Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323: 147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative co-operativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.

Gifts, Loans and Intergenerational Support for Young Adults

Young adults in the UK are increasingly dependent on family support to offset the costs of living independently. This article explores these complex intergenerational exchanges from the perspective of a group of single young adults in their mid-twenties to mid-thirties who had been in receipt of various forms of financial and material support from family members since leaving the parental home. We outline the nature of this support and then consider how these forms of assistance are understood by those in receipt of them. We conclude that the co-existence of a sense of both gratitude and discomfort which is often generated by these exchanges is managed but by no means resolved by a blurring of the boundaries between gifts and loans, a set of negotiations which may not even be an option amongst less advantaged young adults.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Government Aid and Film Legislation : 'An elastoplast to stop a haemorrhage'

This chapter explores the relationship between the British film industry and the government throughout the 1970s and evaluates the levels of support offered to the industry in an uncertain political deade.

British Film Censorship and the BBFC in the 1970s

This chapter is an exploration of film censorship in the 1970s and the role of the British Board of Film Censors. It draws on material from the BBFC archive files and addresses issues of popular taste, taboo and changing standards of permission.

Gamma Irradiation and Targeted Radionuclides Enhance the Expression of the Noradrenaline Transporter Transgene Controlled by the Radio-Inducible p21(WAF1/CIP1) Promoter

The use of radiation-inducible promoters to drive transgene expression offers the possibility of temporal and spatial regulation of gene activation. This study assessed the potential of one such promoter element, p21(WAF1/CIP1) (WAF1), to drive expression of the noradrenaline transporter (NAT) gene, which conveys sensitivity to radioiodinated meta-iodobenzylguanidine (MIBG). An expression vector containing NAT under the control of the radiation-inducible WAF1 promoter (pWAF/NAT) was produced. The non-NAT expressing cell lines UVW (glioma) and HCT116 (colorectal cancer) were transfected with this construct to assess radiation-controlled WAF1 activation of the NAT gene. Transfection of UVW and HCT cells with pWAF/NAT conferred upon them the ability to accumulate [(131)I]MIBG, which led to increased sensitivity to the radiopharmaceutical. Pretreatment of transfected cells with ? radiation or the radiopharmaceuticals [(123)I]MIBG or [(131)I]MIBG induced dose- and time-dependent increases in subsequent [(131)I]MIBG uptake and led to enhanced efficacy of [(131)I]MIBG-mediated cell kill. Gene therapy using WAF1-driven expression of NAT has the potential to expand the use of this therapeutic modality to tumors that lack a radio-targetable feature.

Evaluating the effectiveness of community-based dementia care networks:The Dementia Care Networks' Study

Purpose: The Dementia Care Networks' Study examined the effectiveness of four community-based, not-for-profit dementia networks. The study involved assessing the relationship between the types of administrative and service-delivery exchanges that occurred among the networked agencies and the network members' perception of the effectiveness of these exchanges. Design and Methods: With the use of a case-study method, the evolution, structure, and processes of each network were documented. Social network analysis using a standardized questionnaire completed by member agencies identified patterns of administrative and clinical exchanges among networked agencies. Results: Differences were found between the four networks in terms of their perceptions of service-delivery effectiveness; perceptions of administrative effectiveness did not factor significantly. Exchanges between groups of agencies (cliques) within each of the four networks were found to be more critical than those between individual agencies within each network. Implications: Integration-measured by the types of exchanges within as opposed to across networks-differentiated the four networks studied. This research contributes to our understanding of the use of multiple measures to evaluate the inner workings of service delivery and their impact on elder health and elder health care. Copyright 2005 by The Gerontological Society of America.

A time-resolved immunoassay to measure serum antibodies to the rotavirus VP6 capsid protein

The rotavirus (RV) inner capsid protein VP6 is widely used to evaluate immune response during natural infection and in vaccine studies. Recombinant VP6 from the most prevalent circulating rotavirus strains in each subgroup (SG) identified in a birth cohort of children in southern India [SGII (G1P[8]) and SGI (G10P[11])] were produced. The purified proteins were used to measure VP6-specific antibodies in a Dissociation-Enhanced Lanthanide Fluorometric Immunoassay (DELFIA). The ability of the assay to detect a =2 fold rise in IgG level in a panel of serum samples from a longitudinal study was compared to a gold standard virus-capture ELISA. A strong association was observed between the assays (p

Rotavirus enterotoxin NSP4 has mucosal adjuvant properties

Rotavirus nonstructural protein 4 (NSP4) is a protein with pleiotropic properties. It functions in rotavirus morphogenesis, pathogenesis, and is the first described viral enterotoxin. Since many bacterial toxins function as potent mucosal adjuvants, we evaluated whether baculovirus-expressed recombinant simian rotavirus SA11 NSP4 possesses adjuvant activity by co-administering NSP4 with keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) or ovalbumin (OVA) as model antigens in mice. Following intranasal immunization, NSP4 significantly enhanced both systemic and mucosal immune responses to model immunogens, as compared to the control group, in an antigen-specific manner. Both full-length and a cleavage product of SA11 NSP4 had adjuvant activity, localizing this activity to the C-terminus of the protein. NSP4 forms from virulent and avirulent porcine rotavirus OSU strain, and SA11 NSP4 localized within a 2/6-virus-like particle (VLP) also exhibited adjuvant effects. These studies suggest that the rotavirus enterotoxin NSP4 can function as an adjuvant to enhance immune responses for a co-administered antigen.