Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit vascular smooth muscle cell proliferation via differential effects on the cell cycle

Abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of both atherosclerosis and restenosis. Recent studies suggest that high-dose salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in-vitro and in-vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAIDs) exert similar anti proliferative effects on VSMCs, and do so via a common mechanism of action, remains to be shown. In this study, we demonstrate that the NSAIDs aspirin, sodium salicylate, diclofenac, ibuprofen, indometacin and sulindac induce a dose-dependent inhibition of proliferation in rat A10 VSMCs in the absence of significant cytotoxicity. Flow cytometric analyses showed that exposure of A10 cells to diclofenac, indometacin, ibuprofen and sulindac, in the presence of the mitotic inhibitor, nocodazole, led to a significant G0/G1 arrest. In contrast, the salicylates failed to induce a significant G1 arrest since flow cytometry profiles were not significantly different from control cells. Cyclin A levels were elevated, and hyperphosphorylated p107 was present at significant levels, in salicylate-treated A10 cells, consistent with a post-G1/S block, whereas cyclin A levels were low, and hypophosphorylated p107 was the dominant form, in cells treated with other NSAIDs consistent with a G1 arrest. The ubiquitously expressed cyclin-dependent kinase (CDK) inhibitors, p21 and p27, were increased in all NSAID-treated cells. Our results suggest that diclofenac, indometacin, ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase, whereas the growth inhibitory effect of salicylates probably affects the late S and/or G2/M phases. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit in the treatment of certain vasculoproliferative disorders.

Vision 2020 - A whole life-cycle information management system for built environments

A whole life-cycle information management vision is proposed, the organizational requirements for the realization of the scenario is investigated. Preliminary interviews with construction professionals are reported. Discontinuities at information transfer throughout life-cycle of built environments are resulting from lack of coordination and multiple data collection/storage practices. A more coherent history of these activities can improve the work practices of various teams by augmenting decision making processes and creating organizational learning opportunities. Therefore, there is a need for unifying these fragmented bits of data to create a meaningful, semantically rich and standardized information repository for built environment. The proposed vision utilizes embedded technologies and distributed building information models. Two diverse construction project types (large one-off design, small repetitive design) are investigated for the applicability of the vision. A functional prototype software/hardware system for demonstrating the practical use of this vision is developed and discussed. Plans for case-studies for validating the proposed model at a large PFI hospital and housing association projects are discussed.

Generative topographic mapping applied to clustering and visualization of motor unit action potentials

The identification and visualization of clusters formed by motor unit action potentials (MUAPs) is an essential step in investigations seeking to explain the control of the neuromuscular system. This work introduces the generative topographic mapping (GTM), a novel machine learning tool, for clustering of MUAPs, and also it extends the GTM technique to provide a way of visualizing MUAPs. The performance of GTM was compared to that of three other clustering methods: the self-organizing map (SOM), a Gaussian mixture model (GMM), and the neural-gas network (NGN). The results, based on the study of experimental MUAPs, showed that the rate of success of both GTM and SOM outperformed that of GMM and NGN, and also that GTM may in practice be used as a principled alternative to the SOM in the study of MUAPs. A visualization tool, which we called GTM grid, was devised for visualization of MUAPs lying in a high-dimensional space. The visualization provided by the GTM grid was compared to that obtained from principal component analysis (PCA). (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Shaking hands: Priming by social action effects

In a semi-naturalistic response-effect compatibility paradigm, participants were given the opportunity to learn that hand-shaking actions would be followed by social effects (human hand-shaking stimuli from a third-person perspective) or inanimate effects (block arrow stimuli). Relative to the actions, these effects appeared on the same or the opposite side of the screen (positional compatibility), and pointed towards or away from the response hand (directional compatibility). After learning, response times indicated a positional compatibility effect for both social and inanimate effects, but a directional compatibility effect occurred only for social action effects. These findings indicate that actions can be represented, not only by their effects on the inanimate world, but also by their effects on the actions of others. They are consistent with ideomotor theory, and with the view that actions are represented by bidirectional response-effect associations. They also have implications with respect to the origins and on-line control of imitation and the systems supporting imitation.

Learning to understand others' actions

Despite nearly two decades of research on mirror neurons, there is still much debate about what they do. The most enduring hypothesis is that they enable ‘action understanding’. However, recent critical reviews have failed to find compelling evidence in favour of this view. Instead, these authors argue that mirror neurons are produced by associative learning and therefore that they cannot contribute to action understanding. The present opinion piece suggests that this argument is flawed. We argue that mirror neurons may both develop through associative learning and contribute to inferences about the actions of others.

Path planning of robots in noisy workspaces using learning automata

The problem of a manipulator operating in a noisy workspace and required to move from an initial fixed position P0 to a final position Pf is considered. However, Pf is corrupted by noise, giving rise to Pˆf, which may be obtained by sensors. The use of learning automata is proposed to tackle this problem. An automaton is placed at each joint of the manipulator which moves according to the action chosen by the automaton (forward, backward, stationary) at each instant. The simultaneous reward or penalty of the automata enables avoiding any inverse kinematics computations that would be necessary if the distance of each joint from the final position had to be calculated. Three variable-structure learning algorithms are used, i.e., the discretized linear reward-penalty (DLR-P, the linear reward-penalty (LR-P ) and a nonlinear scheme. Each algorithm is separately tested with two (forward, backward) and three forward, backward, stationary) actions.

Learning across business sectors: context, embeddedness and conceptual chasms

While the construction industry is frequently encouraged to learn from other business sectors, the difficulties of transferring knowledge from one context to another are rarely acknowledged. The problematic nature of knowledge is addressed with particular emphasis on the concept of contextual embeddedness. From this point of view, the process of 'knowledge transfer' depends upon a prolonged process of socialization between actors from both the 'receiving' and 'sending' contexts networking. It is contended that a significant conceptual chasm exists between the exhortations of industry leaders to learn from other sectors and the theoretical complexities associated with knowledge transfer. An ongoing research project is described that seeks to facilitate knowledge sharing between construction and aerospace. A novel approach to knowledge sharing based upon soft systems methodology (SSM) (Mode 2) is described and justified. Initial findings from the first cycle of the research are discussed and used to highlight the importance of context in the implementation of supply chain management.

The impact of Group Intelligence software on enquiry-based learning

Despite the increasing use of groupware technologies in education, there is little evidence of their impact, especially within an enquiry-based learning (EBL) context. In this paper, we examine the use of a commercial standard Group Intelligence software called GroupSystems®ThinkTank. To date, ThinkTank has been adopted mainly in the USA and supports teams in generating ideas, categorising, prioritising, voting and multi-criteria decision-making and automatically generates a report at the end of each session. The software was used by students carrying out an EBL project, set by employers, for a full academic year. The criteria for assessing the impact of ThinkTank on student learning were those of creativity, participation, productivity, engagement and understanding. Data was collected throughout the year using a combination of interviews and questionnaires, and written feedback from employers. The overall findings show an increase in levels of productivity and creativity, evidence of a deeper understanding of their work but some variation in attitudes towards participation in the early stages of the project.

Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells.

Time valued life cycle greenhouse gas emissions from buildings

The UK has adopted legally binding carbon reduction targets of 34% by 2020 and 80% by 2050 (measured against the 1990 baseline). Buildings are estimated to be responsible for more than 50% of greenhouse gas (GHG) emissions in the UK. These consist of both operational, produced during use, and embodied, produced during manufacture of materials and components, and during construction, refurbishments and demolition. A brief assessment suggests that it is unlikely that UK emission reduction targets can be met without substantial reductions in both Oc and Ec. Oc occurs over the lifetime of a building whereas the bulk of Ec occurs at the start of a building’s life. A time value for emissions could influence the decision making process when it comes to comparing mitigation measures which have benefits that occur at different times. An example might be the choice between building construction using low Ec construction materials versus building construction using high Ec construction materials but with lower Oc, although the use of high Ec materials does not necessarily imply a lower Oc. Particular time related issues examined here are: the urgency of the need to achieve large emissions reductions during the next 10 to 20 years; the earlier effective action is taken, the less costly it will be; future reduction in carbon intensity of energy supply; the carbon cycle and relationship between the release of GHG’s and their subsequent concentrations in the atmosphere. An equation is proposed, which weights emissions according to when they occur during the building life cycle, and which effectively increases Ec as a proportion of the total, suggesting that reducing Ec is likely to be more beneficial, in terms of climate change, for most new buildings. Thus, giving higher priority to Ec reductions is likely to result in a bigger positive impact on climate change and mitigation costs.

Diversifying into technical clothing manufacture as entrepreneurial learning: a situated learning theory perspective

Purpose – The purpose of this paper is to demonstrate analytically how entrepreneurial action as learning relating to diversifying into technical clothing – i.e. a high-value manufacturing sector – can take place. This is particularly relevant to recent discussion and debate in academic and policy-making circles concerning the survival of the clothing manufacture industry in developed industrialised countries. Design/methodology/approach – Using situated learning theory (SLT) as the major analytical lens, this case study examines an episode of entrepreneurial action relating to diversification into a high-value manufacturing sector. It is considered on instrumentality grounds, revealing wider tendencies in the management of knowledge and capabilities requisite for effective entrepreneurial action of this kind. Findings – Boundary events, brokers, boundary objects, membership structures and inclusive participation that addresses power asymmetries are found to be crucial organisational design elements, enabling the development of inter- and intracommunal capacities. These together constitute a dynamic learning capability, which underpins entrepreneurial action, such as diversification into high-value manufacturing sectors. Originality/value – Through a refinement of SLT in the context of entrepreneurial action, the paper contributes to an advancement of a substantive theory of managing technological knowledge and capabilities for effective diversification into high-value manufacturing sectors.

Placing defects at the heart of high quality new homes: a learning perspective

The UK new-build housing sector is facing dual pressures to expand supply, whilst delivering against tougher planning and Building Regulation requirements; predominantly in the areas of sustainability. The sector is currently responding by significantly scaling up production and incorporating new technical solutions into new homes. This trajectory of up-scaling and technical innovation has been of research interest; but this research has primarily focus on the ‘upstream’ implications for house builders’ business models and standardised design templates. There has been little attention, though, to the potential ‘downstream’ implications of the ramping up of supply and the introduction of new technologies for build quality and defects. This paper contributes to our understanding of the ‘downstream’ implications through a synthesis of the current UK defect literature with respect to new-build housing. It is found that the prevailing emphasis in the literature is limited to the responsibility, pathology and statistical analysis of defects (and failures). The literature does not extend to how house builders individually and collectively, in practice, collect and learn from defects information. The paper concludes by describing an ongoing collaborative research programme with the National House Building Council (NHBC) to: (a) understand house builders’ localised defects analysis procedures, and their current knowledge feedback loops to inform risk management strategies; and, (b) building on this understanding, design and test action research interventions to develop new data capture, learning processes and systems to reduce targeted defects.

The plasticity of the mirror system: how reward learning modulates cortical motor simulation of others

Cortical motor simulation supports the understanding of others' actions and intentions. This mechanism is thought to rely on the mirror neuron system (MNS), a brain network that is active both during action execution and observation. Indirect evidence suggests that alpha/beta suppression, an electroencephalographic (EEG) index of MNS activity, is modulated by reward. In this study we aimed to test the plasticity of the MNS by directly investigating the link between alpha/beta suppression and reward. 40 individuals from a general population sample took part in an evaluative conditioning experiment, where different neutral faces were associated with high or low reward values. In the test phase, EEG was recorded while participants viewed videoclips of happy expressions made by the conditioned faces. Alpha/beta suppression (identified using event-related desynchronisation of specific independent components) in response to rewarding faces was found to be greater than for non-rewarding faces. This result provides a mechanistic insight into the plasticity of the MNS and, more generally, into the role of reward in modulating physiological responses linked to empathy.

Detecting defects in UK new-build housing: a learning perspective

House builders play a key role in controlling the quality of new homes in the UK. The UK house building sector is, however, currently facing pressures to expand supply as well as conform to tougher low carbon planning and Building Regulation requirements; primarily in the areas of sustainability. There is growing evidence that the pressure the UK house building industry is currently under may be eroding build quality and causing an increase in defects. It is found that the prevailing defect literature is limited to the causes, pathology and statistical analysis of defects (and failures). The literature does not extend to examine how house builders individually and collectively, in practice, collect and learn from defects experience in order to reduce the prevalence of defects in future homes. The theoretical lens for the research is organisational learning. This paper contributes to our understanding of organisational learning in construction through a synthesis of current literature. Further, a suitable organisational learning model is adopted. The paper concludes by reporting the research design of an ongoing collaborative action research project with the National House Building Council (NHBC), focused on developing a better understanding of house builders’ localised defects analysis procedures and learning processes.