Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200–400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of t-tubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

CREATING INDEPENDENT ADVOCATES FOR ENTREPRENEURS WITHIN GOVERNMENT: SOME REFLECTIONS ON THE SMALL BUSINESS COMMISSIONER MODEL

This paper provides a critical overview of a recent attempt to create an independent statutory "voice" for small enterprises within the formal government bureaucracy in one Australian jurisdiction. It discusses the creation and eighteen months of activity of the Small Business Commissioner of the Australian Capital Territory.In 2003 the ACT government foreshadowed that, as part of its strategy to create the most small-business-friendly location in Australia, it would establish a Small Business Commissioner as a statutory appointment. The Legislative Assembly passed the Small Business Commissioner Act in 2004 and activity began in March 2005.The key activities of the Commissioner have been to examine small business complaints about ACT government agencies; to promote the use of mediation and/or other alternative dispute resolution tools for the settlement of disputes between small enterprises and other businesses; to provide independent advice to the Territory government about laws, regulations and policies that may affect small firms; to oversee the introduction of small business service charters within government agencies; and to establish a more "business friendly" service culture within ACT government agencies.On one hand, it is clear that a Commissioner role has a potentially significant strategic importance for small and medium-sized enterprises, principally through the provision of independent commentary, pushing for red tape and regulatory reduction, and by providing mediation services and investigative functions. However, there are also some current problems with the role. These include potential overlap with other regulatory and investigative bodies; lack of formal compulsive powers; its dependence on political support for its effectiveness; insufficient resources; and the nature of the relationship it has with other government entities.Australia, Canberra, Australian capital territory, entrepreneurship, small business, public policy, service charters, mediation, Ombudsman, small business commissioner, advocate, SME, envoy

Competition regulation, open markets and small business

Competition is an essential ingredient in the entrepreneurial process. Businesses seek to generate income, win sales and gain customers, but there is only a finite amount of these. As a result, all business ventures must engage in a contest for the limited resources (and pockets) of consumers. Firms engage in a constant process of contestability, differentiation and rivalry as they seek to win customers and generate profits. In the process, those that are more efficient, more attuned to consumer demands, and managed more effectively, will generally succeed. But competition also comes at a cost. Implicit in the notion of contestability is the fact that there will be both winners and losers. Some firms will succeed, and their owners will be enriched, whilst others emerge second best—which, in the worst case, will mean the business ceases to exist and investment capital is lost

Understanding the green entrepreneur

This introductory chapter provides an overview of the phenomenon of ‘environmental entrepreneurship’. It examines the key characteristics of entrepreneurs and entrepreneurial firms, and the link with sustainability and environmental responsibility. Ecopreneurship is a relatively new field of academic inquiry and study, and, although some work on the phenomena began in the 1970s, it was not until the 1990s that the topic began to receive much attention. Today there are still many areas in which more understanding of ecopreneurship and individual green entrepreneurs is needed. Current issues that require greater investigation include the development of an accurate and widely acceptable definition of the concept; profiling and identifying 'typical' characteristics of green entrepreneurs and the industries they occur in; identifying the factors that act as barriers and triggers to environmental entrepreneurship; the development of a body of research-based case studies and quantitative studies; and understanding policies which can be used to encourage a greater level of ecopreneurship. Difficulties in researching and understanding ecopreneurs include the problem of developing effective operational definitions of the concept, the choice between emphasizing qualitative or quantitative research approaches, and the fact that most studies only examine business ventures already in action, thus omitting both nascent green entrepreneurs and terminated ventures

Creating independent advocates for entrepreneurs within government : some reflections on the small business commissioner model

This paper provides a critical overview of a recent attempt to create an independent statutory “voice” for small enterprises within the formal government bureaucracy in one Australian jurisdiction. It discusses the creation and eighteen months of activity of the Small Business Commissioner of the Australian Capital Territory. In 2003 the ACT government foreshadowed that, as part of its strategy to create the most small-business-friendly location in Australia, it would establish a Small Business Commissioner as a statutory appointment. The Legislative Assembly passed the Small Business Commissioner Act in 2004 and activity began in March 2005. The key activities of the Commissioner have been to examine small business complaints about ACT government agencies; to promote the use of mediation and/or other alternative dispute resolution tools for the settlement of disputes between small enterprises and other businesses; to provide independent advice to the Territory government about laws, regulations and policies that may affect small firms; to oversee the introduction of small business service charters within government agencies; and to establish a more “business friendly” service culture within ACT government agencies. On one hand, it is clear that a Commissioner role has a potentially significant strategic importance for small and medium-sized enterprises, principally through the provision of independent commentary, pushing for red tape and regulatory reduction, and by providing mediation services and investigative functions. However, there are also some current problems with the role. These include potential overlap with other regulatory and investigative bodies; lack of formal compulsive powers; its dependence on political support for its effectiveness; insufficient resources; and the nature of the relationship it has with other government entities

Franchising regulation in Australia : recent trends and current issues

The Australian franchising sector consists of almost 1,200 different franchise systems and some 73,000 individual franchisee units. Since 1998, a mandatory national industry code of practice, the Franchising Code of Conduct, has spelt out certain prescribed minimum standards of information disclosure, dispute resolution and associated issues. Franchising is also subject to the Competition and Consumer Act. Both of these laws are enforced by the Australian Competition and Consumer Commission, which also has responsibility for educating the sector. This article broadly outlines the current state of Australian franchising, explains the key elements of both the Code and Act that are relevant to franchise systems, and gives a brief overview of the ACCC's enforcement and education work in the sector. It concludes by discussing some recent developments, including the introduction of Small Business Commissioners, possible pecuniary penalties for breaches of the Franchising Code, state-based franchising laws, and increasing international linkages between franchising regulators

Microboards : what are they and how do they work?

Traditional company boards are a well-recognized feature of management in most types of modern organization. Boards have a number of key roles to play: setting strategic goals and directions; hiring and performance managing executive officers; ensuring legal compliance in all aspects of the business; assisting the senior management team; identifying and mitigating risks; ensuring that sound financial practices are used; and numerous other tasks necessary for good governance and effective oversight. But can using a team of skilled directors also produce benefits in other contexts: We believe that they can and would like you to meet the microboard – an application of boardroom principles designed to produce results for individuals rather than companies. This paper describes the history of microboards and discusses the key concepts and features that underpin their operation. We describe how microboards have proved to be effective for individuals whose lives are directly affected by disability, especially in Canada. Finally, we examine how microboard principles and practices might also be applied to emerging entrepreneurs and small-business operators