986 resultados para Agonist-antagonist relationship


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Davies, Jeffrey, 'Gates, beads and Danubians. The defences and garrison of the auxiliary fort at Castell Collen: a speculative relationship', Bayerische Vorgeschichtsblatter (2006) 71 pp.3-13 RAE2008

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Mitchell defined and axiomatized a subtyping relationship (also known as containment, coercibility, or subsumption) over the types of System F (with "→" and "∀"). This subtyping relationship is quite simple and does not involve bounded quantification. Tiuryn and Urzyczyn quite recently proved this subtyping relationship to be undecidable. This paper supplies a new undecidability proof for this subtyping relationship. First, a new syntax-directed axiomatization of the subtyping relationship is defined. Then, this axiomatization is used to prove a reduction from the undecidable problem of semi-unification to subtyping. The undecidability of subtyping implies the undecidability of type checking for System F extended with Mitchell's subtyping, also known as "F plus eta".

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Recent measurements of local-area and wide-area traffic have shown that network traffic exhibits variability at a wide range of scales self-similarity. In this paper, we examine a mechanism that gives rise to self-similar network traffic and present some of its performance implications. The mechanism we study is the transfer of files or messages whose size is drawn from a heavy-tailed distribution. We examine its effects through detailed transport-level simulations of multiple TCP streams in an internetwork. First, we show that in a "realistic" client/server network environment i.e., one with bounded resources and coupling among traffic sources competing for resources the degree to which file sizes are heavy-tailed can directly determine the degree of traffic self-similarity at the link level. We show that this causal relationship is not significantly affected by changes in network resources (bottleneck bandwidth and buffer capacity), network topology, the influence of cross-traffic, or the distribution of interarrival times. Second, we show that properties of the transport layer play an important role in preserving and modulating this relationship. In particular, the reliable transmission and flow control mechanisms of TCP (Reno, Tahoe, or Vegas) serve to maintain the long-range dependency structure induced by heavy-tailed file size distributions. In contrast, if a non-flow-controlled and unreliable (UDP-based) transport protocol is used, the resulting traffic shows little self-similar characteristics: although still bursty at short time scales, it has little long-range dependence. If flow-controlled, unreliable transport is employed, the degree of traffic self-similarity is positively correlated with the degree of throttling at the source. Third, in exploring the relationship between file sizes, transport protocols, and self-similarity, we are also able to show some of the performance implications of self-similarity. We present data on the relationship between traffic self-similarity and network performance as captured by performance measures including packet loss rate, retransmission rate, and queueing delay. Increased self-similarity, as expected, results in degradation of performance. Queueing delay, in particular, exhibits a drastic increase with increasing self-similarity. Throughput-related measures such as packet loss and retransmission rate, however, increase only gradually with increasing traffic self-similarity as long as reliable, flow-controlled transport protocol is used.

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In this paper, we introduce the Generalized Equality Classifier (GEC) for use as an unsupervised clustering algorithm in categorizing analog data. GEC is based on a formal definition of inexact equality originally developed for voting in fault tolerant software applications. GEC is defined using a metric space framework. The only parameter in GEC is a scalar threshold which defines the approximate equality of two patterns. Here, we compare the characteristics of GEC to the ART2-A algorithm (Carpenter, Grossberg, and Rosen, 1991). In particular, we show that GEC with the Hamming distance performs the same optimization as ART2. Moreover, GEC has lower computational requirements than AR12 on serial machines.

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In the area of food and pharmacy cold storage, temperature distribution is considered as a key factor. Inappropriate distribution of temperature during the cooling process in cold rooms will cause the deterioration of the quality of products and therefore shorten their life-span. In practice, in order to maintain the distribution of temperature at an appropriate level, large amount of electrical energy has to be consumed to cool down the volume of space, based on the reading of a single temperature sensor placed in every cold room. However, it is not clear and visible that what is the change of energy consumption and temperature distribution over time. It lacks of effective tools to visualise such a phenomenon. In this poster, we initially present a solution which combines a visualisation tool with a Computational Fluid Dynamics (CFD) model together to enable users to explore such phenomenon.

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The Lisbon Agenda places Europe in a uniquely difficult position globally, most particularly as an example of a social and regulatory experiment which many consider to be doomed to failure. The drive towards economic competitiveness has led to a focus on regulation and its effect on entrepreneurship, productivity and business growth but assessing this relationship is complex for a number of reasons. First, not all regulatory effects can be predicted precisely in relation to behavioural outcomes. Path-dependency scholars have also demonstrated that the regulation will have varying effects depending on context. Second, theoretically it is clear that many non-regulatory factors may contribute to economic and competitive success. Third, there is evidence of internal conflict within the Commission as to the relative importance of the Lisbon goals. Finally, the experience of distinct Member States presents challenges both for assessment and prescriptive remedies. The Commission has estimated that the cost of regulatory compliance obligations on businesses in the EU is between 4% and 6% of gross domestic product and that 15% of this figure is avoidable 'red tape' (the term used specifically to signify unnecessary compliance burdens). This article proposes to assess the likely outcomes of de-regulation as we rapidly approach 2010, the year for attainment of the Lisbon goals.

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This research asks the question: “What are the relational dynamics in Masters (MA) supervision?” It does so by focusing upon the supervisory relationship itself. It does this through dialoguing with the voices of both MA supervisors and supervisees in the Humanities using a Cultural Historical Activity Theory (CHAT) framework. In so doing, this research argues for a re-evaluation of how MA supervision is conceptualised and proposes a new theoretical framework for conceptualising MA supervision as a relational phenomenon. The research design was derived from an Activity Theory-influenced methodology. Data collection procedures included the administration of Activity Theory Logs, individual semi-structured interviews with both supervisors and supervisees and the completion of reflective journals. Grounded Theory was used to analyse the data. The sample for the study consists of three supervisor-supervisee dyads from three disciplines in the Humanities. Data was collected over the course of one academic year, 2010-2011. This research found that both individual and shared relational dynamics play an important role in MA supervision. Individual dynamics, such as supervisors’ iterative negotiation of ambiguity/clarity and supervisees’ boundary work, revealed that both parties attempt to negotiate a separation between their professional-academic identities and personal identities. However, an inherent paradox emerged when the shared relational dynamics of MA supervision were investigated. It was found that the shared space created by the supervisory relationship did not only exist in a physical setting, but was also psychoactive in nature and held strong emotional resonances for both parties involved. This served to undermine the separation between professional-academic and personal identities. As a result, this research argues that the interaction between the individual and shared relational dynamics in MA supervision enables, for both supervisors and supervisees, a disciplined improvisation of academic identity.

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The GABAB receptor has been postulated as a possible drug target in the treatment of anxiety disorders and cocaine addiction. Indeed, a wealth of preclinical data is emerging that has shown that mice lacking functional GABAB receptors display a highly anxious behaviour across a range of behavioural models of anxiety. Additionally, novel compounds that act by altering the allosteric conformation of the GABAB receptor to a more active state; the GABAB receptor positive modulators, have been repeatedly demonstrated to have anxiolytic effects in animals. In addition to being a putative anxiolytic drug target, the GABAB receptor has been identified as a novel target for antiaddictive therapies. Indeed GABAB receptor positive modulators have been demonstrated to have anti-addictive properties across a broad variety of behavioural paradigms. Despite these findings, several gaps in our knowledge of the role played by the GABAB receptor in both anxiety and drug abuse disorder exist. The aim of this thesis was to use preclinical animal models in an effort to further probe the role played by the GABAB receptor in anxiety and addiction. Our studies initially examined the role played by the GABAB receptor in the neurodevelopmental processes underpinning of anxiety. Our studies demonstrated that treating mouse pups in early life with the GABAB receptor agonist baclofen produced an anxious phenotype in adult life, whereas treatment with the GABAB receptor antagonist CGP52432 produced no effects on adult behaviour. Further to this, we examined whether the anxious behaviour induced by early life blockade of the serotonin reuptake transporter was dependant on alterations in GABAB receptor function. Our studies however revealed no effect of early life selective serotonin reuptake inhibitor treatment on adult life baclofen sensitivity. The next issue addressed in this thesis is the characterization of the effects of a GABAB receptor positive modulator and a GABAB receptor antagonist in a behavioural model of conditioned fear behaviour. These novel classes of GABAB receptor ligands have been considerably less well characterized in this facet of preclinical anxiety behaviour than in terms of innate anxiety behaviour. Our study however revealed that the GABAB receptor positive modulator GS39783 and the GABAB receptor antagonist CGP52432 were without effect on the acquisition, expression or extinction of conditioned fear in our model. The next element of this thesis dealt with the characterization of a novel mouse model, the GABAB(2)- S892A mouse. This mouse has been engineered to express a form of the GABAB(2) receptor subunit wherein the function determining serine phosphorylation site cannot be phosphorylated. We initially tested this mouse in terms of its GABAB receptor function in adult life, followed by testing it in a battery of tests of unconditioned and learned anxiety behaviour. We also examined the behavioural and molecular responses of the GABAB(2)-S892A mouse to cocaine. All of our studies appear to show that the GABAB(2)-S892A mouse is indistinguishable from wildtype controls. The final aim of the thesis was to investigate the behavioural and molecular sensitivity of the GABAB(1) subunit isoform null mice, the GABAB(1a) -/- and GABAB(1b) -/- mice to cocaine. Our studies revealed that these mice display differing behavioural responses to cocaine, with the GABAB(1a) -/- mouse displaying a hypersensitivity to the acute locomotor effects of cocaine, while the GABAB(1b) -/- displayed blunted locomotor sensitisation to cocaine.

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Accepted Version

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Initial studies have demonstrated that intra- renal infusion of Ang (1-7) caused a diuresis and natriuresis that was proportional to the degree of activation of the Renin Angiotensin Aldosterone System (RAAS). This raised the question as why the magnitude of this diuresis and natriuresis was compromised in rats receiving a high sodium diet (suppressed RAAS) and enhanced in low sodium fed rats (activated RAAS)? Could the answer lie with changes in intra-renal AT1 or Mas receptor expression? Interestingly, the observed Ang (1-7) induced increases in sodium and water excretion in rats receiving either a low or normal sodium diet were and blocked in the presence of the AT 1 receptor antagonist (Losartan) in the presence of the, 'Mas' receptor antagonist (A-779). These data suggest that both AT1 and 'Mas' receptors need to be functional in order to fully mediate the renal responses to intra-renal Ang (1-7) infusion. Importantly, further experimentation also revealed that there is a proportional relationship between AT 1 receptor expression in the rat renal cortex and the magnitude of the excretory actions of intra renal Ang (1-7) infusion, which is only partially dependent on the level of 'Mas' receptor expression. These observations suggest that although Ang (1-7) induced increases in sodium and water excretion are mediated by the Mas receptor, the magnitude of these excretory responses appear to be dependent upon the level of AT 1 receptor expression and more specifically Ang II/ AT 1 receptor signalling. Thus in rats receiving a low sodium diet, Ang (1-7) acts via the Mas receptor to inhibit Ang II/ AT 1 receptor signalling. In rats receiving a high sodium diet the down regulated AT 1 receptor expression implies a reduction in Ang II/ AT 1 receptor signalling which renders the counter-regulatory effects of intra-renal Ang (1-7) infusion redundant.

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This study examines the relationship between rural livelihoods and livestock keeping in Sidama Zones, southern Ethiopia. The livelihood context, assets and strategies of households are the key features of rural livelihoods considered in the study; while households’ livestock ownership, dependence on livestock and livestock management are the main aspects of livestock keeping examined. The study used the sustainable livelihood approach as a framework for data collection and analysis. Describing the main features of rural livelihoods and livestock keeping, and the general pattern of relationship between them, this study mainly aims at identifying the main livelihood factors that determine livestock keeping in the study area. Descriptive statistics, pair wise correlations, mean comparisons and analysis of variance were used to describe rural livelihoods and livestock keeping as well as the relationship between them. Tobit regressions were used to examine the effect of the various livelihood factors on households’ livestock ownership and dependence; Poisson regressions are used to investigate the factors that influence the intensity of livestock management measured by the use of different technologies and inputs. The findings indicated that a number of livelihood factors - assets, livelihood strategies, livelihood shocks and institutional supports - significantly determine the different aspects of livestock keeping. These include: human assets such as age, education and family size; social assets such as membership to social groups; financial assets such as credit; natural assets such as land, and household physical assets; and livelihood strategies such as diversification into farm and nonfarm activities, and coping mechanisms. In addition the livelihood vulnerability context such as shocks and institutional support are among the main determinants of livestock keeping. The results, by and large, matched the findings of previous studies, and it is concluded that households livestock keeping depends on their livelihoods. Accordingly, it is recommended that policies aiming at livestock asset building and productivity improvement should take the livelihoods of rural households in to consideration. As such the study contribute to scholarly works in the area of rural livelihoods, in general, and livestock keeping, in particular. It also contributes to a better understanding of the problems of livestock keeping within the context of rural livelihoods in the country and to the formulation of appropriate policy for the development of the sector.

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This thesis presents research theorising the use of social network sites (SNS) for the consumption of cultural goods. SNS are Internet-based applications that enable people to connect, interact, discover, and share user-generated content. They have transformed communication practices and are facilitating users to present their identity online through the disclosure of information on a profile. SNS are especially effective for propagating content far and wide within a network of connections. Cultural goods constitute hedonic experiential goods with cultural, artistic, and entertainment value, such as music, books, films, and fashion. Their consumption is culturally dependant and they have unique characteristics that distinguish them from utilitarian products. The way in which users express their identity on SNS is through the sharing of cultural interests and tastes. This makes cultural good consumption vulnerable to the exchange of content and ideas that occurs across an expansive network of connections within these social systems. This study proposes the lens of affordances to theorise the use of social network sites for the consumption of cultural goods. Qualitative case study research using two phases of data collection is proposed in the application of affordances to the research topic. The interaction between task, technology, and user characteristics is investigated by examining each characteristic in detail, before investigating the actual interaction between the user and the artifact for a particular purpose. The study contributes to knowledge by (i) improving our understanding of the affordances of social network sites for the consumption of cultural goods, (ii) demonstrating the role of task, technology and user characteristics in mediating user behaviour for user-artifact interactions, (iii) explaining the technical features and user activities important to the process of consuming cultural goods using social network sites, and (iv) theorising the consumption of cultural goods using SNS by presenting a theoretical research model which identifies empirical indicators of model constructs and maps out affordance dependencies and hierarchies. The study also provides a systematic research process for applying the concept of affordances to the study of system use.

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This paper uses a model of trade in two commodities between two countries to establish the following proposition. If the foreign offer curve has no points of inflection and if for each home rate of duty the equilibrium most favorable to the home country is selected (or else there is only one equilibrium), then as the rate of duty increases from zero, home welfare first rises then declines while foreign welfare steadily falls. © 1975.

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Interleukin-1 beta (IL1β) is a proinflammatory cytokine that mediates arthritic pathologies. Our objectives were to evaluate pain and limb dysfunction resulting from IL1β over-expression in the rat knee and to investigate the ability of local IL1 receptor antagonist (IL1Ra) delivery to reverse-associated pathology. IL1β over-expression was induced in the right knees of 30 Wistar rats via intra-articular injection of rat fibroblasts retrovirally infected with human IL1β cDNA. A subset of animals received a 30 µl intra-articular injection of saline or human IL1Ra on day 1 after cell delivery (0.65 µg/µl hIL1Ra, n = 7 per group). Joint swelling, gait, and sensitivity were investigated over 1 week. On day 8, animals were sacrificed and joints were collected for histological evaluation. Joint inflammation and elevated levels of endogenous IL1β were observed in knees receiving IL1β-infected fibroblasts. Asymmetric gaits favoring the affected limb and heightened mechanical sensitivity (allodynia) reflected a unilateral pathology. Histopathology revealed cartilage loss on the femoral groove and condyle of affected joints. Intra-articular IL1Ra injection failed to restore gait and sensitivity to preoperative levels and did not reduce cartilage degeneration observed in histopathology. Joint swelling and degeneration subsequent to IL1β over-expression is associated limb hypersensitivity and gait compensation. Intra-articular IL1Ra delivery did not result in marked improvement for this model; this may be driven by rapid clearance of administered IL1Ra from the joint space. These results motivate work to further investigate the behavioral consequences of monoarticular arthritis and sustained release drug delivery strategies for the joint space.

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We developed a high-throughput yeast-based assay to screen for chemical inhibitors of Ca(2+)/calmodulin-dependent kinase pathways. After screening two small libraries, we identified the novel antagonist 125-C9, a substituted ethyleneamine. In vitro kinase assays confirmed that 125-C9 inhibited several calmodulin-dependent kinases (CaMKs) competitively with Ca(2+)/calmodulin (Ca(2+)/CaM). This suggested that 125-C9 acted as an antagonist for Ca(2+)/CaM rather than for CaMKs. We confirmed this hypothesis by showing that 125-C9 binds directly to Ca(2+)/CaM using isothermal titration calorimetry. We further characterized binding of 125-C9 to Ca(2+)/CaM and compared its properties with those of two well-studied CaM antagonists: trifluoperazine (TFP) and W-13. Isothermal titration calorimetry revealed that binding of 125-C9 to CaM is absolutely Ca(2+)-dependent, likely occurs with a stoichiometry of five 125-C9 molecules to one CaM molecule, and involves an exchange of two protons at pH 7.0. Binding of 125-C9 is driven overall by entropy and appears to be competitive with TFP and W-13, which is consistent with occupation of similar binding sites. To test the effects of 125-C9 in living cells, we evaluated mitogen-stimulated re-entry of quiescent cells into proliferation and found similar, although slightly better, levels of inhibition by 125-C9 than by TFP and W-13. Our results not only define a novel Ca(2+)/CaM inhibitor but also reveal that chemically unique CaM antagonists can bind CaM by distinct mechanisms but similarly inhibit cellular actions of CaM.