Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor

We present new homology-based models of the glutamate binding site (in closed and open forms) of the NMDA receptor NR2B subunit derived from X-ray structures of the water soluble AMPA sensitive glutamate receptor. The models were used for revealing binding modes of agonists and competitive antagonists, as well as for rationalizing known experimental facts concerning structure-activity relationships: (i) the switching between the agonist and the antagonist modes of action upon lengthening the chain between the distal acidic group and the amino acid moiety, (ii) the preference for the methyl group attached to the a-amino group of ligands, (iii) the preference for the D-configuration of agonists and antagonists, and (iv) the existence of "superacidic" agonists.

The UNCRC and social workers' relationships with young children

In the UK, The Munro Review of Child Protection (2010, 2011a, 2011b) has recently highlighted that among the failings in safeguarding children known to social services is the lack of meaningful relationships between social workers and children. In her final report, Munro (2011b) has made recommendations for a more child-centred system anchored on two themes – the child's journey and the United Nations Convention on the Rights of the Child (UNCRC). This article illustrates by way of practical examples how the UNCRC, together with the detailed advice and guidance contained in the UNCRC general comments numbers 5, 7 and 12, provides the best framework for developing effective social work relationships with, and safeguarding, young children.

Cube, cylinder, core and pull-off strength relationships

This limited experimental investigation examined the relationships between the compressive strengths of cubes, cylinders, cores and the estimated compressive strengths derived from pull-off tests for a relatively low-strength structural-grade concrete (<35 N/mm2). Test specimens were cast and tested at 7, 14, 28, 56 and 84 days. The relationships of the trends of the test results to the trends of results of standard cube specimens and standard cylinder specimens were compared. It was found that the mean strength of each type of specimen tended to increase as a function of the natural logarithm of the specimen age. The mean strength of cylinders of length/diameter ratio 2.0 was found to be slightly greater (by about 7.5%) than the generally accepted value of 80% of the mean cube strength. Core results were corrected using correction factors defined in BS 6089 and the UK national annex to BS EN 12504-1. The mean corrected cube strength of cores taken from cubes was approximately 12% greater than the mean companion cube strength. The mean corrected cylinder strength of cores taken from cubes was approximately 5% greater than the mean companion cylinder strength. The potential cube and cylinder strengths of cores taken from slabs cured under different environmental conditions correlated well with companion cube and cylinder strengths respectively at 28 days. The pull-off test results gave a variable but, on average, slightly conservative estimate of the cube compressive strength of the relatively low-strength structural-grade concrete, using a simple general linear estimated compressive cube strength to tensile strength correlation factor of 10.

Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica

The helminth parasite Fasciola hepatica secretes cysteine proteases to facilitate tissue invasion, migration, and development within the mammalian host. The major proteases cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) were recombinantly produced and biochemically characterized. By using site-directed mutagenesis, we show that residues at position 67 and 205, which lie within the S2 pocket of the active site, are critical in determining the substrate and inhibitor specificity. FheCL1 exhibits a broader specificity and a higher substrate turnover rate compared with FheCL2. However, FheCL2 can efficiently cleave substrates with a Pro in the P2 position and degrade collagen within the triple helices at physiological pH, an activity that among cysteine proteases has only been reported for human cathepsin K. The 1.4-A three-dimensional structure of the FheCL1 was determined by x-ray crystallography, and the three-dimensional structure of FheCL2 was constructed via homology-based modeling. Analysis and comparison of these structures and our biochemical data with those of human cathepsins L and K provided an interpretation of the substrate-recognition mechanisms of these major parasite proteases. Furthermore, our studies suggest that a configuration involving residue 67 and the "gatekeeper" residues 157 and 158 situated at the entrance of the active site pocket create a topology that endows FheCL2 with its unusual collagenolytic activity. The emergence of a specialized collagenolytic function in Fasciola likely contributes to the success of this tissue-invasive parasite.

Do Recessions Transform Work and Employment? Evidence from Ireland

Two contrasting views tend to dominate the literature on the impact of recessions on employment. One view is that recessions amount to a ‘critical conjuncture’ for work and employment systems, a time when firms try to transform radically existing employment models. The alternative perspective is that firms, constrained mostly by the forces of path dependency, seek to adjust to the immediate or short-term pressures of the recession but otherwise maintain the established way of organizing the employment relationship. The purpose of this article is to contribute to this literature by reporting the findings of a major study of the effects of the recession on work and employment in firms based in Ireland. The main finding to emerge from the study is that firms mostly have made improvised adaptations in response to the crisis and have shied away from far-reaching transformational strategies.

Arsenic shoot-grain relationships in field grown rice cultivars

Arsenic (As) accumulation in rice grains is a risk to human health. The mechanism of transfer of As from the shoot into the grain during grain filling is unknown at present. In this study As speciation in the shoot and grains at maturity were examined, and the relationships between phosphorus (P) and As, and silicon (Si) and As were established in a wide range of cultivars grown in As contaminated field trials in Bangladesh and China. No correlations were observed between shoot and grain speciation, with the inorganic form comprising 93.0-97.0% of As in the shoot and 63.0-83.7% in the grains. The percentage of dimethylarsinic acid (DMA) was between 1.4 and 6.6% in the shoot and 14.6 and 37.0% in the grains; however, the concentrations were comparable, ranging from 0.07 to 0.26 mg kg(-1) in the shoots and 0.03 to 0.25 mg kg(-1) in the grains. A positive correlation was observed between shoot As and shoot Si, however, no correlation was observed between shoot Si and grain As. A significant negative correlation was observed between shoot P and grain As concentrations. These results suggest that the translocation of As into the grain from the shoots is potentially using P rather than Si transport mechanisms. The findings also indicate that inorganic As and DMA translocation to the grain differ considerably.

Quantitative structure-toxicity relationships for chlorophenols to bioluminescent lux-marked bacteria using atom-based semi-empirical molecular-orbital descriptors

Literature data on the toxicity of chlorophenols for three luminescent bacteria (Vibrio fischeri, and the lux-marked Pseudomonas fluorescens 10586s pUCD607 and Burkholderia spp. RASC c2 (Tn4431)) have been analyzed in relation to a set of computed molecular physico-chemical properties. The quantitative structure-toxicity relationships of the compounds in each species showed marked differences when based upon semi-empirical molecular-orbital molecular and atom based properties. For mono-, di- and tri-chlorophenols multiple linear regression analysis of V. fischeri toxicity showed a good correlation with the solvent accessible surface area and the charge on the oxygen atom. This correlation successfully predicted the toxicity of the heavily chlorinated phenols, suggesting in V. fischeri only one overall mechanism is present for all chlorophenols. Good correlations were also found for RASC c2 with molecular properties, such as the surface area and the nucleophilic super-delocalizability of the oxygen. In contrast the best QSTR for P. fluorescens contained the 2nd order connectivity index and ELUMO suggesting a different, more reactive mechanism. Cross-species correlations were examined, and between V. fischeri and RASC c2 the inclusion of the minimum value of the nucleophilic susceptibility on the ring carbons produced good results. Poorer correlations were found with P. fluorescens highlighting the relative similarity of V. fischeri and RASC c2, in contrast to that of P. fluorescens.

Contact and context: sharing education and building relationships in a divided society

One approach to tackling problems of division in society has been to promote collaboration and engagement between schools separated on ethno-religious lines. Based on some variant of contact theory, the received wisdom is that inter-group encounters can contribute to prejudice reduction and promote more harmonious relationships. Evidence to support this analysis is convincing; however, relatively little is known about the environmental factors that impede or enhance the potential for contact in different contexts. The importance of understanding such factors is underscored in divided jurisdictions, where separate education has been linked to the perpetuation of division and hostility. This paper adopts a qualitative approach to exploring the impact of two inter-school initiatives in Northern Ireland. The projects are located in contrasting socio-political and demographic environments, and research findings point to very different contact outcomes for participants in each. Seemingly relevant factors include the degree of congruence between school and community norms and values, the opportunity to develop relationships outside the school context, the relationships developed between the schools and local communities and the historical, political and social referents used by individuals to navigate the contact experience. The paper concludes with some reflections on factors that may help foster social harmony and on potential policy implications of the findings.

Vulnerability and multiple deprivation perspectives on economic exclusion in Europe: A latent class analysis

In this paper we address issues relating to vulnerability to economic exclusion and levels of economic exclusion in Europe. We do so by applying latent class models to data from the European Community Household Panel for thirteen countries. This approach allows us to distinguish between vulnerability to economic exclusion and exposure to multiple deprivation at a particular point in time. The results of our analysis confirm that in every country it is possible to distinguish between a vulnerable and a non-vulnerable class. Association between income poverty, life-style deprivation and subjective economic strain is accounted for by allocating individuals to the categories of this latent variable. The size of the vulnerable class varies across countries in line with expectations derived from welfare regime theory. Between class differentiation is weakest in social democratic regimes but otherwise the pattern of differentiation is remarkably similar. The key discriminatory factor is life-style deprivation, followed by income and economic strain. Social class and employment status are powerful predictors of latent class membership in all countries but the strength of these relationships varies across welfare regimes. Individual biography and life events are also related to vulnerability to economic exclusion. However, there is no evidence that they account for any significant part of the socio-economic structuring of vulnerability and no support is found for the hypothesis that social exclusion has come to transcend class boundaries and become a matter of individual biography. However, the extent of socio-economic structuring does vary substantially across welfare regimes. Levels of economic exclusion, in the sense of current exposure to multiple deprivation, also vary systematically by welfare regime and social class. Taking both vulnerability to economic exclusion and levels of exclusion into account suggests that care should be exercised in moving from evidence on the dynamic nature of poverty and economic exclusion to arguments relating to the superiority of selective over universal social policies.

GENDER AND CLASS MOBILITY - EVIDENCE FROM THE REPUBLIC-OF-IRELAND

Gender has frequently been identified as the most controversial issue confronting class analysis. In this paper we make use of data from the Republic of Ireland to assess the extent to which the incorporation of women in class mobility analysis alters our understanding of the central processes of social mobility. We find that for married women their husband's class is a more powerful predictor of household poverty and life-style than their own 'class' as indicated by current or previous occupation. With regard to employment mobility we find that the sole source of gender variation in mobility chances relates to differences in the objective opportunity structures faced by men and women. Applying a measured variable model to 'men only' and 'complete' mobility tables reveals only modest differences in the patterns of social fluidity. The inclusion of women in class mobility tables requires little in the way of substantial modification of our understanding of the pattern of class relationships underlying the observed pattern of mobility.