Extracellular matrix sub-types and mechanical stretch impact human cardiac fibroblast responses to transforming growth factor beta

Understanding the impact of extracellular matrix sub-types and mechanical stretch on cardiac fibroblast activity is required to help unravel the pathophysiology of myocardial fibrotic diseases. Therefore, the purpose of this study was to investigate pro-fibrotic responses of primary human cardiac fibroblast cells exposed to different extracellular matrix components, including collagen sub-types I, III, IV, VI and laminin. The impact of mechanical cyclical stretch and treatment with transforming growth factor beta 1 (TGFβ1) on collagen 1, collagen 3 and alpha smooth muscle actin mRNA expression on different matrices was assessed using quantitative real-time PCR. Our results revealed that all of the matrices studied not only affected the expression of pro-fibrotic genes in primary human cardiac fibroblast cells at rest but also affected their response to TGFβ1. In addition, differential cellular responses to mechanical cyclical stretch were observed depending on the type of matrix the cells were adhered to. These findings may give insight into the impact of selective pathological deposition of extracellular matrix proteins within different disease states and how these could impact the fibrotic environment.

Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts:a possible defense against transforming growth factor-β mediated fibrosis

BACKGROUND: Mechanical overload of the heart is associated with excessive deposition of extracellular matrix proteins and the development of cardiac fibrosis. This can result in reduced ventricular compliance, diastolic dysfunction, and heart failure. Extracellular matrix synthesis is regulated primarily by cardiac fibroblasts, more specifically, the active myofibroblast. The influence of mechanical stretch on human cardiac fibroblasts' response to pro-fibrotic stimuli, such as transforming growth factor beta (TGFβ), is unknown as is the impact of stretch on B-type natriuretic peptide (BNP) and natriuretic peptide receptor A (NPRA) expression. BNP, acting via NPRA, has been shown to play a role in modulation of cardiac fibrosis.

METHODS AND RESULTS: The effect of cyclical mechanical stretch on TGFβ induction of myofibroblast differentiation in primary human cardiac fibroblasts and whether differences in response to stretch were associated with changes in the natriuretic peptide system were investigated. Cyclical mechanical stretch attenuated the effectiveness of TGFβ in inducing myofibroblast differentiation. This finding was associated with a novel observation that mechanical stretch can increase BNP and NPRA expression in human cardiac fibroblasts, which could have important implications in modulating myocardial fibrosis. Exogenous BNP treatment further reduced the potency of TGFβ on mechanically stretched fibroblasts.

CONCLUSION: We postulate that stretch induced up-regulation of the natriuretic peptide system may contribute to the observed reduction in myofibroblast differentiation.

Paramilitary punishments in Belfast: policing beneath the peace

As an enduring legacy of the conflict, paramilitary policing remains an unpalatable but indisputable fact within Belfast's working-class, Republican communities. Historically, while much attention has been devoted to the causes and consequences of paramilitarism along with the terrorist threat posed by such organizations, little attention has been paid to the influence upon, or relations between, such nonstate policing actors, the communities in which they exist and the delivery of policing by the Police Service of Northern Ireland. While local and international literature surrounding paramilitary violence has tended towards political axiom or physical impact of such activity, the current paper presents an empirical study of the relations between communities and Republican paramilitary organizations who seek to exploit a perceived dearth of state-based policing at the community level within Belfast. Framing the ontology of paramilitary policing and its support from a community, rather than political or security perspective, the paper argues that continuing grass-roots support for this ‘new’ paramilitary policing within Republican communities of Belfast is more complex and nuanced than the political antecedents of the conflict from which such activity emerged – especially in terms of such support surviving successive political negotiations and police reforms since the ‘Good Friday’ Agreement of 1998.

Parading through the Peace Process:Anthropology, Governance and Crisis in Northern Ireland

Because the authors both did work on the North Ireland parades, they became integrally involved as fieldworking anthropologists in the monitoring of these events, and in the creation of policy for their management. They detail how they worked with individuals and groups at every level, from protestors on the street up to the Secretary of State for the region. Later funded to examine legal and policing approaches to protests in other countries, especially South Africa, they show how they used this comparative knowledge to urge the implementation of measures which appear to have led to a diminution of violence in the parades. Finally, they assess their own contribution to the peace process in terms of contingency, timing, luck, flexibility, and industry.

Peace Building and Conflict Transformation: A Case Study of Northern Ireland

This paper provides an overview of the transition from armed conflict to peace in Northern Ireland between 1994 and 2016. It discusses the main stages of the peace process and the main elements of the peace Agreement in relation to the development of global thinking around peacebuilding as set out in the United Nations 1992 report Agenda for Peace and the 2000 Brahimi Report. The paper argues that while Northern Ireland is often highlighted as a positive example of peacebuilding, it is not without its limitations and overall the experience of the past twenty years emphasises the importance of ensuring a broadly inclusive process and the need for a sustained commitment over a long period of time.