Briefing: Auditor/company interactions in the 2007 UK regulatory environment

No abstract availabl

The Solent Disturbance & Mitigation Project. Phase II – results of the Solent household survey

This report sets out the results of the postal household survey component of the Solent Disturbance and Mitigation project. The work was commissioned by the Solent Forum in response to concerns over the impact of recreational pressure on features of the Solent SPA, SAC and Ramsar Sites. Of particular concern are the cumulative impacts of recreational use arising from potential new housing developments in Chichester District and South Hampshire. The household survey was distributed to 5000 households within 25km of the coastline between Hurst Castle, including the north shoreline of the Isle of Wight. The questionnaires and reminders were sent between October and December 2010. The household survey contained three sections which elicited information relating to general and specific visits to the coast and household demographics. A total of 1382 completed questionnaires were returned and 42% of these households had visited the coast the week prior to completing the survey. Only 4% of households (56) stated they never visited the coast. Households which did not visit the coast contained a lower number of people, lower number of dogs and a higher percentage did not have regular access to a private vehicle when compared to households that made regular coastal visits. Of the households which visited the coast, 50% visited at least once a week. A total of 55% of households visited the coast equally all year and an additional 39% of households made more visits in the summer. There was a significant difference in coastal visit frequency between households which owned a least one dog and non dog owning households, with dog owning households making more visits. There was no significant difference in visit frequency between households who had garden access or whether the household dwelling type was a flat or ‘non- flat’. The 1155 households providing full responses to the survey made an estimated annual total of 153,433 visits to the Solent coastline. The project and this survey divided the coastline into 103 numbered sections. Households made on average 133 annual coastal visits to 3.7 different sections of the coastline. On average each section received a total of 1490 annual visits but the number of coastal visits made to different sections was significantly different. The most frequently given activities undertaken during a coastal visit were walking (20% of all activity responses) and enjoying the scenery (20%), followed by being on the beach (11%) and meeting up with friends (11% of all activity responses). Households indicated where they undertook their activity during the coastal visit and for 47% of the visit responses the activity (walking, cycling, enjoying the scenery etc) was undertaken on the sea wall or the river bank. A further 39% of responses by households indicated they venture onto the beach/mudflat and 15% of responses actually took to the water. The majority (52%) of coastal visits by households were made by car with 39% made by foot, 4% by bicycle and 5% by public transport. Of the households which made visits by car, 50% travelled 9.5km or less by road to the section they visited and 90% travelled 29.0km or less to their visited section by road. Of the households who visited specific sections by foot half lived within 1.0km of the section (straight line distance from postcode to nearest point on section) and 90% lived within 4.0km of the visited section. Features that act as a deterrent for some households when selecting a coastal location to visit may also attract other households. For example, a requirement for dogs to be on leads and the presence of dog restrictions is rated as attractive to non dog owning households but as a deterrent by dog owning households. By far the most popular attractive feature when households choose which coastal location to visit was ‘sea views and attractive scenery’ followed by ‘feel safe’, ‘ability to do a range of different walks/routes ‘and the ‘presence of wildlife’. Predictions were derived by fitting formal statistical models to the observed (household survey) data. Specifically these models used observed visitor numbers per section per distance band and analysed these in relation to factors representing distance to section and section characteristics. Different models are presented within the report and separate models were generated for car and foot visitors, with each model showing a declining visitor rate with distance from the section – i.e. the further away people live the fewer visits they make. These models suggest some 52 million visits are made each year, by households within a 30km radius of the coastline between Hurst Castle to Chichester Harbour, including the north shore of the Isle of Wight. The models identify Portsmouth’s seafront (South Parade Pier to Fort Cumberland) as the most heavily visited coastal section, with over 3 million household visits per annum. These predictive visit models will be used alongside the bird models, commissioned separately and subject to a further report, to assess the impacts of disturbance to wintering birds under different housing scenarios. The use of the visitor models and how they will link to the bird models within the next stages of the Solent Disturbance and Mitigation Project are discussed

Using exomarkers to assess mitochondrial reactive species in vivo

Background: The ability to measure the concentrations of small damaging and signalling molecules such as reactive oxygen species (ROS) in vivo is essential to understanding their biological roles. While a range of methods can be applied to in vitro systems, measuring the levels and relative changes in reactive species in vivo is challenging. Scope of review: One approach towards achieving this goal is the use of exomarkers. In this, exogenous probe compounds are administered to the intact organism and are then transformed by the reactive molecules in vivo to produce a diagnostic exomarker. The exomarker and the precursor probe can be analysed ex vivo to infer the identity and amounts of the reactive species present in vivo. This is akin to the measurement of biomarkers produced by the interaction of reactive species with endogenous biomolecules. Major conclusions and general significance: Our laboratories have developed mitochondria-targeted probes that generate exomarkers that can be analysed ex vivo by mass spectrometry to assess levels of reactive species within mitochondria in vivo. We have used one of these compounds, MitoB, to infer the levels of mitochondrial hydrogen peroxide within flies and mice. Here we describe the development of MitoB and expand on this example to discuss how better probes and exomarkers can be developed. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. Abbreviations: EPR, electron paramagnetic resonance; GFP, green fluorescent protein; 4-HNE, 4-hydroxynonenal; MitoB, 3-(dihydroxyboronyl)benzyltriphenylphosphonium bromide; MitoP, (3-hydroxybenzyl)triphenylphosphonium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase; TPMP, methyltriphenylphosphonium; TPP, triphenylphosphonium catio

Identification and quantification of protein S-nitrosation by nitrite in the mouse heart during ischemia.

Nitrate (NO3-) and nitrite (NO2-) are known to be cardioprotective and to alter energy metabolism in vivo NO3- action results from its conversion to NO2- by salivary bacteria, but the mechanism(s) by which NO2- affects metabolism remains obscure. NO2- may act by S-nitrosating protein thiols, thereby altering protein activity. But how this occurs, and the functional importance of S-nitrosation sites across the mammalian proteome, remain largely uncharacterized. Here we analyzed protein thiols within mouse hearts in vivo using quantitative proteomics to determine S-nitrosation site occupancy. We extended the thiol-redox proteomic technique, isotope-coded affinity tag labeling, to quantify the extent of NO2--dependent S-nitrosation of proteins thiols in vivo Using this approach, called SNOxICAT (S-nitrosothiol redox isotope-coded affinity tag), we found that exposure to NO2- under normoxic conditions or exposure to ischemia alone results in minimal S-nitrosation of protein thiols. However, exposure to NO2- in conjunction with ischemia led to extensive S-nitrosation of protein thiols across all cellular compartments. Several mitochondrial protein thiols exposed to the mitochondrial matrix were selectively S-nitrosated under these conditions, potentially contributing to the beneficial effects of NO2- on mitochondrial metabolism. The permeability of the mitochondrial inner membrane to HNO2, but not to NO2-, combined with the lack of S-nitrosation during anoxia alone or by NO2- during normoxia places constraints on how S-nitrosation occurs in vivo and on its mechanisms of cardioprotection and modulation of energy metabolism. Quantifying S-nitrosated protein thiols now allows determination of modified cysteines across the proteome and identification of those most likely responsible for the functional consequences of NO2- exposure

Leibniz's Infinitesimals: Their Fictionality, Their Modern Implementations, And Their Foes From Berkeley To Russell And Beyond

Many historians of the calculus deny significant continuity between infinitesimal calculus of the 17th century and 20th century developments such as Robinson's theory. Robinson's hyperreals, while providing a consistent theory of infinitesimals, require the resources of modern logic; thus many commentators are comfortable denying a historical continuity. A notable exception is Robinson himself, whose identification with the Leibnizian tradition inspired Lakatos, Laugwitz, and others to consider the history of the infinitesimal in a more favorable light. Inspite of his Leibnizian sympathies, Robinson regards Berkeley's criticisms of the infinitesimal calculus as aptly demonstrating the inconsistency of reasoning with historical infinitesimal magnitudes. We argue that Robinson, among others, overestimates the force of Berkeley's criticisms, by underestimating the mathematical and philosophical resources available to Leibniz. Leibniz's infinitesimals are fictions, not logical fictions, as Ishiguro proposed, but rather pure fictions, like imaginaries, which are not eliminable by some syncategorematic paraphrase. We argue that Leibniz's defense of infinitesimals is more firmly grounded than Berkeley's criticism thereof. We show, moreover, that Leibniz's system for differential calculus was free of logical fallacies. Our argument strengthens the conception of modern infinitesimals as a development of Leibniz's strategy of relating inassignable to assignable quantities by means of his transcendental law of homogeneity.Comment: 69 pages, 3 figure

LNCS

Discrete-time Markov Chains (MCs) and Markov Decision Processes (MDPs) are two standard formalisms in system analysis. Their main associated quantitative objectives are hitting probabilities, discounted sum, and mean payoff. Although there are many techniques for computing these objectives in general MCs/MDPs, they have not been thoroughly studied in terms of parameterized algorithms, particularly when treewidth is used as the parameter. This is in sharp contrast to qualitative objectives for MCs, MDPs and graph games, for which treewidth-based algorithms yield significant complexity improvements. In this work, we show that treewidth can also be used to obtain faster algorithms for the quantitative problems. For an MC with n states and m transitions, we show that each of the classical quantitative objectives can be computed in O((n+m)⋅t2) time, given a tree decomposition of the MC with width t. Our results also imply a bound of O(κ⋅(n+m)⋅t2) for each objective on MDPs, where κ is the number of strategy-iteration refinements required for the given input and objective. Finally, we make an experimental evaluation of our new algorithms on low-treewidth MCs and MDPs obtained from the DaCapo benchmark suite. Our experiments show that on low-treewidth MCs and MDPs, our algorithms outperform existing well-established methods by one or more orders of magnitude

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis

Methodology: We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-Angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-Angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis