heavily on the development of appropriate databases. This paper addresses the issues that need to be considered in developing databases of emotional speech, and shows how the challenge of developing apropriate databases is being addressed in three major recent projects - the Belfast project, the Reading-Leeds project and the CREST-ESP project. From these and other studies the paper draws together the tools and methods that have been developed, addresses the problems that arise and indicates the future directions for the development of emotional speech databases.

Material effects on stress-induced defect generation in trenched silicon-on-insulator structures

We have investigated the influence of the material properties of the silicon device layer on the generation of defects, and in particular slip dislocations, in trenched and refilled fusion-bonded silicon-on-insulator structures. A strong dependence of the ease of slip generation on the type of dopant species was observed, with the samples falling into three basic categories; heavily boron-doped silicon showed ready slip generation, arsenic and antimony-doped material was fairly resistant to slip, while silicon moderately or lightly doped with phosphorous or boron gave intermediate behavior. The observed behavior appears to be controlled by differences in the dislocation generation mechanism rather than by dislocation mobility. The introduction of an implanted buried layer at the bonding interface was found to result in an increase in slip generation in the silicon, again with a variation according to the dopant species. Here, the greatest slip occurred for both boron and antimony-implanted samples. The weakening of the implanted material may be related to the presence of a band of precipitates observed in the silicon near the bonding interface. (C) 2001 The Electrochemical Society.

Effects of tip structure on the generation of metal clusters by an STM tip: a way to control the orientation of nanocrystallites?

The role of the crystalline orientation of the STM tip in the generation of metal clusters is studied by atom dynamics simulations. When a (111) facet is facing the surface, the process is accompanied by a perturbation of the surface stronger than that observed for more open tip structures. This implies a technological application: the possibility of orienting a nanocrystallite deposited on a tip according to the changes observed in the force on the tip.

Generation of macroscopic superposition states with small nonlinearity

We suggest a scheme to generate a macroscopic superposition state ("Schrodinger cat state") of a free-propagating optical field using a beam splitter, homodyne measurement, and a very small Kerr nonlinear effect. Our scheme makes it possible to reduce considerably the required nonlinear effect to generate an optical cat state using simple and efficient optical elements.

Entanglement generation in harmonic chains: Tagging by squeezing

We address the problem of springlike coupling between bosons in an open-chain configuration where the counter-rotating terms are explicitly included. We show that fruitful insight can be gained by decomposing the time-evolution operator of this problem into a pattern of linear-optics elements. This allows us to provide a clear picture of the effects of the counter-rotating terms in the important problem of long-haul entanglement distribution. The analytic control over the variance matrix of the state of the bosonic register allows us to track the dynamics of the entanglement. This helps in designing a global addressing scheme, complemented by a proper initialization of the register, which quantitatively improves the entanglement between the extremal oscillators in the chain, thus providing a strategy for feasible long-distance entanglement distribution.

Finite temperature dense matter studies on next-generation light sources

The construction of short-pulse tunable soft x-ray free electron laser sources based on the self-amplified spontaneous emission process will provide a major advance in capability for dense plasma-related and warm dense matter (WDM) research. The sources will provide 10(13) photons in a 200-fs duration pulse that is tunable from approximately 6 to 100 nm. Here we discuss only two of the many applications made possible for WDM that has been severely hampered by the fact that laser-based methods have been unavailable because visible light will not propagate at electron densities of n(e) greater than or equal to 10(22) cm(-3). The next-generation light sources will remove these restrictions.