Characterisation and biological activity of Glu(3) amino acid substituted GIP receptor antagonists

Glucose-dependent insulinotropic polypeptide (GIP) is an important gastrointestinal hormone, which regulates insulin release and glucose homeostasis, but is rapidly inactivated by enzymatic N-terminal truncation. Here we report the enzyme resistance and biological activity of several Glu(3) -substituted analogues of GIP namely; (Ala(3))GIP, (Lys(3))GIP, (Phe(3))GIP, (Trp(3))GIP and (Tyr(3))GIP. Only (Lys(3))- GIP demonstrated moderately enhanced resistance to DPP-IV (p <0.05 to p <0.01) compared to native GIP. All analogues demonstrated a decreased potency in cAMP production (EC50 1.47 to 11.02 nM; p <0.01 to p <0.001) with (Lys(3))GIP and (Phe(3))GIP significantly inhibiting GIP-stimulated cAMP production (p <0.05). In BRIN-BD11 cells, (Lys(3))GIP, (Phe(3))GIP, (Trp(3))GIP and (Tyr(3))- GIP did not stimulate insulin secretion with both (Lys(3))GIP and (Phe(3))GIP significantly inhibiting GIP-stimulated insulin secretion (p <0.05). Injection of each GIP analogue together with glucose in oblob mice significantly increased the glycaemic excursion compared to control (p <0.05 to p <0.001). This was associated with lack of significant insulin responses. (Ala(3))GIP, (Phe(3))GIP and (Tyr(3))GIP, when administered together with GIP, significantly reduced plasma insulin (p <0.05 top <0.01) and impaired the glucose-lowering ability (p <0.05 to p <0.01) of the native peptide. The DPP-IV resistance and GIP antagonism observed were similar but less pronounced than (Pro(3))GIP. These data demonstrate that position 3 amino acid substitution of GIP with (Ala(3)), (Phe(3)), (Tyr(3)) or (Pro(3)) provides a new class of functional GIP receptor antagonists. (C) 2007 Elsevier Inc. All rights reserved.

Nutrient regulation of pancreatic beta-cell function in diabetes: problems and potential solutions

increasing prevalence of obesity combined with longevity will produce an epidemic of Type 2 (non-insulin-dependent) diabetes in the next 20 years. This. disease is associated with defects in insulin secretion, specifically abnormalities of insulin secretory kinetics and pancreatic beta-cell glucose responsiveness. Mechanisms underlying beta-cell dysfunction include glucose toxicity, lipotoxicity and beta-cell hyperactivity. Defects at various sites in beta-cell signal transduction pathways contribute, but no single lesion can account for the common form of Type 2 diabetes. Recent studies highlight diverse beta-cell actions of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). These intestinal hormones target the beta-cell to stimulate glucose-dependent insulin secretion through activation of protein kinase A and associated pathways. Both increase gene expression and proinsulin biosynthesis, protect against apoptosis and stimulate replication/neogenesis of beta-cells. Incretin hormones therefore represent an exciting future multi-action solution to correct beta-cell defect in Type 2 diabetes.

Cyclic AMP production and insulin releasing activity of synthetic fragment peptides of glucose-dependent insulinotropic polypeptide

Synthetic fragment peptides of glucose-dependent insulinotropic polypeptide (GIP) were evaluated for their ability to elevate cellular cAMP production and stimulate insulin secretion. In GIP receptor transfected CHL cells, GIP(4-42) and GIP(17-30) dose-dependently inhibited GIP-stimulated cAMP production (40 +/- 8%; p <0.01 and 15 +/- 6%; p <0.05, respectively), while GIP(1-16) exerted very weak agonist effects on cAMP production. In the clonal pancreatic beta-cell line, BRIN-BD11, GIP(1-16) demonstrated weak insulin releasing activity compared with native GIP. In contrast, GIP(4-42) and GIP (17-30) weakly antagonized the insulin releasing activity of the native peptide (23 +/- 6%; p <0.05 and 11 +/- 3%, respectively). These data demonstrate the critical role of the N-terminus and the involvement of regions of the C-terminal domain in generating full biological potency of GIP.

Characterization of the cellular and metabolic effects of a novel enzyme-resistant antagonist of glucose-dependent insulinotropic polypeptide

A novel N-terminally substituted Pro(3) analogue of glucose-dependent insulinotropic polypeptide (GIP) was synthesized and tested for plasma stability and biological activity both in vitro and in vivo. Native GIP was rapidly degraded by human plasma with only 39 +/- 6% remaining intact after 8 h, whereas (Pro(3))GIP was completely stable even after 24 h. In CHL cells expressing the human GIP receptor, (Pro(3))GIP antagonized the cyclic adenosine monophosphate (cAMP) stimulatory ability of 10(-7)M native GIP, with an IC50 value of 2.6 muM. In the clonal pancreatic beta cell line BRIN-BD11, (Pro(3))GIP over the concentration range 10(-13) to 10(-8) M dose dependently inhibited GIP-stimulated (10(-7) M) insulin release (1.2- to 1.7-fold; P <0.05 to P <0.001). In obese diabetic (ob/ob) mice, intraperitoneal administration of (Pro(3))GIP (25 nmol/kg body wt) countered the ability of native GIP to stimulate plasma insulin (2.4-fold decrease; P <0.001) and lower the glycemic excursion (1.5-fold decrease; P <0.001) induced by a glucose load (18 mmol/kg body wt). Collectively these data demonstrate that (Pro(3))GIP is a novel and potent enzyme-resistant GIP receptor antagonist capable of blocking the ability of native GIP to increase cAMP, stimulate insulin secretion, and improve glucose homeostasis in a commonly employed animal model of type 2 diabetes. (C) 2002 Elsevier Science (USA).

Can traditional harvesting methods for cockles be accommodated in a Special Area of Conservation?

The European Natura 2000 project attempts to balance conservation and exploitation by permitting activities that do not affect the conservation status of designated sites. Given the scale of Natura 2000, guidelines are needed to facilitate the drafting of simple site management plans. This need is particularly acute for traditional harvesting methods for which there is usually strong local opposition to the imposition of controls. These issues were examined in Strangford Lough, a special area of conservation where cockles have traditionally been harvested by hand-raking. Raking was found not to affect the ability of cockles to rebury. There were significant reductions in Zostera biomass when raking was carried out within eelgrass beds (a 90% reduction in biomass available to winter migrant birds from summer raking). Traditional harvesting methods could therefore be accepted in Strangford as long as Zostera beds are avoided. A relatively low intensity of harvesting activity in Strangford Lough probably reflects low cockle densities (average 91.8 m(-2)), with the most economically valuable individuals at some distance from points of access to the shore. An economically feasible management plan could sanction traditional harvesting and result in the implementation of more resource-intensive management only if increases in cockle stocks and market prices stimulate large increases in harvesting activity.

Older, Louder and Stronger: the Changing Ageing Partnership putting older people first

The Changing Ageing Partnership (Cap) in Northern Ireland was established to help place older people’s voices at the heart of policy development. Making research relevant to the needs of society and translating the findings of research into policy and practice are challenges shared by all working in the field of ageing. This paper describes Cap’s development and evolution over the past three years. It provides an insight into the strategies used by Cap to stimulate interest in ageing related research across Queen’s University Belfast and in enabling older people and others to be active participants in the research process. The paper concludes by highlighting the challenges that remain.

Substance P induces histamine release from human pulmonary mast cells.

Substance P elicits histamine release from human skin and rodent mast cells. Since neuropeptide-mediated reflexes may be important in asthma, we examined the ability of substance P to stimulate human mast cells obtained at bronchoalveolar lavage (BAL). BAL samples were obtained at routine bronchoscopy from 35 non-preselected patients. Histamine release experiments were performed in a standard manner using substance P and the calcium ionophore A23187. Both substance P (50 μM) and A23187 caused histamine release (median 26.7%, range 6.2–62.8% and 32.1%, 7.7–56.8% respectively) which was significantly greater (P < 0.0001) than the spontaneous release (median 15.6%, range 4.1–33.4%), i.e. that in the absence of any stimulus. Substance P induced histamine release was via an energy dependent process and was blocked by preincubation with antimycin A. A significant correlation was observed between substance P induced release and spontaneous release but was not observed with A23187 induced release. Mast cell counts correlated significantly with substance P induced release but not with spontaneous or A23187 induced release. The substance P induced histamine secretion was elicited at similar concentrations to those used with rodent and human skin mast cells. Asthma is associated with increased numbers of mast cells which have both increased spontaneous and stimulated secretory responses. Thus, in vivo, the bronchoconstrictor action of substance P may in part result from activation of mast cells in the bronchial lumen.

The schistosome excretory system: a key to regulation of metabolism, drug excretion and host interaction

There is a gulf between the enormous information content of the various genome projects and the understanding of the life of the parasite in the host. In vitro studies with adult Schistosoma mansoni using several substrates suggest that the excretory system contains both P-glycoproteins and multiresistance proteins. If both these families of protein were active in vivo, they could regulate parasite metabolism and be responsible for the excretion of drugs. During skin penetration, membrane-impermeant molecules of a wide range of molecular weights can be taken into the cercaria and schistosomulum through the nephridiopore, through the surface membrane or through both. We speculate that this uptake process might stimulate novel signalling pathways involved in growth and development.

‘‘Capital of Culture - you must be having a laugh!” Challenging the official rhetoric of Liverpool as the 2008 European cultural capital’

Major cultural events are increasingly seen by local stakeholders as important opportunities to stimulate urban regeneration, city branding and economic development. The European Capital of Culture programme is a prominent example. Since 1985 over thirty cities have hosted the title and today it remains a highly sought-after prize. This paper analyses competing interpretations of the success of Liverpool's hosting of the European Capital of Culture in 2008. It unpacks contrasting views of Liverpool08, from the official triumphant message of urban regeneration and economic renaissance to more critical analyses that problematise important elements of the event and its social and spatial impacts. In so doing, it challenges the hyperbole of culture-led transformation to reveal different geographies of culture, different cultural experiences and different socio-economic realities; it also offers an additional cultural reading of Liverpool in 2008. Through the example of Liverpool this paper shows how local culture is politicised, manipulated and sanitised in order to stimulate urban regeneration and construct a spatial re-branding of the city.

De grands événements culturels sont de plus en plus perçus par les rentiers locaux comme des opportunités importantes pour stimuler la régénération urbaine, produire la devise des villes et le développement économique. L'initiative La Capitale Européenne de la Culture est un exemple proéminent. Depuis 1985, plus de trente villes ont accueilli le titre et maintenant il reste un prix largement recherché. Cet article analyse des interprétations en concurrence du succès de l'accueil de Liverpool de la Capitale Européenne de la Culture en 2008. Il déballe des vues contrastées de Liverpool08, du message officiel et triomphal de la régénération urbaine et de la renaissance économique à des analyses plus critiques qui problématisent des éléments importants de l'événement et ses impacts sociaux et spatiaux. De cette façon, il conteste l'hyperbole de la transformation menée par la culture pour révéler des géographies différentes de la culture, des expériences différentes de la culture et des réalités socioéconomiques différentes; il offre aussi une interprétation culturelle différente de Liverpool en 2008. Au travers de l'exemple de Liverpool cet article montre comment la culture locale est politisée, manipulée et aseptisée pour stimuler la régénération urbaine et construire un relookage spatial de la ville.

Cada vez más, los inversores locales vean a los eventos culturales como oportunidades importantes para estimular regeneración urbana, el desarollo económico y la branding a una ciudad. El Capital Europeo de Cultura es un ejemplo prominente. Desde 1985, más que treinta ciudades han presentado el título y hoy sigue siendo un premio deseable. Este papel se analiza interpretaciones competitivos del éxito del Capital Europea de Cultura 2008 en Liverpool. Se deshace las perspectivas opuestas del Liverpool08, del mensaje triunfante de regeneración urbana y renacimiento económico, a analices críticos que problematizan elementos importantes del evento y sus impactos sociales y espaciales. Al hacer esto, se cuestiona el hipérbole de la transformación cultural para revelar geografías diferentes de cultura, experiencias culturales diferentes y realidades diferentes socio-económicas; también ofrece un entendimiento cultural adicional de Liverpool en el 2008. Através el ejemplo de Liverpool, este papel demuestra como la cultura local está politizada, manipulada, y desinfectado para estimular regeneración urbana y construir una nueva branding de la ciudad.

Attitudes, norms, identity and environmental behaviour: Using an expanded theory of planned behaviour to predict participation in a kerbside recycling programme

In an effort to contribute to greater understanding of norms and identity in the theory of planned behaviour, an extended model was used to predict residential kerbside recycling, with self-identity, personal norms, neighbourhood identification, and injunctive and descriptive social norms as additional predictors. Data from a field study (N = 527) using questionnaire measures of predictor variables and an observational measure of recycling behaviour supported the theory. Intentions predicted behaviour, while attitudes, perceived control, and the personal norm predicted intention to recycle. The interaction between neighbourhood identification and injunctive social norms in turn predicted personal norms. Self-identity and the descriptive social norm significantly added to the original theory in predicting intentions as well as behaviour directly. A replication survey on the self-reported recycling behaviours of a random residential sample (N = 264) supported the model obtained previously. These findings offer a useful extension of the theory of planned behaviour and some practicable suggestions for pro-recycling interventions. It may be productive to appeal to self-identity by making people feel like recyclers, and to stimulate both injunctive and descriptive norms in the neighbourhood.

Systematic review of the effect of diet and exercise lifestyle interventions in the secondary prevention of coronary heart disease.

The effectiveness of lifestyle interventions within secondary prevention of coronary heart disease(CHD)remains unclear.This systematic review aimed to determine their effectiveness and included randomized controlled trials of lifestyle interventions, in primary care or community settings, with a minimum follow-up of three months, published since 1990. 21 trials with 10,799 patients were included; the interventions were multifactorial (10), educational (4), psychological (3), dietary (1), organisational (2), and exercise(1). The overall results for modifiable risk factors suggested improvements in dietary and exercise outcomes but no overall effect on smoking outcomes. In trials that examined mortality and morbidity,significant benefits were reported for total mortality (in 4 of 6 trials;overall risk ratio(RR) 0.75 (95%confidence intervals (CI) 0.65, 0.87)), cardiovascular mortality (3 of 8 trials; overall RR 0.63(95%CI 0.47, 0.84)), and nonfatal cardiac events(5 of 9 trials; overall RR 0.68(95%CI 0.55, 0.84)). The heterogeneity between trials and generally poor quality of trials make any concrete conclusions difficult. However, the beneficial effects observed in this review are encouraging and should stimulate further research.

Understanding Accountability in Social Enterprise Organisations: A Framework

Purpose: Social enterprise organisations (SEOs) operate across the boundaries of the public, private and not‐for‐profit (NFP) sectors in delivering public services and competing for resources and legitimacy. While there is a rich literature on accountability in the private and public sectors, together with the wider NFP sector, SEOs have received comparatively little attention and remain a relatively under‐researched organisational form. Drawing on accountability, legitimacy and user‐needs theories, the purpose of this paper is to develop a practical framework which can be used to explore how accountability within SEOs is constructed and discharged.

Design/methodology/approach: This paper draws on user‐needs, accountability, legitimacy and impression management theories expounded in relation to the private, public and NFP sectors.

Findings: A framework to better understand how accountability can be discharged by SEOs is developed and discussed.

Research limitations/implications: While a framework for better understanding SEO accountability is presented, it is not empirically tested. However, the framework has the potential to facilitate a deeper appreciation of the theory and practice of accountability within SEOs and, notwithstanding the inherent difficulties in measuring and managing accountability, could be used to stimulate practitioner involvement.

Practical implications
– As little is known about the current extent of SEO information disclosure or accountability relationships, the framework could be used to assess the discharge of accountability by SEOs, with the findings informing future developments. This should provide useful insights into internal processes and organisational views on accountability bases and mechanisms and can then be used to inform the debate on how SEOs can best discharge their duty to account.

Social implications
– Understanding the nature of SEO accountability reporting has important implications for those involved in advancing the SEO agenda. At a time of public sector cutbacks, and with the government searching for new and more effective ways of delivering services, the role of SEOs in this process is likely to receive greater attention and scrutiny.

Originality/value
– SEOs have grown extensively in size and prominence in recent years and policymakers have come to embrace the role that they play in societal development. This paper responds to a gap in the theoretical literature and contributes to the debate by developing a framework which can be empirically tested. Moreover, it can be used to prompt practitioner involvement and facilitate a better understanding of the complex issues surrounding accounting and accountability in this under‐researched area.

Spatial segregation and labour market processes in Belfast

This article examines the nature of labour market exclusion in Belfast and policy responses to the dilemmas of ethnic space. It highlights the value of an area-based approach to understanding the way in which social and ethno-sectarian segregation mediates access to production sites and job opportunities in the wider urban economy. Research from the Belfast metropolitan labour market is used to identify the importance of employment in neutral areas, which can stimulate access from ethnically and socially polarised communities. The article argues for a spatial approach to understanding the structuring of labour market opportunities and constraints and it concludes by highlighting the implications for policy and practice in ethnically territorialised spaces.

Leadership for inclusion: Conceptualising and enacting inclusion in integrated schools in a troubled society

Inclusion is increasingly understood as an educational reform that responds to the diversity of all learners, challenging the marginalization, exclusion and underachievement which may result from all forms of ‘difference’. Leadership for inclusion is conceptualized here as driving a constant struggle to create shared meanings of inclusion and to build collaborative practice, an effort that needs to be rooted in critical practice lest it risk replicating existing patterns of disadvantage. In response to calls for further research that challenge how school leaders conceptualize inclusion and for research that investigates how leaders enact their understandings of inclusion, this paper aims to increase our understanding of the extent to which leadership vision can map onto a school’s culture and of the organizational conditions in schools that drive responses to diversity. We investigate the enactment of leadership for inclusion in the troubled context of Northern Ireland by looking at two schools that primarily aim to integrate Catholic and Protestant children but which are also sites for a range of other dimensions of student ‘difference’ to come together. Whilst the two schools express differing visions of the integration of Catholics and Protestants, leadership vision of inclusion is enacted by members of the school community with a consensus around this vision brought about by formal and informal aspects of school culture. Multiple and intersecting spheres of difference stimulate a concerted educational response in both schools but integration remains the primary focus. In this divided society, religious diversity poses a significant challenge to inclusion and further support is required from leaders to enable teachers to break through cultural restraints.

Cytosol protein regulation in H295R steroidogenesis model induced by the zearalenone metabolites, α- and β-zearalenol.

a- and b-zearalenol (a-ZOL and b-ZOL, respectively) are metabolites of the mycotoxin zearalenone (ZEN). All three individual mycotoxins have shown to be biological active i.e. being estrogenic and able to stimulate cellular proliferation albeit at different strengths. In this work, cytosol protein expression was determined by using stable-isotope labelling by amino acids in cell culture (SILAC) upon exposure of a-ZOL and b-ZOL to the steroidogenesis cell model H295R. A total of 14 and 5 individual proteins were found to be significantly regulated by a-ZOL and b-ZOL, respectively. Interestingly, there were no common protein regulations by the metabolites or the parent mycotoxin ZEN. Furthermore, the regulated proteins were assigned to networks and groups of actions that also differed from one another suggesting that the three individual mycotoxins may have unique biological activities.