G-protein-coupled-receptor-mediated presynaptic inhibition in the cerebellum

Throughout the central nervous system a dominant form of inhibition of neurotransmitter release from presynaptic terminals is mediated by G-protein-coupled receptors (GPCRs). Neurotransmitter release is typically induced by action potentials (APs), but can also occur spontaneously. Presynaptic inhibition by GPCRs has been associated with modulation of voltage-dependent ion channels. However, electrophysiological recordings of spontaneous, AP-independent (so-called ‘miniature’) postsynaptic events reveal an additional, important form of GPCR-mediated presynaptic inhibition, distinct from effects on ionic conductances and consistent with a direct action on the vesicle release machinery. Recent studies suggest that such miniature events might be of physiological relevance not only in signalling but also in development. In the cerebellum, neurotransmitter release onto Purkinje cells occurs by AP-dependent and AP-independent pathways. Here, I focus on inhibitory synapses between interneurons and Purkinje cells, which are subject to strong, identifiable regulation by endogenous GPCR agonists, to consider mechanisms of GPCR-mediated presynaptic inhibition.

Characterisation and regulation of E2F-6 and E2F-6b in the rat heart: a potential target for myocardial regeneration?

The E2F transcription factors are instrumental in regulating cell cycle progression and growth, including that in cardiomyocytes, which exit the cell cycle shortly after birth. E2F-6 has been demonstrated to act as a transcriptional repressor; however, its potential role in normal cardiomyocyte proliferation and hypertrophy has not previously been investigated. Here we report the isolation and characterisation of E2F-6 and E2F-6b in rat cardiomyocytes and consider its potential as a target for myocardial regeneration following injury. At the mRNA level, both rat E2F-6 and the alternatively spliced variant, E2F-6b, were expressed in E18 myocytes and levels were maintained throughout development into adulthood. Interestingly, E2F-6 protein expression was down-regulated during myocyte development suggesting that it is regulated post-transcriptionally in these cells. During myocyte hypertrophy, the mRNA expressions of E2F-6 and E2F-6b were not regulated whereas E2F-6 protein was up-regulated significantly. Indeed, E2F-6 protein expression levels closely parallel the developmental withdrawal of myocytes from the cell cycle and the subsequent reactivation of their cell cycle machinery during hypertrophic growth. Furthermore, depletion of E2F-6, using anti-sense technology, results in death of cultured neonatal myocytes. Taken together, abrogation of E2F-6 expression in neonatal cardiomyocytes leads to a significant decrease in their viability, consistent with the notion that E2F-6 might be required for maintaining normal myocyte growth.

Targeting the cell cycle machinery for the treatment of cardiovascular disease

Cardiovascular disease represents a major clinical problem affecting a significant proportion of the world's population and remains the main cause of death in the UK. The majority of therapies currently available for the treatment of cardiovascular disease do not cure the problem but merely treat the symptoms. Furthermore, many cardioactive drugs have serious side effects and have narrow therapeutic windows that can limit their usefulness in the clinic. Thus, the development of more selective and highly effective therapeutic strategies that could cure specific cardiovascular diseases would be of enormous benefit both to the patient and to those countries where healthcare systems are responsible for an increasing number of patients. In this review, we discuss the evidence that suggests that targeting the cell cycle machinery in cardiovascular cells provides a novel strategy for the treatment of certain cardiovascular diseases. Those cell cycle molecules that are important for regulating terminal differentiation of cardiac myocytes and whether they can be targeted to reinitiate cell division and myocardial repair will be discussed as will the molecules that control vascular smooth muscle cell (VSMC) and endothelial cell proliferation in disorders such as atherosclerosis and restenosis. The main approaches currently used to target the cell cycle machinery in cardiovascular disease have employed gene therapy techniques. We will overview the different methods and routes of gene delivery to the cardiovascular system and describe possible future drug therapies for these disorders. Although the majority of the published data comes from animal studies, there are several instances where potential therapies have moved into the clinical setting with promising results.

Reprogramming the cell cycle machinery to treat cardiovascular disease

Coronary artery disease is one of the most common heart pathologies. Restriction of blood flow to the heart by atherosclerotic lesions, leading to angina pectoris and myocardial infarction, damages the heart, resulting in impaired cardiac function. Damaged myocardium is replaced by scar tissue since surviving cardiomyocytes are unable to proliferate to replace lost heart tissue. Although narrowing of the coronary arteries can be treated successfully using coronary revascularisation procedures, re-occlusion of the treated vessels remains a significant clinical problem. Cell cycle control mechanisms are key in both the impaired cardiac repair by surviving cardiomyocytes and re-narrowing of treated vessels by maladaptive proliferation of vascular smooth muscle cells. Strategies targeting the cell cycle machinery in the heart and vasculature offer promise both for the improvement of cardiac repair following MI and the prevention of restenosis and bypass graft failure following revascularisation procedures.

Auditory distraction from low-intensity noise: a review of the consequences for learning and workplace environments

The 'irrelevant sound effect' in short-term memory is commonly believed to entail a number of direct consequences for cognitive performance in the office and other workplaces (e.g. S. P. Banbury, S. Tremblay, W. J. Macken, & D. M. Jones, 2001). It may also help to identify what types of sound are most suitable as auditory warning signals. However, the conclusions drawn are based primarily upon evidence from a single task (serial recall) and a single population (young adults). This evidence is reconsidered from the standpoint of different worker populations confronted with common workplace tasks and auditory environments. Recommendations are put forward for factors to be considered when assessing the impact of auditory distraction in the workplace. Copyright (c) 2005 John Wiley & Sons, Ltd.

Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors

Like most other cells in the body, foetal and neonatal cardiac myocytes are able to divide and proliferate. However, the ability of these cells to undergo cell division decreases progressively during development such that adult myocytes are unable to divide. A major problem arising from this inability of adult cardiac myocytes to proliferate is that the mature heart is unable to regenerate new myocardial tissue following severe injury, e.g. infarction, which can lead to compromised cardiac pump function and even death. Studies in proliferating cells have identified a group of genes and proteins that controls cell division. These proteins include cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs), which interact with each other to form complexes that are essential for controlling normal cell cycle progression. A variety of other proteins, e.g. the retinoblastoma protein (pRb) and members of the E2F family of transcription factors, also can interact with, and modulate the activities of, these complexes. Despite the major role that these proteins play in other cell types, little was known until recently about their existence and activities in immature (proliferating) or mature (non-proliferating) cardiac myocytes. The reason(s) why cardiac myocytes lose their ability to divide during development remains unknown, but if strategies were developed to understand the mechanisms underlying cardiac myocyte growth, it could open up new avenues for the treatment of cardiovascular disease. In this article, we shall review the function of the cell cycle machinery and outline some of our recent findings pertaining to the involvement of the cell cycle in modulating cardiac myocyte growth and hypertrophy.

Developing construction professional services in the international market: SWOT analysis of China

Construction professional services (CPSs), such as architecture, engineering, and consultancy, are not only high value-added profit centers in their own right but also have a knock-on effect on other businesses, such as construction and the export of materials and machinery. Arguably, competition in the international construction market has shifted to these knowledge-intensive CPS areas. Yet CPSs represent a research frontier that has received scant attention. This research aims to enrich the body of knowledge on CPSs by examining strengths, weaknesses, opportunities, and threats (SWOT) of Chinese CPSs (CCPSs) in the international context. It does so by triangulating theories with quantitative and qualitative data gleaned from yearbooks, annual reports, interviews, seminars, and interactions with managers in major CCPS companies. It is found that CCPSs present both strengths and weaknesses in talents, administration systems, and development strategies in dealing with the external opportunities and threats brought about by globalization and market evolution. Low price, which has helped the Chinese construction business to succeed in the international market, is also a major CCPS strength. An opportunity for CCPSs is the relatively strong delivery capability possessed by Chinese contractors; by partnering with them CCPSs can better establish themselves in the international arena. This is probably the first ever comprehensive study on the performance of CCPSs in the international marketplace. The research is conducted at an opportune time, particularly when the world is witnessing the burgeoning force of Chinese businesses in many areas including manufacturing, construction, and, potentially, professional services. It adds new insights to the knowledge body of CPSs and provides valuable references to other countries faced with the challenge of developing CPS business efficiently in the international market.

Developing construction professional services in the international market: a SWOT analysis of China

In contrast to their bustling construction counterparts, Chinese construction professional services (CPS) such as architecture, engineering, and consultancy, seem still to be stagnant in the international market. CPS are not only high value-added profit centers in their own right, but also have a knock-on effect on subsequent businesses such as construction, and the export of materials and machinery. Arguably, competition in the international construction market has shifted to knowledge-intensive CPS. Yet,CPS represent a research area that has been paid scant attention. This research aims to add to the body of knowledge of CPS by examining strengths, weaknesses, opportunities, and threats (SWOT) of Chinese CPS (CCPS) in the international context. It does so by triangulating theories with quantitative and qualitative data gleaned from yearbooks, annual reports, interviews, seminars, and interactions with managers in major CCPS companies. It is found that CCPS present both strengths and weaknesses in talents, administration systems, and development strategies in dealing with the external opportunities and threats brought about by globalization and market evolvement. Low price, which has helped the Chinese construction business to succeed in the international market, is also a CCPS major strength. An opportunity for CCPS is the relatively strong delivery capability possessed by Chinese contractors. By partnering with them CCPS can better edge into the international arena. This is probably the first ever comprehensive study in investigating the performance of CCPS in the international market. The research is also timely, particularly when the world is witnessing the burgeoning force of Chinese businesses in many areas including manufacturing, construction, and potentially, professional services.

'Mental mobility’ in the digital age: entrepreneurs and the online home-based business

Home-based online business ventures are an increasingly pervasive yet under-researched phenomenon. The experiences and mindset of entrepreneurs setting up and running such enterprises require better understanding. Using data from a qualitative study of 23 online home-based business entrepreneurs, we propose the augmented concept of ‘mental mobility’ to encapsulate how they approach their business activities. Drawing on Howard P. Becker's early theorising of mobility, together with Victor Turner's later notion of liminality, we conceptualise mental mobility as the process through which individuals navigate the liminal spaces between the physical and digital spheres of work and the overlapping home/workplace, enabling them to manipulate and partially reconcile the spatial, temporal and emotional tensions that are present in such work environments. Our research also holds important applications for alternative employment contexts and broader social orderings because of the increasingly pervasive and disruptive influence of technology on experiences of remunerated work.

Il/legitimate risks? Occupational health and safety and the public in Britain, c. 1960-2015

The last 20 years have seen the emergence of a popular climate of antipathy towards occupational health and safety regulation within the UK, particularly within the mainstream British media. The governance of health and safety has thus in recent years become an increasingly visible and contested public and political issue. The extent of this contestation, and its impact on the State’s governance of health and safety in the workplace and beyond, is explained and historicized within this chapter. Why has public rhetoric about health and safety apparently become so important in framing the ways in which the State could legitimately act in recent years? The chapter demonstrates how since 1960 the State remained a significant player – one among many, admittedly – and that while its roles in managing health and safety had long been bounded by a number of factors, a variable that emerged with particular saliency over the last 20 years has been a mediated notion of ‘public opinion’. This focus serves to remind us of the ways in which State action has at certain moments been pushed in particular directions by factors beyond formal mechanisms of rule.

Frontline safety: understanding the workplace as a site of regulatory engagement

The concept of frontline safety encapsulates an approach to occupational health and safety that emphasizes the 'other side of the regulatory relationship' – the ways in which safety culture, individual responsibility, organizational citizenship, trust, and compliance are interpreted and experienced at the local level. By exploring theoretical tensions over the most appropriate way of conceptualizing and framing frontline regulatory engagement, we can better identify the ways in which conceptions of individuals (as rational, responsible, economic actors) are constructed and maintained through workplace interactions and decision-making, as part of the fulfilment of the ideological and constitutive needs of neoliberal labor markets.