Mechanisms of bacterially induced bone destruction

Bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. These molecules and their actions on the cells and mediators orchestrating the homeostasis of bone have been the focus of the work presented here. In the first study saline extraction of S. aureus yielded a proteinaceous stimulator of in vitro osteolysis and osteoclastogenesis. This osteoclastogenesis could be blocked with calcitonin. Immunoassay for 1,25-dihydroxyvitamin D3 suggested osteolysis was not operating via upregulation of this hormone's synthesis. Osteoclastogenesis was unaffected by indomethacin and only partially blocked by the IL-1 receptor antagonist. Neutralising antibodies to TNF and IL-6 inhibited osteoclastogenesis, as did 5-lipoxygenase (LOX) inhibition. The finding that 5-LOX activity could modulate osteolysis instigated an investigation into a wider role for 5-LOX products in osteolysis. This revealed the osteolytic activities of several inflammatory agents and hormones to be unaffected by 5-LOX inhibition, however osteolysis and osteoclastogenesis induced by A. actinomycetemcomitans LPS was. It was also demonstrated that the A. actinomycetemcomitans LPS was able to stimulate in vitro production of 5- LOX products. The LPSs from other oral bacteria also proved able to stimulate osteolysis and induce osteoclastogenesis by processes that were inhibited by 5-LOX inhibition. Attention then focused on the effects of A. actinomycetemcomitans LPS on the expression of LOXs and cyclooxygenases (COXs) in human osteoblasts. This LPS increased the synthesis of several LOX products, however 5-LOX mRNA expression was constituitive and was not altered by exposure to LPS, except with high doses and long exposure times when it was downregulated. COX-2 and 12-LOX mRNAs were found to be induced on exposure to the LPS, whilst neither 15-LOX nor COX-1 mRNAs were detected. Finally work moved to M. tuberculosis induced osteolysis. Of all the molecules tested only M. Tuberculosis cpn10 was found to be a potent stimulator of in vitro osteolysis and osteoclastogenesis, and to inhibit osteoblast proliferation. Studies with synthetic peptides of M. tuberculosis cpn10 revealed a single conformational unit, the flexible loop, encompassing its osteolytic activity

Towards ‘Smarter’ Systems: Key Cyber-Physical Performance-Cost Tradeoffs in Smart Electric Vehicle Charging with Distributed Generation

The growing penetration of electric vehicles (EV) into the market is driving sharper spikes in consumer power demand. Meanwhile, growing renewable distributed generation (DG) is driving sharper spikes in localised power supply. This leads to growing temporally unsynchronised spikes in generation and consumption, which manifest as localised over- or undervoltage and disrupt grid service quality. Smart Grid solutions can respond to voltage conditions by curtailing charging EVs or available DG through a network of cyber-enabled sensors and actuators. How to optimise efficiency, ensure stable operation, deliver required performance outputs and minimally overhaul existing hardware remains an open research topic. This thesis models key performance-cost tradeoffs relating to Smart EV Charging with DG, including architectural design challenges in the underpinning Information and Communications Technology (ICT). Crucial deployment optimisation balancing various Key Performance Indicators (KPI) is achieved. The contributions are as follows: • Two Smart EV Charging schemes are designed for secondary voltage control in the distribution network. One is optimised for the network operator, the other for consumers/generators. This is used to evaluate resulting performance implications via targeted case study. • To support these schemes, a multi-tier hierarchical distributed ICT architecture is designed that alleviates computation and traffic load from the central controller and achieves user fairness in the network. In this way it is scalable and adaptable to a wide range of network sizes. • Both schemes are modelled under practical latency constraints to derive interlocking effects on various KPIs. Multiple latency-mitigation strategies are designed in each case. • KPIs, including voltage control, peak shaving, user inconvenience, renewable energy input, CO2 emissions and EV & DG capacity are evaluated statistically under 172 days of power readings. This is used to establish key performancecost tradeoffs relevant to multiple invested bodies in the power grid. • Finally, the ICT architecture is modelled for growing network sizes. Quality-of- Service (QoS) provision is studied for various multi-tier hierarchical topologies under increasing number of end devices to gauge performance-cost tradeoffs related to demand-response latency and network deployment

An Interview with John Heron: Exploring the Interface between Cooperative Inquiry and Transpersonal Studies

In this interview, John Heron—the founder of cooperative inquiry (CI; Heron, 1996, 1998)—discusses this experiential, participatory approach to research and learning with participatory research special issue guest editor Olga Sohmer. After presenting a summary of cooperative inquiry, Heron and Sohmer discuss CI in the context of transpersonal studies, including past and prospective future applications. Questioning the emphasis on “trans” in transpersonal, Heron unfolds the three dimensions of human spirituality that CI engages and offers a vision for transpersonal studies in light of CI ideals. Additional themes that are explored include cultivating authentic relationships in CI, the role of the nonhuman natural world in CI, practices based on CI principles that can be used in daily life, applying extended epistemology and radical assessment in education, self-generating culture, and the role of CI in human evolution

Method for sequencing heteropolymeric target nucleic acid sequence

The invention relates to a method for sequencing a heteropolymeric target nucleic acid sequence that involves stochastic sensing. The invention also relates to a method for improving a pore for sequencing a target nucleic acid sequence by modifying one or more sites in the pore