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.

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.

Sequencing and its consequences:Path dependence and the relationships between genetics and medicalization

Both advocacy for and critiques of the Human Genome Project assume a self-sustaining relationship between genetics and. medicalization. However, this assumption ignores the ways in which the meanings of genetic research are conditional on its position in sequences of events. Based, on analyses of three conditions for which at least one putative gene or genetic marker has been identified, this article argues that critical junctures in the institutional stabilization of phenotypes and the mechanisms that sustain such classifications over time configure the practices and meanings of genetic research. Path dependence is critical to understanding the lack of consistent fit between genetics and medlcalization.

European Union Cross-Border Cooperation and Conflict Amelioration

The relevance of European Union (EU) cross-border cooperation for European border con?ict amelioration may be questioned in the contemporary global climate of threat and insecurity posed by forces of ’dark globalisation’. In any case, empirical evidence exposes the limitations of cross-border cooperation in advancing con?ict amelioration in some border regions. Nevertheless, in an enlarged EU which encompasses Central and East European member states and reaches out to neighbouring states through cross-border cooperation initiatives, the number of real and potential border con?icts with which it is concerned has risen exponentially. Fortunately, there are cases of EU ’borderscapes’ that have adopted a cross-border ’peace-building from below’ approach leading to border con?ict amelioration. Unfortunately, countervailing pressures on EU cross-border cooperation from border security regimes (principally Schengen), the Eurozone crisis, EU budgetary constraints, the conceptualisation of ’Europe as Empire’, and the possible recon?guration of the EU itself compromises this approach. Therefore, the path of European integration may well shift from one of inter-state peace-building and regional crossborder cooperation after the Second World War, to border con?ict and coercion in constituting and reconstituting state borders after the recon?guration of the EU.

Queering the Family: Attitudes towards Lesbian and Gay Relationships and Families in Northern Ireland

The Northern Ireland Life andTimes (NILT) Survey has asked questions on lesbian, gay, bisexual and transgender (LGBT) issues since 1998. To date survey data have focused primarily on issues relating to prejudice, discrimination and tolerance. In 2012 a range of questions focussing more specifically on LGBT1 issues was included. This collected information on knowledge and perceptions of the LGBT population; personal prejudice; attitudes on equality issues; the visibility of LGBT people and family-related issues.

This update provides an overview of some of the information emerging from this data. It discusses attitudes towards same-sex relations and notable changes over time. Given recent political debate the primary focus of this paper is on attitudes relating to ‘queer’ marriage, family and parenting. We use the term ‘queer’ here to refer to ‘the diverse family structures formed by those with non-normative gender behaviours or sexual orientations’ (Bernstein and Reimann, 2001: 3). As previous updates have noted, there have been significant legislative and policy changes in this area (Jarman, 2010) and this continues with ongoing discussions regarding the development of a Sexual Orientation Strategy for Northern Ireland (Gray et al, 2013).

Personalising Crime and Crime-fighting in Factual Television:an Analysis of Social Actors and Transitivity in Language and Images

This article addresses the lack of work on media and crime in Critical Discourse Analysis (CDA), using an example of a factual television crime report. The existing research in media studies and criminology points to the way that the media misrepresents crime by distorting public understandings and backgrounding structural issues, such as poverty, which are related to crime thereby legitimising a criminal justice system that serves the interests of the powerful in society. Using social actor and transitivity analysis, this article shows how multimodal CDA can make an important contribution as it reveals the more subtle linguistic strategies and visual representations by which this process is accomplished, showing how each plays a part in the recontextualisation of social practice. This programme backgrounds which crimes are committed but foregrounds mental states and the neutrality of policing.

From the past to the Future: integrating archaeology and conflict resolution in Northern Ireland

Contested understandings about the past continue to reify the divided character of post-Troubles Northern Ireland. In particular, the unresolved legacies of the extension of English control over Ireland in the late sixteenth and early seventeenth centuries through warfare and plantation continue to structure daily lives in the province. Yet the archaeological record of this period complicates the accepted dichotomous narratives through highlighting complexity. These nuances, however, have been lost in recent decades as an overly simplistic model of colonizer versus colonized has emerged as the dominant political paradigm. The management and presentation of sites associated with the process of plantation can arguably create the space necessary to bridge the divide, and to challenge accepted understandings. Cross-community engagement in the process of archaeological discovery and interpretation on plantation-period sites in Northern Ireland highlights the critical role archaeology can play in peace and reconciliation in post-conflict societies.

Evangelicalism and Conflict in Northern Ireland

This book explores the role of evangelicalism in the conflict in Northern Ireland and discusses how it may contribute to a peaceful transition. Ganiel analyses the 'traditional' evangelicals who are associated with the Rev. Ian Paisley, as well as a new breed of 'mediating' evangelicals who have broken with the traditions of the past. Comparing evangelical politics in Northern Ireland to the US and Canada, this book sheds light on future directions for Northern Irish evangelicalism. The conclusion has global reverberations as it reflects on the place of 'strong' religions -- such as evangelicalism and other forms of fundamentalism -- in contemporary world politics.