Novel genomic methods for drug discovery and mechanism-based toxicological assessment

Genomics encompasses a range of powerful technologies that can be applied at all levels of gene expression, from transcription to mRNA translation. Collectively, these technologies have great potential for improving drug discovery, both target and molecule recognition, and development. In this article we review the current and potential future status of established and novel genomic methods within drug discovery.

Uncertainty and Sensitivity Analysis in Aircraft Operating Costs in Structural Design Optimization

The paper focuses on the development of an aircraft design optimization methodology that models uncertainty and sensitivity analysis in the tradeoff between manufacturing cost, structural requirements, andaircraft direct operating cost.Specifically,ratherthanonlylooking atmanufacturingcost, direct operatingcost is also consideredintermsof the impact of weight on fuel burn, in addition to the acquisition cost to be borne by the operator. Ultimately, there is a tradeoff between driving design according to minimal weight and driving it according to reduced manufacturing cost. Theanalysis of cost is facilitated withagenetic-causal cost-modeling methodology,andthe structural analysis is driven by numerical expressions of appropriate failure modes that use ESDU International reference data. However, a key contribution of the paper is to investigate the modeling of uncertainty and to perform a sensitivity analysis to investigate the robustness of the optimization methodology. Stochastic distributions are used to characterize manufacturing cost distributions, andMonteCarlo analysis is performed in modeling the impact of uncertainty on the cost modeling. The results are then used in a sensitivity analysis that incorporates the optimization methodology. In addition to investigating manufacturing cost variance, the sensitivity of the optimization to fuel burn cost and structural loading are also investigated. It is found that the consideration of manufacturing cost does make an impact and results in a different optimal design configuration from that delivered by the minimal-weight method. However, it was shown that at lower applied loads there is a threshold fuel burn cost at which the optimization process needs to reduce weight, and this threshold decreases with increasing load. The new optimal solution results in lower direct operating cost with a predicted savings of 640=m2 of fuselage skin over the life, relating to a rough order-of-magnitude direct operating cost savings of $500,000 for the fuselage alone of a small regional jet. Moreover, it was found through the uncertainty analysis that the principle was not sensitive to cost variance, although the margins do change.

Costs, outputs and outcomes in school PFI contracts and the significance of project size

This article examines operational Private Finance Initiative (PFI) school projects and reports the experiences of UK headteachers. It considers the impact of project size on value for money (VFM). Headteachers involved in small projects are more satisfied with costs than those involved in large projects, but headteachers involved in larger projects are more satisfied with affordability. Generally, heads are more satisfied with the buildings than with the services. The authors question the government’s recent policy changes to increase the size of PFI projects.

Assessing the Transaction Costs of Firms in the EU ETS: Lessons form Ireland

Until now, there has been little empirical evidence that EU Emissions Trading Scheme (ETS) transaction costs are incurred at firm level. The transaction costs (internal costs, capital costs, consultancy and trading costs) incurred by Irish firms under the EU ETS during its pilot phase (2005-2007) were measured and analysed. Evidence for the sources of transaction costs, their magnitude and the distribution of costs shows that these were mainly administrative in nature. Considerable variation in costs was found due to economies of scale, as the costs per tonne of CO2 were lower for participants with larger allocations. For the largest firms - accounting for over half the emissions - average transaction costs were €0.05 per tonne. However, for small firms, average transaction costs were €2.02 - over 18% of the current allowance price. This supports the concerns that transaction costs are excessive for smaller participants. The immediate policy implication is that additional attention will be needed to address different sizes of firms, number of installations per firm, and the size of the initial allocations.

Drug delivery strategies for photodynamic antimicrobial chemotherapy: From benchtop to clinical practice

Light and photosensitizer-mediated killing of many pathogens, termed photodynamic antimicrobial chemotherapy (PACT), has been extensively investigated in vitro. A wide range of organisms from the Gram-positive Staphylococcus aureus to the Gram-negative Pseudomonas aeruginosa have been proven to be susceptible to PACT. Multidrug-resistant strains are just as susceptible to this treatment as their naive counterparts. Both enveloped and non-enveloped viruses have demonstrated susceptibility in vitro, in addition to fungi and protozoa. Significantly, however, no clinical treatments based on PACT are currently licensed. This paper provides a comprehensive review of work carried out to date on delivery of photosensitizers for use in PACT, including topical, intranasal and oral/buccal delivery, as well as targeted delivery. We have also reviewed photo-antimicrobial surfaces. It is hoped that, through a rational approach to formulation design and subsequent success in small-scale clinical trials, more widespread use will be made of PACT in the clinic, to the benefit of patients worldwide. (C) 2009 Elsevier B.V. All rights reserved.