The role of government research establishments : a study of the concept of public patronage for applied research and development

This thesis follows the argument that, to fully understand the current position of national research laboratories in Great Britain one needs to study the historical development of the government research establishment as a specific social institution. A particular model is outlined in which it is argued that institutional characteristics evolve through the continual interplay between internal development and environmental factors within a changing political and economic context, and that the continuous development of an institution depends on its ability to adapt to changes in its operational environment. Within this framework important historical precedents for formal government institutional support for applied research are identified. and the transition from private to public patronage documented. The emergence and consolidation of government research laboratories in Britain is described in detail. The subsequent relative decline of public laboratories is interpreted in terms of the undermining of a traditional role resulting in legitimation crisis. It is concluded that it is no longer feasible to consider the public research laboratory as a coherent institutional form, and that the future of each individual laboratory can only be considered in relation to the institutional needs of its own sphere of operation. Nevertheless the laboratories have been forced into decline in an essentially unplanned way which may have serious consequences for the maintenance of the scientific and technical infrastructures, necessary for material progress in the national context.

Implementation of a generic autonomic framework

Based on insights from the implementation of commercial products for data-centre resource management, we identified key challenges in the development of cost-effective autonomic solutions, and best practices for overcoming these challenges. In a related paper, we proposed a generic autonomic framework that complies with these best practices, and suggested ways in which existing technologies could be used to realise this framework. In this paper, we describe the actual implementation of our autonomic framework as a service-oriented architecture, and we show how the universal policy engine at its core can be configured to manage the allocation of server capacity to services of different priorities. This case study demonstrates the effectiveness of our generic approach to autonomic solution development in an area of great interest for commercial data centres, research laboratories and application service providers.

A heat metering system for energy management on an industrial site

Faced with a future of rising energy costs there is a need for industry to manage energy more carefully in order to meet its economic objectives. A problem besetting the growth of energy conservation in the UK is that a large proportion of energy consumption is used in a low intensive manner in organisations where they would be responsibility for energy efficiency is spread over a large number of personnel who each see only small energy costs. In relation to this problem in the non-energy intensive industrial sector, an application of an energy management technique known as monitoring and targeting (M & T) has been installed at the Whetstone site of the General Electric Company Limited in an attempt to prove it as a means for motivating line management and personnel to save energy. The objective energy saving for which the M & T was devised is very specific. During early energy conservation work at the site there had been a change from continuous to intermittent heating but the maintenance of the strategy was receiving a poor level of commitment from line management and performance was some 5% - 10% less than expected. The M & T is concerned therefore with heat for space heating for which a heat metering system was required. Metering of the site high pressure hot water system posed technical difficulties and expenditure was also limited. This led to a ‘tin-house' design being installed for a price less than the commercial equivalent. The timespan of work to achieve an operational heat metering system was 3 years which meant that energy saving results from the scheme were not observed during the study. If successful the replication potential is the larger non energy intensive sites from which some 30 PT savings could be expected in the UK.

Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

Objective: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting: Research laboratories of Hannover Medical School and Harvard Medical School. Patients: Septic patients/C57Bl/6 mice and human endothelial cells. Interventions: Food and Drug Administration-approved library screening. Measurements and Main Results: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.