Synthesis and SAR of centrally active mGlu(5) positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. Published by Elsevier Ltd.

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl) benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phen-cyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl) phenyl) methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl) ethynyl) nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

The 'Unhomely' White Women of Antillean Writing

While the field known as ‘Whiteness Studies’ has been thriving in Anglophone criticism and theory for over 25 years, it is almost unknown in France. This is partly due to epistemological and political differences, but also to demographic factors — in contrast with the post-plantation culture of the US, for example, whites in Martinique and Guadeloupe are a tiny minority of small island populations. Yet ‘whiteness’ remains a phantasized and a fetishized state in the Antillean imaginary, and is strongly inflected by gender. This article sketches the emergence of ‘white’ femininity during slavery, then examines its representation in the work of a number of major Antillean writers (Condé, Placoly, Confiant, Chamoiseau). In their work, a cluster of recurring images and leitmotifs convey the idealization or, more commonly, the pathologization, of the white woman; these images resonate strongly with Bhabha’s ‘unhomely’, and convey the disturbing imbrication of sex and race in Antillean history.

'Grooming' and the Sexual Abuse of Children:Institutional, Internet and Familial Dimensions

‘Grooming’ and the Sexual Abuse of Children: Institutional, Internet and Familial Dimensions critically examines the official and popular discourses on grooming, predominantly framed within the context of on-line sexual exploitation and abuse committed by strangers, and institutional child abuse committed by those in positions of trust.

Set against the broader theoretical framework of risk, security and governance, this book argues that due to the difficulties of drawing clear boundaries between innocuous and harmful motivations towards children, pre-emptive risk-based criminal law and policy are inherently limited in preventing, targeting and criminalising ‘grooming’ behaviour prior to the manifestation of actual harm. Through examination of grooming against the complexities of the onset of sexual offending against children and its actual role in this process, the author broadens existing discourses by providing a fuller, more nuanced conceptualisation of grooming, including its role in intra-familial and extra-familial contexts. There is also timely discussion of new and emerging forms of grooming, such as ‘street’ or ‘localised’ grooming, as typified by recent cases in Rochdale and Oldham, and ‘peer-to-peer’ grooming.

The first inter-disciplinary, thematic, and empirical investigation of grooming in a multi-jurisdictional context, ‘Grooming’ and the Sexual Abuse of Children draws on extensive empirical research in the form of over fifty interviews with professionals, working in the fields of sex offender risk assessment, management or treatment, as well as child protection or victim support in the four jurisdictions of the United Kingdom and the Republic of Ireland. Impeccably presented and meticulously considered, this book will be of interest to criminologists and those working and studying in the field of policing and criminal justice studies, as well as policy makers and practitioners in the areas of child protection and sex offender management.

Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation

Objective: Enhanced oxidative stress is involved in mediating the endothelial dysfunction associated with hypertension. The aim of this study was to investigate the relative contributions of pro-oxidant and anti-oxidant enzymes to the pathogenesis of endothelial dysfunction in genetic hypertension. Methods: Dilator responses to endothelium-dependent and endothelium-independent agents such as acetylcholine (ACh) and sodium nitroprusside were measured in the thoracic aortas of 28-week-old spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar Kyoto rats (WKY). The activity and expression (mRNA and protein levels) of endothelial nitric oxide synthase (eNOS), p22-phox, a membrane-bound component of NAD(P)H oxidase, and antioxidant enzymes, namely, superoxide dismutases (CuZn- and Mn-SOD), catalase and glutathione peroxidase (GPx), were also investigated in aortic rings. Results: Relaxant responses to ACh were attenuated in phenylephrine-precontracted SHR aortic rings, despite a 2-fold increase in eNOS expression and activity. Although the activity and/or expression of SODs, NAD(P)H oxidase (p22-phox) and GPx were elevated in SHR aorta, catalase activity and expression remained unchanged compared to WKY. Pretreatment of SHR aortic rings with the inhibitor of xanthine oxidase, allopurinol, and the inhibitor of cyclooxygenase, indomethacin, significantly potentiated ACh-induced relaxation. Pretreatment of SHR rings with catalase and Tiron, a superoxide anion (O) scavenger, increased the relaxant responses to the levels observed in WKY rings whereas pyrogallol, a O -generator, abolished relaxant responses to ACh. Conclusion: These data demonstrate that dysregulation of several enzymes, resulting in oxidative stress, contributes to the pathogenesis of endothelial dysfunction in SHR and indicate that the antioxidant enzyme catalase is of particular importance in the reversal of this defect. © 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Sex hormone binding globulin and insulin resistance

Sex hormone binding globulin (SHBG) is a glycoprotein composed of two 373-amino-acid subunits. The SHBG gene and a promotor region have been identified. The SHBG receptor has yet to be cloned but is known to act through a G-protein-linked second-messenger system following plasma membrane binding. The principal function of SHBG has traditionally been considered to be that of a transport protein for sex steroids, regulating circulating concentrations of free (unbound) hormones and their transport to target tissues. Recent research suggests that SHBG has functions in addition to the binding and transport of sex steroids. Observational studies have associated a low SHBG concentration with an increased incidence of type 2 diabetes mellitus (DM) independent of sex hormone levels in men and women. Genetic studies using Mendelian randomization analysis linking three single nucleotide polymorphisms of the SHBG gene to risk of developing type 2 DM suggest SHBG may have a role in the pathogenesis of type 2 DM. The correlation between SHBG and insulin resistance that is evident in a number of cross-sectional studies is in keeping with the suggestion that the association between SHBG and incidence of type 2 DM is explained by insulin resistance. Several potential mechanisms may account for this association, including the identification of dietary factors that influence SHBG gene transcription. Further research to characterize the SHBG-receptor and the SHBG second messenger system is required. An interventional study examining the effects on insulin resistance of altering SHBG concentrations may help in determining whether this association is causal.

Wave action modifies the effects of consumer diversity and warming on algal assemblages

To understand the consequences of biodiversity loss, it is necessary to test how biodiversity-ecosystem functioning relationships may vary with predicted environmental change. In particular, our understanding will be advanced by studies addressing the interactive effects of multiple stressors on the role of biodiversity across trophic levels. Predicted increases in wave disturbance and ocean warming, together with climate-driven range shifts of key consumer species, are likely to have profound impacts on the dynamics of coastal marine communities. We tested whether wave action and temperature modified the effects of gastropod grazer diversity (Patella vulgata, Littorina littorea and Gibbula umbilicalis) on algal assemblages in experimental rock pools. The presence or absence of L. littorea appeared to drive changes in microalgal and macroalgal biomass and macroalgal assemblage structure. Macroalgal biomass also decreased with increasing grazer species richness, but only when wave action was enhanced. Further, independently of grazer diversity, wave action and temperature had interactive effects on macroalgal assemblage structure. Warming also led to a reversal of grazer-macroalgal interaction strengths from negative to positive, but only when there was no wave action. Our results show that hydrodynamic disturbance can exacerbate the effects of changing consumer diversity, and may also disrupt the influence of other environmental stressors on key consumer-resource interactions. These findings suggest that the combined effects of anticipated abiotic and biotic change on the functioning of coastal marine ecosystems, although difficult to predict, may be substantial.

Organising EU non-discrimination law around the nodes of ‘race’ gender and disability?

EU non-discrimination law has seen a proliferation of discrimination grounds from 2000. Dis-crimination on grounds of gender (in the field of equal pay) and on grounds of nationality (generally within the scope of application of EU law) were the only prohibited forms of discrimination in EU law, until the Treaty of Amsterdam empowered the Community to legislate in order to combat discrimination on grounds of sex, racial or ethnic origin, religion or belief, disability, age or sexual orientation (Article 13 EC). Proliferation of non-discrimination grounds is also characteristic for international and national non-discrimination law. As such, proliferation of grounds results in an increase in potential cases of “multiple discrimination” and the danger of diluting the demands of equality law by ever more multiplication of grounds. The hierarchy of equality, which has been so widely criticised in EU law, is a signifier of the latter danger.
This chapter proposes to structure the confusing field of non-discrimination grounds by organising them around nodes of discrimination fields. It will first reflect different ways of establishing hierarchies between grounds. This will be followed by a recount of different (narrow and wide) reading of grounds. A comprehensive reading of the grounds gender, ‘race’ and disability as establishing overlapping fields of discrimination grounds will be mapped out, with some examples for practical uses.

Restorative Justice and Sex Offending

This essay examines the origins and uses of restorative justice with sexual offending and the contemporary challenges and controversies surrounding this. It charts the range of ad hoc initiatives which have sought to apply a restorative form of intervention with violent or sexual offending from first time and ‘acquaintance’ rape as well as young sexual abusers to high risk sexual offenders in the form of circles of support and accountability. Such schemes are often presented as a counter to the failings of retributive forms of justice and are premised on Braithwaite’s (1989) notion of ‘reintegrative shaming’ that seek to reintegrate offenders into the community. Critics of restorative justice traditionally put forward a number of core objectives when restorative justice is applied to serious forms of offending such as sexual offending. The essay also sets out and seeks to counter these principal challenges and how they may be overcome. For the most part, however, restorative justice has failed to reach its potential as a fully fledged sentencing rationale in being applied as a mainstream response to a wide range of offending including that at the higher end of the spectrum. The essay also seeks to examine barriers to restorative justice within contemporary penal policy and to highlight some of the most controversial applications of the restorative paradigm including those related to clergy sexual abuse. It concludes by offering some thoughts on the future of restorative justice as a mainstream responses to serious forms of offending.

Gendered Violence and International Human Rights: Thinking Non-Discrimination Beyond the Sex Binary

The concept of non-discrimination has been central in the feminist challenge to gendered violence within international human rights law. This article critically explores non-discrimination and the challenge it seeks to pose to gendered violence through the work of Judith Butler. Drawing upon Butler’s critique of heteronormative sex/gender, the article utilises an understanding of gendered violence as effected by the restrictive scripts of sex/gender within heteronormativity to illustrate how the development of non-discrimination within international human rights law renders it ineffective to challenge gendered violence due to its own commitments to binarised and asymmetrical sex/gender. However, the article also seeks to encourage a reworking of non-discrimination beyond the heteronormative sex binary through employing Butler’s concept of cultural translation. Analysis via the lens of cultural translation reveals the fluidity of non-discrimination as a universal concept and offers new possibilities for feminist engagement with universal human rights.

Intersectionality and the Notion of Disability in EU discrimination law

Defining the characteristics targeted by banning discrimination constitutes a central challenge for EU discrimination law, and defining disability is particular-ly challenging due to the dispute around the very concept of disability. From 2006, the Court of Justice has wrestled with this definition in six judgments, five of which were delivered from 2013. Instead of classifying the case law definition as conforming to a medical or social model of disability, this article analyses the case law with a view to illustrate challenges of defining discrimination grounds generally, demanding that a sufficiently precise and non-exclusive definition of each discrimination ground can be achieved by re-focusing EU discrimination law around the nodes of sex, race and disability. The analysis exposes that the ECJ definition of disability neither complies with the UN CRPD nor adequately responds to intersectionality theory, for example because the definition is exclu-sionary in relation to female experience of disability.

The role of knowledge in the contraceptive behaviour of sexually active young people in state care

Aim: To analyse the role of sex-focused knowledge in the contraceptive behaviour of sexually active young people in state care.

Methods: The sample consisted of 19 care leavers (young people previously in state care) aged 18-22 years, 16 females and 3 males. In-depth interviewing was the method of data collection, and a qualitative strategy resembling modified analytical induction was used to analyse data.

Findings: Findings indicated that a lack of information was not the sole, or even the primary reason for engaging in unsafe sexual practices. Other factors such as ambivalence to becoming pregnant also featured in participants’ accounts. Several participants conveyed a relatively weak sense of agency about consistently using contraception. A small number of participants expressed a strong determination to avoid pregnancy, and these appeared to have a level of anxiety about becoming pregnant that motivated them to engage with knowledge about contraception and its use.

Conclusion: Lack of sex-focused information is just one aspect of a myriad of complex factors, including socioeconomic disadvantage and/or emotional deprivation, that influences contraceptive behaviour.

Computerized key to the genus Bursaphelenchus Fuchs, analysis of species clusters based on morphology, using information of insect vectors and associated plants, with a revision of the genus.

The genus Bursaphelenchus includes B. xylophilus (Steiner et Buhrer, 1934) Nickle, 1981, which is of world economic and quarantine importance. Distinction among several species of the pinewood nematodes species complex (PWNSC) is often difficult. Besides standard morphology, morphometrics and molecular biology, new tools are welcome to better understand this group. The computerized (or e-) key of this genus, presented in this communication, includes 74 species (complete list of valid species of the world fauna) and 35 characters, that were used by the taxonomic experts of this group, in the original descriptions. Morphology of sex organs (male spicules and female vulval region) was digitized and classified to distinguish alternative types. Several qualitative characters with overlapping character states (expressions) were transformed into the morphometric indices with the discontinuous ranges (characters of ratios of the spicule dimensions). Characters and their states (expressions) were illustrated in detail and supplied by brief user-friendly comments. E-key was created in the BIKEY identification system (Dianov & Lobanov, 1996-2004). The system has built-algorithm ranging characters depending on their diagnostic values at each step of identification. Matrix of species and the character states (structural part of the e-key database) may be easily transformed using statistical packages into the dendrograms of general phenetic similarities (UPGMA, standard distance: mean character difference). It may be useful in the detailed analysis of taxonomy and evolution of the genus and in its splitting to the species groups based on morphology. The verification of the dendrogram using the information on the species links with insect vectors and their associated plants, provided an opportunity to recognize the five clusters (xylophilus, hunti, eremus sensu stricto, tusciae and piniperdae sensu stricto), which seem to be the natural species groups. The hypothesis about the origin and the first stages of the genus evolution is proposed. A general review of the genus Bursaphelenchus is presented.

Mythotextuality and the evolution of ideologies the reuse of the Epic of Gilgamesh in North American texts

When the scribes of ancient Mesopotamia rewrote the Epic of Gilgamesh over a period of over two thousand years, the modifications made reflected the social transformations occurring during the same era. The dethroning of the goddess Inanna-Ishtar and the devaluation of other female characters in the evolving Epic of Gilgamesh coincided with the declining status of women in society. Since the 1960s, translations into modern languages have been readily available. The Mesopotamian myth has been reused in a wide variety of mythic and mythological texts by Quebecois, Canadian and American authors. Our analysis of the first group of mythic texts, written in the 1960s and 1970s, shows a reversal of the tendency of the Mesopotamian texts. Written at a time when the feminist movement was transforming North American society, these retellings feature a goddess with her high status restored and her ancient attributes re-established. Another group of writers, publishing in the 1980s and 1990s, makes a radical shift away from these feminist tendencies while still basically rewriting the Epic. In this group of mythic texts, the goddess and other female characters find their roles reduced while the male gods and characters have expanded and glorified roles. The third group of texts analysed does not rewrite the Epic. The Epic is reused here intertextually to give depth to mythological works set in the twentieth century or later. The dialogue created between the contemporary text and the Epic emphasises the role that the individual has in society. A large-scale comparative mythotextual study of texts that share a common hypotext can, especially when socio-historical factors are considered, provide a window onto the relationship between text and society. A comparative study of how the Epic of Gilgamesh is rewritten and referred to intertextually through time can help us relativize the understanding of our own time and culture.

Protecting children from sex offenders online: when strangers become 'virtual friends'

This article describes findings from research funded by the Metropolitan Police and Crimestoppers which aimed to explore children's online experiences. A non-random, stratified sample of 200 London school children aged 10- 13 participated in focus groups. Preliminary findings are also presented from unpublished ongoing PhD research, which seeks to explore sex offender behaviour online and the policing of the internet (Martellozzo, 2005 ongoing). The findings are discussed in the context of sex offender's use of the internet. This research indicates that children do have some basic knowledge about 'stranger danger' but are not necessarily applying these lessons to cyberspace. The children in this study had sufficient awareness to not give personal details to strangers on the internet, and would not arrange to meet them. However, they made a distinction between 'strangers' and 'virtual friends' and this is an important point. Preliminary findings also highlight the difficulty of policing the internet and serve to illustrate the manner in which the Sexual Offences Act 2003 is applied to internet sexual offending in practice.