Partial agonism, neutral antagonism, and inverse agonism at the human wild-type and constitutively active cholecystokinin-2 receptors

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3- yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2- methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino] propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]} -butanoate N-methyl-D-glucamine (PD135, 158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2- oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1- (2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoylmethyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.

A critical review of some recent developments in quantitative research on gender and achievement in the United Kingdom

Over recent years the findings of a number of quantitative research studies have been published in the UK on gender and achievement. Much of this work has emanated from Stephen Gorard and his colleagues and has not only been highly critical of existing approaches to handling quantitative data but has also suggested a number of alternative and, what they claim to be, more valid ways of measuring differential patterns of achievement and underachievement between groups. This article shows how much of this work has been based upon rather under-developed measures of achievement and underachievement that tend, in turn, to generate a number of misleading findings that have questionable implications for practice. It will be argued that this body of work provides a useful case study in the problems of quantitative research that fails to engage adequately with the substantive theoretical and empirical literature and considers some of the implications of this for future research in this area.

A Population-Based Study of IGF Axis Polymorphisms and the Esophageal Inflammation, Metaplasia, Adenocarcinoma Sequence

BACKGROUND & AIMS: Insulin-like growth factor (IGF) axis plays a key role in cell development, proliferation, and survival and is implicated in the etiology of several cancers. Few studies have examined the relationship between genetic variation of this axis and esophageal adenocarcinoma (EAC) or its precursors. METHODS: In a population-based case-control study, we investigated the association of common polymorphisms of IGF-1, IGF-2, IGF-1 receptor, IGF binding protein -3, growth hormones (GH) 1 and GH2, and GH receptor with reflux esophagitis (RE), Barrett esophagus (BE), and EAC. Two hundred and thirty RE, 224 BE, 227 EAC cases, and 260 controls were studied. Gene polymorphisms were identified using publicly available online resources; 102 IGF axis tag and putatively functional single-nucleotide polymorphisms (SNPs) were analyzed using MassARRAY iPLEX and Taqman assays. Results were analyzed using Haploview.
RESULTS: Three polymorphisms were disease-associated. IGF1 SNP rs6214 was associated with BE (adjusted P = .039). Using GG genotype as reference, odds ratio for BE in AA (wild-type) was 0.43 (95% confidence interval [CI], 0.24-0.75). GH receptor SNP rs6898743 was associated with EAC (adjusted P = .0112). With GG as reference, odds ratio for EAC in CC (wildtype) genotype was 0.42 (95% CI, 0.23-0.76). IGF1 (CA)(17) 185-bp allele was associated with RE (adjusted P = .0116). Using IGF1(non17) as reference, odds ratio for RE in IGF1(17) carriers was 7.29 (95% CI, 1.57-46.7).
CONCLUSIONS: In this study, 3 polymorphisms of IGF genes were associated with EAC or its precursors. These polymorphisms may be markers of disease risk; independent validation of our findings is required. These results suggest the IGF pathway is involved in EAC development.

Entrepreneurial and Business Growth and the Quest for a “Comprehensive Theory”: Tilting at Windmills?

Even though there has been sustained interest in growth for almost 50 years, relatively little is known about this phenomenon and much confusion and misunderstanding surrounds it. Based on a literature review and the articles in this special issue we make three recommendations that we believe will allow theory to advance and be applicable in practice. First, that discourse between key stakeholders is encouraged in order to achieve greater understanding. Second, that focus is placed on " growth as a process," rather than as a " change in amount." Third, that knowledge production requires inclusivity and pluralism in research perspectives and approaches. © 2010 Baylor University.

Introduction

Introduction to special issue The Politics of Dance

Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer's disease in Northern Ireland

alpha 1-antichymotrypsin (AACT) is a serine protease inhibitor that has been associated with amyloid plaques in the brains of patients with Alzheimer's disease (AD). It has been reported that AACT serum levels are higher in AD patients than in age and sex matched controls. In addition, polymorphisms in the signal peptide and 5' of the AACT gene have been reported to increase the risk of developing AD, Serum AACT has also been suggested to be associated with cognitive decline in elderly subjects. Our objective was to investigate whether a relationship existed between serum AACT levels, AACT genotypes and risk for AD in a case control association study using 108 clinically well defined late onset AD cases and 108 age and sex matched controls from Northern Ireland. We also wished to determine whether higher serum AACT affected levels of cognition as had been previously reported. Serum AACT levels were found to bet significantly raised in cases compared to controls (t = 3.8, df = 209, p

Maternal imagination: Reconceiving first impressions

The concept of maternal imagination, whereby the disordered thoughts and impressions of pregnant women are used to explain the prevalence of monstrous births, was at its height during the early modern period, albeit it with many prior and subsequent manifestations. Against a more familiar, and enduring, medieval and Renaissance context of supernatural agency at work, the device of MI was seen as a 'naturalistic' model more in keeping with the advent of Enlightenment scientism. Nonetheless, the debate around it was ferocious and indicative more of a masculine anxiety about female desire and generative power than of a concern for impartial explanation. In problematizing a simply descriptive approach to archival material, my purpose is to explore what is at stake in the competing discourses that seem alternately, and even simultaneously, to empower and degrade the place of the mother. What is the unspoken of an historical debate that prefigures our contemporary interest in feminine excess?

Passive Intermodulation in Printed Lines: Effects of Trace Dimensions and Substrate

A comprehensive experimental study was performed to identify and discriminate mechanisms contributing to passive intermodulation (PIM) in microstrip transmission lines. The effects of strip length and width, and substrate materials on PIM performance of printed lines were investigated in the GSM900, DCS1800 and UMTS frequency bands. The major features of the experiment design, sample preparation and test setup are discussed in detail. The measurement results have demonstrated that the PIM level cumulatively grows on the longer microstrip lines and decreases on wider strips and, thus, indicated that the distributed resistive nonlinearity of the printed traces represents the dominant mechanism of intermodulation generation in the printed lines on PTFE-based substrates. © 2009 The Institution of Engineering and Technology.

Inquiring into Non-Accidental Child Deaths: Reviewing the Review Process

There is significant public and professional interest in the non-accidental death of children where abuse and neglect are suspected of being contributory factors. Systems for reviewing these deaths have been developed in each of the four jurisdictions within the UK. The main aims are to ensure that individuals and professionals are held to account if practice falls below the expected standard, whilst also seeking to strengthen the systems for protecting children through reflecting on what lessons, if any, can be learnt from the death of a child through abuse or neglect. Recently, the benefit of such inquiries and the quality of serious case reviews have come under scrutiny. In this paper, the authors report the findings of a Delphi study that sought to explore how the process of conducting reviews following the death of a child could be improved through seeking the views of experienced professionals responsible for child protection in Northern Ireland. The authors conclude that the system does command professional support, but could be improved through greater attention to process issues and a stronger emphasis on translating learning into action. In common with research looking at other recent practice developments, there is a need to focus on process indicators as a means to ensuring that well intentioned policies are translated into workable and functioning practices.

Enforcing Member State Compliance with EU Environmental Law: A Critical Evaulation of the Use of Financial Penalties

The 1993 Treaty on European Union finally closed a legal vacuum in
EU law, by giving the Court the power to impose financial penalties to
enforce compliance with its judgments. Today, this power is found
within Article 260(2) of the Treaty on the Functioning of the
European Union. Drawing upon case law, this article examines the
role that the Court’s enforcement powers have played in relation to
EU environmental law. It argues that EU law has yet to make full use
of their potential. The article commences with the Commission and
questions whether it has sufficient resources to carry out its functions
under Article 260(2). The article also examines the ongoing problem of
Member State delay in complying with Court judgments and the
weight given to environmental considerations in the Court’s decision
making on financial penalties. The article concludes by examining the
implications of the Lisbon Treaty.

mVps34 is activated following high-resistance contractions

Following resistance exercise in the fasted state, both protein synthesis and degradation in skeletal muscle are increased. The addition of essential amino acids potentiates the synthetic response suggesting that an amino acid sensor, which is involved in both synthesis and degradation, may be activated by resistance exercise. One such candidate protein is the class 3 phosphatidylinositol 3OH-kinase (PI3K) Vps34. To determine whether mammalian Vps34 (mVps34) is modulated by high-resistance contractions, mVps34 and S6K1 (an index of mTORC1) activity were measured in the distal hindlimb muscles of rats 0.5, 3, 6 and 18 h after acute unilateral high-resistance contractions with the contralateral muscles serving as a control. In the lengthening tibialis anterior (TA) muscle, S6K1 (0.5 h = 366.3 +/- 112.08%, 3 h = 124.7 +/- 15.96% and 6 h = 129.2 +/- 0%) and mVps34 (3 h = 68.8 +/- 15.1% and 6 h = 36.0 +/- 8.79%) activity both increased, whereas in the shortening soleus and plantaris (PLN) muscles the increase was significantly lower (PLN S6K1 0.5 h = 33.1 +/- 2.29% and 3 h = 47.0 +/- 6.65%; mVps34 3 h = 24.5 +/- 7.92%). HPLC analysis of the TA demonstrated a 25% increase in intramuscular leucine concentration in rats 1.5 h after exercise. A similar level of leucine added to C2C12 cells in vitro increased mVps34 activity 3.2-fold. These data suggest that, following high-resistance contractions, mVps34 activity is stimulated by an influx of essential amino acids such as leucine and this may prolong mTORC1 signalling and contribute to muscle hypertrophy.

Teaching and learning technologies in Higher Education: Applied behaviour analysis and autism.

Professionals on both international and national levels who work with children with autism are expressing the need for graduate-level training in applied behaviour analysis. The implementation of effective instruction in higher education for professionals working with children with autism and their families is a complex undertaking: the learner needs to acquire an understanding of the principles and procedures of applied behaviour analysis and also adapt this knowledge to the learning prerequisites of individuals with autism. In this paper we outline some current thinking about adult education and blended learning technologies and then describe and illustrate with examples emerging possibilities of multimedia technology in the development of teaching materials. We conclude that synergies between graduate-level curriculum requirements, knowledge of adult learning, and communication technology are necessary to establish comprehensive learning environments for professionals who specialize in autism intervention.