Targeting Gbeta gamma signaling in arterial vascular smooth muscle proliferation: a novel strategy to limit restenosis.

Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular smooth muscle (VSM) cell proliferation have not been elucidated. betagamma subunits of heterotrimeric G proteins (Gbetagamma) are known to activate mitogen-activated protein (MAP) kinases after stimulation of certain G protein-coupled receptors; however, their relevance in VSM mitogenesis in vitro or in vivo is not known. Using adenoviral-mediated transfer of a transgene encoding a peptide inhibitor of Gbetagamma signaling (betaARKct), we evaluated the role of Gbetagamma in MAP kinase activation and proliferation in response to several mitogens, including serum, in cultured rat VSM cells. Our results include the striking finding that serum-induced proliferation of VSM cells in vitro is mediated largely via Gbetagamma. Furthermore, we studied the effects of in vivo adenoviral-mediated betaARKct gene transfer on VSM intimal hyperplasia in a rat carotid artery restenosis model. Our in vivo results demonstrated that the presence of the betaARKct in injured rat carotid arteries significantly reduced VSM intimal hyperplasia by 70%. Thus, Gbetagamma plays a critical role in physiological VSM proliferation, and targeted Gbetagamma inhibition represents a novel approach for the treatment of pathological conditions such as restenosis.

Design and Emergence in the Making of American Grand Strategy

The main research question of this thesis is how do grand strategies form. Grand strategy is defined as a state's coherent and consistent pattern of behavior over a long period of time in search of an overarching goal. The political science literature usually explains the formation of grand strategies by using a planning (or design) model. In this dissertation, I use primary sources, interviews with former government officials, and historical scholarship to show that the formation of grand strategy is better understood using a model of emergent learning imported from the business world. My two case studies examine the formation of American grand strategy during the Cold War and the post-Cold War eras. The dissertation concludes that in both these strategic eras the dominating grand strategies were formed primarily by emergent learning rather than flowing from advanced designs.

A scalable strategy for the parallelization of multiphysics unstructured mesh-iterative codes on distributed-memory systems

Realizing scalable performance on high performance computing systems is not straightforward for single-phenomenon codes (such as computational fluid dynamics [CFD]). This task is magnified considerably when the target software involves the interactions of a range of phenomena that have distinctive solution procedures involving different discretization methods. The problems of addressing the key issues of retaining data integrity and the ordering of the calculation procedures are significant. A strategy for parallelizing this multiphysics family of codes is described for software exploiting finite-volume discretization methods on unstructured meshes using iterative solution procedures. A mesh partitioning-based SPMD approach is used. However, since different variables use distinct discretization schemes, this means that distinct partitions are required; techniques for addressing this issue are described using the mesh-partitioning tool, JOSTLE. In this contribution, the strategy is tested for a variety of test cases under a wide range of conditions (e.g., problem size, number of processors, asynchronous / synchronous communications, etc.) using a variety of strategies for mapping the mesh partition onto the processor topology.

An automatable generic strategy for dynamic load balancing in parallel structured mesh CFD codes

Parallel computing is now widely used in numerical simulation, particularly for application codes based on finite difference and finite element methods. A popular and successful technique employed to parallelize such codes onto large distributed memory systems is to partition the mesh into sub-domains that are then allocated to processors. The code then executes in parallel, using the SPMD methodology, with message passing for inter-processor interactions. In order to improve the parallel efficiency of an imbalanced structured mesh CFD code, a new dynamic load balancing (DLB) strategy has been developed in which the processor partition range limits of just one of the partitioned dimensions uses non-coincidental limits, as opposed to coincidental limits. The ‘local’ partition limit change allows greater flexibility in obtaining a balanced load distribution, as the workload increase, or decrease, on a processor is no longer restricted by the ‘global’ (coincidental) limit change. The automatic implementation of this generic DLB strategy within an existing parallel code is presented in this chapter, along with some preliminary results.

Numerical and experimental studies of a substructural identification strategy

For structural health monitoring it is impractical to identify a large structure with complete measurement due to limited number of sensors and difficulty in field instrumentation. Furthermore, it is not desirable to identify a large number of unknown parameters in a full system because of numerical difficulty in convergence. A novel substructural strategy was presented for identification of stiffness matrices and damage assessment with incomplete measurement. The substructural approach was employed to identify large systems in a divide-and-conquer manner. In addition, the concept of model condensation was invoked to avoid the need for complete measurement, and the recovery process to obtain the full set of parameters was formulated. The efficiency of the proposed method is demonstrated numerically through multi-storey shear buildings subjected to random force. A fairly large structural system with 50 DOFs was identified with good results, taking into consideration the effects of noisy signals and the limited number of sensors. Two variations of the method were applied, depending on whether the sensor could be repositioned. The proposed strategy was further substantiated experimentally using an eight-storey steel plane frame model subjected to shaker and impulse hammer excitations. Both numerical and experimental results have shown that the proposed substructural strategy gave reasonably accurate identification in terms of locating and quantifying structural damage.

The benefits of a health impact assessment in relation to fuel poverty: assessing Luton's affordable warmth strategy and the need for a national strategy

The links between fuel poverty and poor health are well documented, yet there is no statutory requirement on local authorities to develop fuel poverty strategies, which tend to be patchy nationally and differ substantially in quality. Fuel poverty starts from the perspective of income, even though interventions can improve health. The current public health agenda calls for more partnership-based, cost-effective strategies based on sound evidence. Fuel poverty represents a key area where there is currently little local evidence quantifying and qualifying health gain arising from strategic interventions. As a result, this initial study sought to apply the principles of a health impact assessment to Luton’s Affordable Warmth Strategy, exploring the potential to identify health impact arising – as a baseline for future research – in the context of the public health agenda. A national strategy would help ensure the promotion of targeted fuel poverty strategies.

South East London Palliative and End of Life Care Education and Training Strategy: Meeting the Education and Training Needs of the Health & Social Care Workforce Involved in the Care of Patients and Carers at the End of Life.

EXECUTIVE SUMMARY Aims 1. The aims of this strategy are • to ensure that a full range of education and training related to the adult end of life care pathway is available across South East London to meet the needs of our health and social care workforce • to enable those responsible for end of life care education and training commissioning to procure comprehensively from a full range of education providers in a systematic and strategic manner. Background 2. The work that underpins this strategy was begun by the South East London Cancer Network via its Palliative and End of Life Care Coordinating Group and then developed by way of the Marie Curie Delivering Choice Programme’s Education and Training work stream.