Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.

Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously that mice lacking (beta)arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the (beta)arr2-muOR interaction in other neuronal systems, we have, in the present study, tested (beta)arr2 knock-out ((beta)arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the (beta)arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the (beta)arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the muOR is differentially regulated in diverse regions of the CNS. Furthermore, although (beta)arr2 appears to be the most prominent and proximal determinant of muOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.

Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice.

The reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of mu-opioid receptors (muOR). Both mu-opioid and dopamine receptors are members of the G-protein-coupled receptor (GPCR) family of proteins. GPCRs are known to undergo desensitization involving phosphorylation of the receptor and the subsequent binding of beta(arrestins), which prevents further receptor-G-protein coupling. Mice lacking beta(arrestin)-2 (beta(arr2)) display enhanced sensitivity to morphine in tests of pain perception attributable to impaired desensitization of muOR. However, whether abrogating muOR desensitization affects the reinforcing and psychomotor properties of morphine has remained unexplored. In the present study, we examined this question by assessing the effects of morphine and cocaine on locomotor activity, behavioral sensitization, conditioned place preference, and striatal dopamine release in beta(arr2) knock-out (beta(arr2)-KO) mice and their wild-type (WT) controls. Cocaine treatment resulted in very similar neurochemical and behavioral responses between the genotypes. However, in the beta(arr2)-KO mice, morphine induced more pronounced increases in striatal extracellular dopamine than in WT mice. Moreover, the rewarding properties of morphine in the conditioned place preference test were greater in the beta(arr2)-KO mice when compared with the WT mice. Thus, beta(arr2) appears to play a more important role in the dopaminergic effects mediated by morphine than those induced by cocaine.

TRANSCENDING FACH: A SEARCH FOR IDENTITY INSIDE AND OUT OF MEZZO-SOPRANO REPERTOIRE

The German Fach system is a tool to classify voices in classical singing. This dissertation comprises three different programs that reflect my search for identity as a mezzo-soprano and my desire to transcend the limitations of Fach. The three programs, all presented at The Clarice Performing Arts Center, contain repertoire written for male and female voices thus allowing me to explore areas outside of the mezzo-soprano Fach, gain a better understanding of the Fach system and guide me as I strive to become a more mature performer. In my first program, I sang the role of Sesto, a role that was composed originally for a castrate, in the opera La Clemenza di Tito by W.A. Mozart. The Maryland Opera Studio production took place April 30, May 2,4&6,2003. Performing this gender-bending role provided an experience of physical behavior from the male view point along with the demands of coloratura singing. Program two (November 30,2004) contained the song cycle Dichterliebe by Robert Schumann and songs by Ludwig van Beethoven, Franz Schubert and Felix Mendelssohn, which are usually sung by male voices. This program experimented with extended range, tessitura and a gender-bending performance in the art song arena. 8 In program three (April 21 &23,2005), I sang the contralto role of Cornelia from Giulio Cesare in Egitto by George Frederic Handel. The role of Cornelia is psychologically complex, expressing emotions such as love, melancholy, rage, malice, joy and fear. To convey these emotions a voice needs warmth and darkness of quality. Although the range is close to that of the mezzo-soprano, Handel wrote Cornelia for contralto voice because he wanted a dark timbre and this role allowed me to develop my lower register and manage suitable ornamentations. The programs are documented in a digital format available on compact disc and are accompanied by the oral presentation at the defense of this dissertation.

Where does energy R&D come from? Examining crowding out from energy R&D

Recent efforts to endogenize technological change in climate policy models demonstrate the importance of accounting for the opportunity cost of climate R&D investments. Because the social returns to R&D investments are typically higher than the social returns to other types of investment, any new climate mitigation R&D that comes at the expense of other R&D investment may dampen the overall gains from induced technological change. Unfortunately, there has been little empirical work to guide modelers as to the potential magnitude of such crowding out effects. This paper considers both the private and social opportunity costs of climate R&D. Addressing private costs, we ask whether an increase in climate R&D represents new R&D spending, or whether some (or all) of the additional climate R&D comes at the expense of other R&D. Addressing social costs, we use patent citations to compare the social value of alternative energy research to other types of R&D that may be crowded out. Beginning at the industry level, we find no evidence of crowding out across sectors-that is, increases in energy R&D do not draw R&D resources away from sectors that do not perform R&D. Given this, we proceed with a detailed look at alternative energy R&D. Linking patent data and financial data by firm, we ask whether an increase in alternative energy patents leads to a decrease in other types of patenting activity. While we find that increases in alternative energy patents do result in fewer patents of other types, the evidence suggests that this is due to profit-maximizing changes in research effort, rather than financial constraints that limit the total amount of R&D possible. Finally, we use patent citation data to compare the social value of alternative energy patents to other patents by these firms. Alternative energy patents are cited more frequently, and by a wider range of other technologies, than other patents by these firms, suggesting that their social value is higher. © 2011 Elsevier B.V.

Modeling of ingot development during the start-up phase of direct chill casting

Direct chill (DC) casting is a core primary process in the production of aluminum ingots. However, its operational optimization is still under investigation with regard to a number of features, one of which is the issue of curvature at the base of the ingot. Analysis of these features requires a computational model of the process that accounts for the fluid flow, heat transfer, solidification phase change, and thermomechanical analysis. This article describes an integrated approach to the modeling of all the preceding phenomena and their interactions.

The knowledge is out there

Review Essay. On Bourdieu, education and society, by Derek Robbins, Oxford, The Bardwell Press, 2006, 596 pp., £75, ISBN 0-95-486836-6. Bringing knowledge back in, from social constructivism to social realism in the sociology of education, by Michael Young, London, Routledge, 2008, 247 pp.,£23.99, ISBN 9-78-041532-121-1. Personal knowledge, towards a post-critical philosophy, by Michael Polanyi, Chicago, University of Chicago Press, 1962, 428 pp., £18.99, ISBN 0-22-667288-3.

We could make a meal out of nothing: contested explanations of inequalities in health

This paper reports on the qualitative findings from a comparative study of public health and lifestyles in South East England and Northern France, regions with similar geographic and economic characteristics. Data from health surveys showed that both countries had an increasing BMI with age, particularly in Northern France. This was despite the finding that the percentage eating fresh fruit and vegetable at least five days a week in Northern France increased with age (from well over 50% to over 90%) compared to around 50% to around 75% in South East England. Qualitative data on health inequalities and how they could be addressed were gathered by focus groups sampling from five tiers using the Townsend Index for comparability (14 in England with 106 participants overall; 13 in France with 143 participants). Both had about two thirds women participants, with a preponderance of middle aged and older people. There was a striking difference in the salience of diet between the two countries; in the French data it was raised only 14 times, whereas in England there were 165 occurrences, and these were often distinguished by their use of narrative. Older respondents contrasted the pressures on families today and the expense of fresh fruit and vegetables with their own childhood or childrearing, when cheap meals could be created using skills which have now been lost. These data therefore provide further evidence that providing food is a moral activity.

To fit in or stand out? The interaction between mortality salience, dissent and self esteem on social projection

Social projection (SP) refers to our tendency to assume that others think the same as we do, but the effect can also be used to detect the extent to which participants want to see themselves as similar to others. Simon et al (1997) found that participants informed that they were deviant increased their SP but those told that they were conformist reduced theirs. This compensatory function supports Brewer’s optimal distinctiveness which states that a balance must be struck between competing desires to feel similar and unique. In line with terror management theory, the effect was particularly apparent under conditions of mortality salience (MS). So far SP has only been examined on measures that target personal identity so this experiment developed a measure to target social identity as well. Participants were provided with either minority or majority dissent feedback, in MS or control conditions, and their SP on items relevant to personal and social identity were recorded. Results showed that group feedback only impacted upon participants SP on social identity measures and interacted with MS and self-esteem; those with high self-esteem had higher SP scores following minority dissent under conditions of mortality salience, indicating an attempt to assert their individuality. On SP measures targeting personal identity, MS and self-esteem interacted; the death prime increased SP scores for those with low self-esteem but decreased it for those with high self-esteem. Findings are interpreted in terms of TMT and optimal distinctiveness theory and their applications.

Advanced product development integration architecture: an out-of-box solution to support distributed production networks

This paper presents novel collaboration methods implemented using a centralized client/server product development integration architecture, and a decentralized peer-to-peer network for smaller and larger companies using open source solutions. The product development integration architecture has been developed for the integration of disparate technologies and software systems for the benefit of collaborative work teams in design and manufacturing. This will facilitate the communication of early design and product development within a distributed and collaborative environment. The novelty of this work is the introduction of an‘out-of-box’ concept which provides a standard framework and deploys this utilizing a proprietary state-of-the-art product lifecycle management system (PLM). The term ‘out-of-box’ means to modify the product development and business processes to suit the technologies rather than vice versa. The key business benefits of adopting such an approach are a rapidly reconfigurable network and minimal requirements for software customization to avoid systems instability

Report on trawling and other investigations carried out in the Bays on the South-East Coast of Devon during 1901 and 1902

Section 1. The Brixham fishing-grounds and fishery statistics. Section 2. Distribution and migrations of food-fishes. Section 3. The reproduction of the flat-fishes. Appendix 1. Preliminary Report on the Trawling Experiments in the Bays on the South Coast of Devon.