Calmodulin disruption impacts growth and motility in juvenile liver fluke

Background: Deficiencies in effective flukicide options and growing issues with drug resistance make current strategies for liver fluke control unsustainable, thereby promoting the need to identify and validate new control targets in Fasciola spp. parasites. Calmodulins (CaMs) are small calcium-sensing proteins with ubiquitous expression in all eukaryotic organisms and generally use fluctuations in intracellular calcium levels to modulate cell signalling events. CaMs are essential for fundamental processes including the phosphorylation of protein kinases, gene transcription, calcium transport and smooth muscle contraction. In the blood fluke Schistosoma mansoni, calmodulins have been implicated in egg hatching, miracidial transformation and larval development. Previously, CaMs have been identified amongst liver fluke excretory-secretory products and three CaM-like proteins have been characterised biochemically from adult Fasciola hepatica, although their functions remain unknown.

Methods: In this study, we set out to investigate the biological function and control target potential of F. hepatica CaMs (FhCaMs) using RNAi methodology alongside novel in vitro bioassays.

Results: Our results reveal that: (i) FhCaMs are widely expressed in parenchymal cells throughout the forebody region of juvenile fluke; (ii) significant transcriptional knockdown of FhCaM1-3 was inducible by exposure to either long (~200 nt) double stranded (ds) RNAs or 27 nt short interfering (si) RNAs, although siRNAs were less effective than long dsRNAs; (iii) transient long dsRNA exposure-induced RNA interference (RNAi) of FhCaMs triggered transcript knockdown that persisted for ≥ 21 days, and led to detectable suppression of FhCaM proteins; (iv) FhCaM RNAi significantly reduced the growth of juvenile flukes maintained in vitro; (v) FhCaM RNAi juveniles also displayed hyperactivity encompassing significantly increased migration; (vi) both the reduced growth and increased motility phenotypes were recapitulated in juvenile fluke using the CaM inhibitor trifluoperazine hydrochloride, supporting phenotype specificity.

Conclusions: These data indicate that the Ca(2+)-modulating functions of FhCaMs are important for juvenile fluke growth and movement and provide the first functional genomics-based example of a growth-defect resulting from gene silencing in liver fluke. Whilst the phenotypic impacts of FhCaM silencing on fluke behaviour do not strongly support their candidature as new flukicide targets, the growth impacts encourage further consideration, especially in light of the speed of juvenile fluke growth in vivo.

Punishment, youth justice and cultural contingency: Towards a balanced approach

Reflecting developments in the broader penological realm, accounts have been advanced over the last number of decades about a ‘punitive turn’ in the youth justice systems of Western democracies. Against the background of this work, this project seeks to identify convergent and divergent trends in the youth justice systems of England, the Republic of Ireland and Northern Ireland as well as the rationalities and discourses animating these. The results lend support to research emphasising the continued salience of national, regional and local factors on penal outcomes but also suggest the need to steer an analytical path somewhere between nomothetic (convergent) and idiographic (divergent) accounts.

Glycosylation of Vitamin D Binding Protein Reduced in Juvenile Idiopathic Arthritis Patients At Risk of Disease Extension.

Background/Purpose:Juvenile idiopathic arthritis (JIA) comprises a poorly understood group of chronic, childhood onset, autoimmune diseases with variable clinical outcomes. We investigated whether profiling of the synovial fluid (SF) proteome by a fluorescent dye based, two-dimensional gel (DIGE) approach could distinguish the subset of patients in whom inflammation extends to affect a large number of joints, early in the disease process. The post-translational modifications to candidate protein markers were verified by a novel deglycosylation strategy.Methods:SF samples from 57 patients were obtained around time of initial diagnosis of JIA. At 1 year from inclusion patients were categorized according to ILAR criteria as oligoarticular arthritis (n=26), extended oligoarticular (n=8) and polyarticular disease (n=18). SF samples were labeled with Cy dyes and separated by two-dimensional electrophoresis. Multivariate analyses were used to isolate a panel of proteins which distinguish patient subgroups. Proteins were identified using MALDI-TOF mass spectrometry with vitamin D binding protein (VDBP) expression and siaylation further verified by immunohistochemistry, ELISA test and immunoprecipitation. Candidate biomarkers were compared to conventional inflammation measure C-reactive protein (CRP). Sialic acid residues were enzymatically cleaved from immunopurified SF VDBP, enriched by hydrophilic interaction liquid chromatography (HILIC) and analysed by mass spectrometry.Results:Hierarchical clustering based on the expression levels of a set of 23 proteins segregated the extended-to-be oligoarticular from the oligoarticular patients. A cleaved isoform of VDBP, spot 873, is present at significantly reduced levels in the SF of oligoarticular patients at risk of disease extension, relative to other subgroups (p<0.05). Conversely total levels of vitamin D binding protein are elevated in plasma and ROC curves indicate an improved diagnostic sensitivity to detect patients at risk of disease extension, over both spot 873 and CRP levels. Sialysed forms of intact immunopurified VDBP were more prevalent in persistent oligoarticular patient synovial fluids.Conclusion:The data indicate that a subset of the synovial fluid proteome may be used to stratify patients to determine risk of disease extension. Reduced conversion of VDBP to a macrophage activation factor may represent a novel pathway contributing to increased risk of disease extension in JIA patients.

Victims, Violence and Voice: Transitional Justice, Oral History and Dealing with the Past

Transitional justice is concerned with the legal and social processes established to deal with the legacy of violence in post-conflict and post-authoritarian contexts. These processes are essentially “creatures of law” – they are established by statute, their work is molded and shaped by lawyers, and their outcomes are benchmarked against what is or is not acceptable in domestic and international law. Concerns have mounted in recent years about the dominance of legalism within the field and the instrumentalization of those most directly affected by past violence. A commonly prescribed – but as yet largely empirically untested – corrective is that transitional justice theory and practice must become more open to interdisciplinary insights and perspectives. The interview – in different guises, contexts and settings – is at the heart of most transitional justice processes. As a historian now working in a School of Law I reflect in this article on the theoretical and practical intersections between law, history, and the interview. Drawing on more than 200 interviews concerning the Northern Ireland conflict and six other international case studies I concentrate in particular on interview-based initiatives that purport to be “victim-centered”. Having identified three interrelated risks - the manipulation of victim voice by vested interests, the affording of authority to particular voices, and the reification or “freezing” of identity - and having related these to the constraints of legal mechanisms and a wider failure to manage victims’ expectations, I argue that a greater familiarity with oral history theory and praxis can usefully illuminate the tensions between legal and historical approaches to engaging voice, and ultimately offer guidance to the shared challenge of victim-centered transitional justice.

Ageing, Justice, and Resource Allocation

Around the world the population is ageing in ways that pose new challenges for health care providers. To date these have mostly been formulated in terms of challenges created by increasing costs, and the focus has been squarely on life prolonging treatments. However, this focus ignores the ways in which many older people require life enhancing treatments to counteract the effects of physical and mental decline. This paper argues that in doing so it misses important aspects of what justice requires when it comes to older people.

Justice, Truth and Oral History: Legislating the Past 'From Below' in Northern Ireland

Drawing on the ‘from below’ perspective which has emerged in transitional justice scholarship and practice
over the past two decades, this article critically examines the dealing with the past debate in Northern
Ireland. The paper begins by offering an outline of the from below perspective in the context of post-conflict
or post-authoritarian societies which are struggling to come to terms with past violence and human rights
abuses. Having provided some of the legal and political background to the most recent efforts to deal with
the past in Northern Ireland, it then critically examines the relevant past-related provisions of the Stormont
House Agreement, namely the institutions which are designed to facilitate ‘justice’, truth recovery and the
establishment of an Oral History Archive. Drawing from the political science and social movement
literature on lobbying and the ways in which interests groups may seek to influence policy, the paper then
explores the efforts of the authors and others to contribute to the broader public debate, including through
drafting and circulating a ‘Model Bill’ on dealing with the past (reproduced elsewhere in this issue) as a
counterweight to the legislation which is required from the British government to implement the Stormont
House Agreement. The authors argue that the combination of technical capacity, grass-roots
credibility and ‘international-savvy’ local solutions offers a framework for praxis from below in other
contexts where activists are struggling to extend ownership of transitional justice beyond political elites.
Keywords: transitional justice; from below; dealing with the past; legislation; truth
recovery; prosecutions; oral history

A prospective comparative evaluation of a Criminal Justice Liaison and Diversion Service in Belfast

There is continued interest in the planning, development and implementation of services designed to identify, detainees with mental illness and connect them to health and social services. However, currently little is known about how best to configure, organise and deliver these services. The study employed a prospective follow-up design with a comparator group to describe and evaluate a police mental health liaison service based in Belfast. Participants were recruited from two neighbouring police stations, only one of which provided a mental health liaison service. Outcomes including mental health status, drug and alcohol misuse, risk-related behaviour and ‘administrative’ outcomes were assessed at the time of arrest and six months later. The service was successful in identifying and assessing detainees though there appeared to be similar between-group levels of mental health problems over time. Results highlight a need to develop firmer linkages and pathways between criminal justice liaison / diversion services and routine health and social services. 

Experiencing Youth Justice and Penality

Much of the recent literature on youth justice has focused on administrative aspects of the system and the socio-political contexts that have led to the ‘production’ of the youthful offender as a subject and locus of intervention. This has largely been driven by the extent to which youth justice has been crafted as a distinct penal sphere, evident in its unyoking from universal children’s services (Muncie and Goldson, 2013) and the establishment of separate agencies to administer and govern this ‘system’ (Souhami, 2014). Driven by policy hyperactivity and a plethora of legislation expanding the reach of the system, for much of the 1990s and 2000s increasing numbers of young people were brought under its gaze.

Particular attention has been paid to the impact of neo-liberal governance on the discourses, rationales and philosophies underpinning contemporary youth justice policy and practice. Writing specifically in the English and Welsh context, several authors have identified that the resulting ‘system’ embodies multiple, contradictory and competing discourses (Muncie, 2006; Fergusson, 2007; Gray, 2013). Within this ‘melting pot’ Fergusson (2007) notes the disjuncture between policy rhetoric, implementation and lived experience and Phoenix (2015) argues that systems-based analyses, much in favour amongst academics, foreclose a wider consideration of questions of what ‘justice’ actually means.

Recent attention towards the perspectives of practitioners working in this sphere has pointed to greater nuances than broader penal narratives suggest (see: Field, 2007; Briggs, 2013; Gray, 2013; Kelly and Armitage, 2015). Yet similar attention has not been given to experiences of youth justice (for an exception see – Phoenix and Kelly, 2013). However, it is precisely young people’s experiences, which would add significantly to current knowledge and potentially bridge the gap between discussions about penal philosophies, how youth justice policies are framed, how they are enacted and how they are experienced.

This chapter provides an overview of recent developments in the field of youth justice and penality in the United Kingdom. The chapter argues that a theoretical focus on macro-level trends (Hannah-Moffat and Lynch, 2012), alongside a narrowly defined research agenda, have largely excluded young people’s experiences of justice and punishment from contemporary analysis. Drawing on young people experiences of different aspects of youth justice in Northern Ireland and beyond, the chapter illuminates what a close understanding of lived experience can add to knowledge. In particular it demonstrates that the effects of interventions can be different to their aims and intentions; and that re-instating the youth experience can add support to calls for greater attention to wider issues of social justice.

Revitalizing the PE social-justice agenda in the global era: Where do we go from here?

Critical theorists have called attention to the intensification of diversity that is now occurring inside and outside of school, while critically engaging with the detrimental effects of globalization on equity, diversity, and social justice. Globalization presents new challenges to education and to issues of social justice. In this article, we argue that there is a need for scholars in the field of physical education (PE) to re-think and re-frame the social-justice agenda to address current inequalities produced by globalization. To support this argument, first, we reflect on the impact of global neoliberalism on PE; second, we discuss the ways in which, as a result of global neoliberalism, public health discourses have an “othering” effect on ethnically diverse young people; third, we propose a theoretical shift from a focus on equality to a focus on difference; and finally, we conclude with considerations for future research and curricula in school PE.

Seawater acidification by CO2 in a coastal lagoon environment: Effects on life history traits of juvenile mussels Mytilus galloprovincialis

The carbonate chemistry of seawater fromthe Ria Formosa lagoon was experimentallymanipulated, by diffusing pure CO2, to attain two reduced pH levels, by−0.3 and−0.6 pH units, relative to unmanipulated seawater. After 84 days of exposure, no differences were detected in terms of growth (somatic or shell) or mortality of juvenile mussels Mytilus galloprovincialis. The naturally elevated total alkalinity of the seawater (≈3550 μmol kg−1) prevented under-saturation of CaCO3, evenunder pCO2 values exceeding 4000 μatm, attenuating the detrimental effects on the carbonate supply-side. Even so, variations in shell weight showed that net calcification was reduced under elevated CO2 and reduced pH, although the magnitude and significance of this effect varied among size-classes. Most of the loss of shell material probably occurred as post-deposition dissolution in the internal aragonitic nacre layer. Our results show that, even when reared under extreme levels of CO2- induced acidification, juvenileM. galloprovincialis can continue to calcify and grow in this coastal lagoon environment. The complex responses of bivalves to ocean acidification suggest a large degree of interspecific and intraspecific variability in their sensitivity to this type of perturbation. Further research is needed to assess the generality of these patterns and to disentangle the relative contributions of acclimation to local variations in seawater chemistry and genetic adaptation.