A study of the exploitation of the properties of natural rubber in tyres

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Improving brain drug targeting through exploitation of the nose-to-brain route:a physiological and pharmacokinetic perspective

With an ageing population and increasing prevalence of central-nervous system (CNS) disorders new approaches are required to sustain the development and successful delivery of therapeutics into the brain and CNS. CNS drug delivery is challenging due to the impermeable nature of the brain microvascular endothelial cells that form the blood-brain barrier (BBB) and which prevent the entry of a wide range of therapeutics into the brain. This review examines the role intranasal delivery may play in achieving direct brain delivery, for small molecular weight drugs, macromolecular therapeutics and cell-based therapeutics, by exploitation of the olfactory and trigeminal nerve pathways. This approach is thought to deliver drugs into the brain and CNS through bypassing the BBB. Details of the mechanism of transfer of administrated therapeutics, the pathways that lead to brain deposition, with a specific focus on therapeutic pharmacokinetics, and examples of successful CNS delivery will be explored. © 2014 Bentham Science Publishers.

The development of a testing procedure for dry friction brakes

A description of the background to testing friction materials for automotive brakes explains the need for a rapid, inexpensive means of assessing their behaviour in a way which is both accurate and meaningful. Various methods of controlling inertia dynamometers to simulate road vehicles are rejected in favour of programming by means of a commercially available XY plotter. Investigation of brake service conditions is used to set up test schedules, and a dynamometer programming unit built to enable service conditions on vehicles to be simulated on a full scale dynamometer. A technique is developed by which accelerated testing can be achieved without operating under overload conditions, saving time and cost without sacrificing validity. The development of programming by XY plotter is described, with a method of operating one XY plotter to programme the machine, monitor its own behaviour, and plot its own results in logical sequence. Commissioning trials are described and the generation of reproducible results in frictional behaviour and material durability is discussed. Teclmiques are developed to cross check the operation of the machine in retrospect, and retrospectively correct results in the event of malfunctions. Sensitivity errors in the measuring circuits are displayed between calibrations, whilst leaving the recorded results almost unaffected by error. Typical results of brake lining tests are used to demonstrate the range of performance parameters which can be studied by use of the machine. Successful test investigations completed on the machine are reported, including comments on behaviour of cast iron drums and discs. The machine shows that materials can repeat their complex friction/ temperature/speed/pressure relationships at a reproducibility of the order of +-0.003u and +~ 0.0002 in. thickness loss during wear tests. Discussion of practical and academic implications completes the report with recommendations for further work in both fields.

Development of a co-culture model of the human lungs for toxicity testing and identification of biomarkers of inhalation toxicity

The airway epithelium is the first point of contact in the lung for inhaled material, including infectious pathogens and particulate matter, and protects against toxicity from these substances by trapping and clearance via the mucociliary escalator, presence of a protective barrier with tight junctions and initiation of a local inflammatory response. The inflammatory response involves recruitment of phagocytic cells to neutralise and remove and invading materials and is oftern modelled using rodents. However, development of valid in vitro airway epithelial models is of great importance due to the restrictions on animal studies for cosmetic compound testing implicit in the 7th amendment to the European Union Cosmetics Directive. Further, rodent innate immune responses have fundamental differences to human. Pulmonary endothelial cells and leukocytes are also involved in the innate response initiated during pulmonary inflammation. Co-culture models of the airways, in particular where epithelial cells are cultured at air liquid interface with the presence of tight junctions and differentiated mucociliary cells, offer a solution to this problem. Ideally validated models will allow for detection of early biomarkers of response to exposure and investigation into inflammatory response during exposure. This thesis describes the approaches taken towards developing an in vitro epithelial/endothelial cell model of the human airways and identification biomarkers of response to exposure to xenobiotics. The model comprised normal human primary microvascular endothelial cells and the bronchial epithelial cell line BEAS-2B or normal human bronchial epithelial cells. BEAS-2B were chosen as their characterisation at air liquid interface is limited but they are robust in culture, thereby predicted to provide a more reliable test system. Proteomics analysis was undertaken on challenged cells to investigate biomarkers of exposure. BEAS-2B morphology was characterised at air liquid interface compared with normal human bronchial epithelial cells. The results indicate that BEAS-2B cells at an air liquid interface form tight junctions as shown by expression of the tight junction protein zonula occludens-1. To this author’s knowledge this is the first time this result has been reported. The inflammatory response of BEAS-2B (measured as secretion of the inflammatory mediators interleukin-8 and -6) air liquid interface mono-cultures to Escherichia coli lipopolysaccharide or particulate matter (fine and ultrafine titanium dioxide) was comparable to published data for epithelial cells. Cells were also exposed to polymers of “commercial interest” which were in the nanoparticle range (and referred to particles hereafter). BEAS-2B mono-cultures showed an increased secretion of inflammatory mediators after challenge. Inclusion of microvascular endothelial cells resulted in protection against LPS- and particle- induced epithelial toxicity, measured as cell viability and inflammatory response, indicating the importance of co-cultures for investigations into toxicity. Two-dimensional proteomic analysis of lysates from particle-challenged cells failed to identify biomarkers of toxicity due to assay interference and experimental variability. Separately, decreased plasma concentrations of serine protease inhibitors, and the negative acute phase proteins transthyretin, histidine-rich glycoprotein and alpha2-HS glycoprotein were identified as potential biomarkers of methyl methacrylate/ethyl methacrylate/butylacrylate treatment in rats.

Shaping strategic action through the rhetorical construction and exploitation of ambiguity

This paper extends existing understandings of how actors' constructions of ambiguity shape the emergent process of strategic action. We theoretically elaborate the role of rhetoric in exploiting strategic ambiguity, based on analysis of a longitudinal case study of an internationalization strategy within a business school. Our data show that actors use rhetoric to construct three types of strategic ambiguity: protective ambiguity that appeals to common values in order to protect particular interests, invitational ambiguity that appeals to common values in order to invite participation in particular actions, and adaptive ambiguity that enables the temporary adoption of specific values in order to appeal to a particular audience at one point in time. These rhetorical constructions of ambiguity follow a processual pattern that shapes the emergent process of strategic action. Our findings show that (1) the strategic actions that emerge are shaped by the way actors construct and exploit ambiguity, (2) the ambiguity intrinsic to the action is analytically distinct from ambiguity that is constructed and exploited by actors, and (3) ambiguity construction shifts over time to accommodate the emerging pattern of actions.

Can psychometric testing be used to explain, predict and measure behavioural competences and the funding resource orchestration of the entrepreneur?

Financing is a critical entrepreneurial activity (Shane et al. 2003) and within the study of entrepreneurship, behaviour has been identified as an area requiring further exploration (Bird et al. 2012). Since 2008 supply side conditions for SMEs have been severe and increasingly entrepreneurs have to bundle or ‘orchestrate’ funding from a variety of sources in order to successfully finance the firm (Wright and Stigliani 2013: p.15). This longitudinal study uses psychometric testing to measure the behavioural competences of a panel of sixty entrepreneurs in the Creative Industries sector. Interviews were conducted over a 3 year period to identify finance finding behaviour. The research takes a pragmatic realism perspective to examine process and the different behavioural competences of entrepreneurs. The predictive qualities of this behaviour are explored in a funding context. The research confirmed a strong behavioural characteristic as validated through interviews and psychometric testing, was an orientation towards engagement and working with other organisations. In a funding context, this manifested itself in entrepreneurs using networks, seeking advice and sharing equity to fund growth. These co-operative, collaborative characteristics are different to the classic image of the entrepreneur as a risk-taker or extrovert. Leadership and achievement orientation were amongst the lowest scores. Three distinctive groups were identified and also shown by subsequent analysis to be a positive contribution to how entrepreneurial behavioural competences can be considered. Belonging to one of these three clusters is a strong predictive indicator of entrepreneurial behaviour – in this context, how entrepreneurs access finance. These Clusters were also proven to have different characteristics in relation to funding outcomes. The study seeks to make a contribution through the development of a methodology for entrepreneurs, policy makers and financial institutions to identify competencies in finding finance and overcome problems in information asymmetry.

The evolution, development and exploitation of SIALON materials

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