A structural basis for the inhibition of collagen-stimulated platelet function by quercetin and structurally related flavonoids

Background and purpose: Molecular mechanisms underlying the links between dietary intake of flavonoids and reduced cardiovascular disease risk are only partially understood. Key events in the pathogenesis of cardiovascular disease, particularly thrombosis, are inhibited by these polyphenolic compounds via mechanisms such as inhibition of platelet activation and associated signal transduction, attenuation of generation of reactive oxygen species, enhancement of nitric oxide production and binding to thromboxane A2 receptors. In vivo, effects of flavonoids are mediated by their metabolites, but the effects and modes of action of these compounds are not well-characterized. A good understanding of flavonoid structure–activity relationships with regard to platelet function is also lacking. Experimental approach: Inhibitory potencies of structurally distinct flavonoids (quercetin, apigenin and catechin) and plasma metabolites (tamarixetin, quercetin-3′-sulphate and quercetin-3-glucuronide) for collagen-stimulated platelet aggregation and 5-hydroxytryptamine secretion were measured in human platelets. Tyrosine phosphorylation of total protein, Syk and PLCγ2 (immunoprecipitation and Western blot analyses), and Fyn kinase activity were also measured in platelets. Internalization of flavonoids and metabolites in a megakaryocytic cell line (MEG-01 cells) was studied by fluorescence confocal microscopy. Key results: The inhibitory mechanisms of these compounds included blocking Fyn kinase activity and the tyrosine phosphorylation of Syk and PLCγ2 following internalization. Principal functional groups attributed to potent inhibition were a planar, C-4 carbonyl substituted and C-3 hydroxylated C ring in addition to a B ring catechol moiety. Conclusions and implications: The structure–activity relationship for flavonoids on platelet function presented here may be exploited to design selective inhibitors of cell signalling.

Position paper on the future of social networking

Social networking mediated by web sites is a relatively new phenomenon and as with all technological innovations there continues to be a period of both technical and social adjustment to fit the services in with people’s behaviours, and for people to adjust their practices in the light of the affordances provided by the technology. Social networking benefits strongly from large scale availability. Users gain greater benefit from social networking services when more of their friends are using them.This applies in social terms, but also in eLearning and professional networks. The network effect provides one explanation for the popularity of internet based social networking sites (SNS) because the number of connections between people which can be maintained by using them is greatly increased in comparison to the networks available before the internet. The ability of users to determine how much they trust information available to them from contacts within their social network is important in almost all modes of use. As sources of information on a range of topics from academic to shopping advice, the level of trust which a user can put in other nodes is a key aspect of the utility of the system.

An ultra-wide passband (5-30µm) filter for FTIR studies of Photosystem II

This paper reports on the design and manufacture of an ultra-wide (5-30µm) infrared edge filter for use in FTIR studies of the low frequency vibrational modes of metallo-proteins. We present details of the spectral design and manufacture of such a filter which meets the demanding bandwidth and transparency requirements of the application, and spectra that present the new data possible with such a filter. A design model of the filter and the materials used in its construction has been developed capable of accurately predicting spectral performance at both 300K and at the reduced operating temperature at 200K. This design model is based on the optical and semiconductor properties of a multilayer filter containing PbTe (IV-VI) layer material in combination with the dielectric dispersion of ZnSe (II-VI) deposited on a CdTe (II-VI) substrate together with the use of BaF2 (II-VII) as an antireflection layer. Comparisons between the computed spectral performance of the model and spectral measurements from manufactured coatings over a wavelength range of 4-30µm and temperature range 300-200K are presented. Finally we present the results of the FTIR measurements of Photosystem II showing the improvement in signal to noise ratio of the measurement due to using the filter, together with a light induced FTIR difference spectrum of Photosystem II.

Interior Life

Interior Life was curated by Tim Renshaw, Mary Maclean and Bernice Donszelmann who together form ‘Outside Architecture’. The aim of this project was to argue that interior space should not be negatively defined as a retreat from the public realm. Instead, following the thought of the philosopher Peter Slotterdijk, interior space was proposed as a human need. The five artists selected by ‘Outside Architecture’ each visualized this need differently. A contention here was that interiors give rise to a multiplicity of experiences that potentially change the way we dwell in contemporary man-made space. This contention was primarily figured in relation to the materiality of contemporary interiors. Each gave attention to the effects of contemporary materials and surfaces and each considered that these forms produce new modes of sensing and immersion in a place. The exhibition included two talks by the members of ‘Outside Architecture. The project was supported by an Arts Council of England grant of £6,323 www.ucreative.ac.uk/galleries

Sleeping with half open eyes: dreams and realities in The Cry of the Owl

This article is a close analysis of The Cry of the Owl (Thraves, 2009). It is also part of larger project to bring together traditions of detailed criticism with those of production history, which culminates in second article on the film due to be published in 2011. The detail of the argument concerns analysing a range of the film’s key signifying systems, with a particular interest in the way the film explores the gap between images / impressions and characters’ realities; engages in a complex way with generic traditions and modes of address; establishes complex patterns of connection and contrast through blocking, camera strategies and narrative structure.

Resource allocation analysis of the stochastic diffusion search

The Stochastic Diffusion Search (SDS) was developed as a solution to the best-fit search problem. Thus, as a special case it is capable of solving the transform invariant pattern recognition problem. SDS is efficient and, although inherently probabilistic, produces very reliable solutions in widely ranging search conditions. However, to date a systematic formal investigation of its properties has not been carried out. This thesis addresses this problem. The thesis reports results pertaining to the global convergence of SDS as well as characterising its time complexity. However, the main emphasis of the work, reports on the resource allocation aspect of the Stochastic Diffusion Search operations. The thesis introduces a novel model of the algorithm, generalising an Ehrenfest Urn Model from statistical physics. This approach makes it possible to obtain a thorough characterisation of the response of the algorithm in terms of the parameters describing the search conditions in case of a unique best-fit pattern in the search space. This model is further generalised in order to account for different search conditions: two solutions in the search space and search for a unique solution in a noisy search space. Also an approximate solution in the case of two alternative solutions is proposed and compared with predictions of the extended Ehrenfest Urn model. The analysis performed enabled a quantitative characterisation of the Stochastic Diffusion Search in terms of exploration and exploitation of the search space. It appeared that SDS is biased towards the latter mode of operation. This novel perspective on the Stochastic Diffusion Search lead to an investigation of extensions of the standard SDS, which would strike a different balance between these two modes of search space processing. Thus, two novel algorithms were derived from the standard Stochastic Diffusion Search, ‘context-free’ and ‘context-sensitive’ SDS, and their properties were analysed with respect to resource allocation. It appeared that they shared some of the desired features of their predecessor but also possessed some properties not present in the classic SDS. The theory developed in the thesis was illustrated throughout with carefully chosen simulations of a best-fit search for a string pattern, a simple but representative domain, enabling careful control of search conditions.

The evolution of strategy: thinking war from antiquity to the present

Latin had no word for "strategy", but the East Romans, whom we call the Byzantines, did. This book tracks the evolution of the concept of warfare being subjected to higher political aims from Antiquity to the Present, using Greek, Latin, French, Spanish, Italian, English and German sources. It tracks the rise, fall, and resurrection of the belief in the Roman and later the medieval and early modern world that warfare was only legitimate if it pursued the higher goal of a just peace, which in the 19th century gave way to a blinkered concentration on military victory as only war aim. It explains why one school of thought, from Antiquity to the present, emphasised eternal principles of warfare, while others emphasised, in Clausewitz's term, the "changing character of war". It tracks ideas from land warfare to naval warfare to air power and nuclear thinking, but it also stresses great leaps and discontinuities in thinking about strategy. It covers asymmetric wars both from the point of view of the weaker power seeking to overthrow a stronger power, and from the stronger power dealing with insurgents and other numerically inferior forces. It concludes with a commentary of the long-known problems of bureaucratic politics, non-centralised command and inter-service rivalry, which since the 16th century or earlier has created obstacles to coherent strategy making.

Guanine specific binding at a DNA junction formed by d[CG(5-BrU)ACG]2 with a topoisomerase poison in the presence of Co2+Ions†,‡

The structure of the duplex d[CG(5-BrU)ACG]2 bound to 9-bromophenazine-4-carboxamide has been solved through MAD phasing at 2.0 Å resolution. It shows an unexpected and previously unreported intercalation cavity stabilized by the drug and novel binding modes of Co2+ ions at certain guanine N7 sites. For the intercalation cavity the terminal cytosine is rotated to pair with the guanine of a symmetry-related duplex to create a pseudo-Holliday junction geometry, with two such cavities linked through the minor groove interactions of the N2/N3 guanine sites at an angle of 40°, creating a quadruplex-like structure. The mode of binding of the drug is shown to be disordered, with the major conformations showing the side chain bound to the N7 position of adjacent guanines. The other end of the duplex exhibits a terminal base fraying in the presence of Co2+ ions linking symmetry-related guanines, causing the helices to intertwine through the minor groove. The stabilization of the structure by the intercalating drug shows that this class of compound may bind to DNA junctions as well as duplex DNA or to strand-nicked DNA (‘hemi-intercalated'), as in the cleavable complex. This suggests a structural basis for the dual poisoning of topoisomerase I and II enzymes by this family of drugs.

Reaping the benefits: science and the sustainable intensification of global agriculture

Food security is one of this century’s key global challenges. By 2050 the world will require increased crop production in order to feed its predicted 9 billion people. This must be done in the face of changing consumption patterns, the impacts of climate change and the growing scarcity of water and land. Crop production methods will also have to sustain the environment, preserve natural resources and support livelihoods of farmers and rural populations around the world. There is a pressing need for the ‘sustainable intensifi cation’ of global agriculture in which yields are increased without adverse environmental impact and without the cultivation of more land. Addressing the need to secure a food supply for the whole world requires an urgent international effort with a clear sense of long-term challenges and possibilities. Biological science, especially publicly funded science, must play a vital role in the sustainable intensifi cation of food crop production. The UK has a responsibility and the capacity to take a leading role in providing a range of scientifi c solutions to mitigate potential food shortages. This will require signifi cant funding of cross-disciplinary science for food security. The constraints on food crop production are well understood, but differ widely across regions. The availability of water and good soils are major limiting factors. Signifi cant losses in crop yields occur due to pests, diseases and weed competition. The effects of climate change will further exacerbate the stresses on crop plants, potentially leading to dramatic yield reductions. Maintaining and enhancing the diversity of crop genetic resources is vital to facilitate crop breeding and thereby enhance the resilience of food crop production. Addressing these constraints requires technologies and approaches that are underpinned by good science. Some of these technologies build on existing knowledge, while others are completely radical approaches, drawing on genomics and high-throughput analysis. Novel research methods have the potential to contribute to food crop production through both genetic improvement of crops and new crop and soil management practices. Genetic improvements to crops can occur through breeding or genetic modifi cation to introduce a range of desirable traits. The application of genetic methods has the potential to refi ne existing crops and provide incremental improvements. These methods also have the potential to introduce radical and highly signifi cant improvements to crops by increasing photosynthetic effi ciency, reducing the need for nitrogen or other fertilisers and unlocking some of the unrealised potential of crop genomes. The science of crop management and agricultural practice also needs to be given particular emphasis as part of a food security grand challenge. These approaches can address key constraints in existing crop varieties and can be applied widely. Current approaches to maximising production within agricultural systems are unsustainable; new methodologies that utilise all elements of the agricultural system are needed, including better soil management and enhancement and exploitation of populations of benefi cial soil microbes. Agronomy, soil science and agroecology—the relevant sciences—have been neglected in recent years. Past debates about the use of new technologies for agriculture have tended to adopt an either/or approach, emphasising the merits of particular agricultural systems or technological approaches and the downsides of others. This has been seen most obviously with respect to genetically modifi ed (GM) crops, the use of pesticides and the arguments for and against organic modes of production. These debates have failed to acknowledge that there is no technological panacea for the global challenge of sustainable and secure global food production. There will always be trade-offs and local complexities. This report considers both new crop varieties and appropriate agroecological crop and soil management practices and adopts an inclusive approach. No techniques or technologies should be ruled out. Global agriculture demands a diversity of approaches, specific to crops, localities, cultures and other circumstances. Such diversity demands that the breadth of relevant scientific enquiry is equally diverse, and that science needs to be combined with social, economic and political perspectives. In addition to supporting high-quality science, the UK needs to maintain and build its capacity to innovate, in collaboration with international and national research centres. UK scientists and agronomists have in the past played a leading role in disciplines relevant to agriculture, but training in agricultural sciences and related topics has recently suffered from a lack of policy attention and support. Agricultural extension services, connecting farmers with new innovations, have been similarly neglected in the UK and elsewhere. There is a major need to review the support for and provision of extension services, particularly in developing countries. The governance of innovation for agriculture needs to maximise opportunities for increasing production, while at the same time protecting societies, economies and the environment from negative side effects. Regulatory systems need to improve their assessment of benefits. Horizon scanning will ensure proactive consideration of technological options by governments. Assessment of benefi ts, risks and uncertainties should be seen broadly, and should include the wider impacts of new technologies and practices on economies and societies. Public and stakeholder dialogue—with NGOs, scientists and farmers in particular—needs to be a part of all governance frameworks.

Understanding the early stages of the innovation diffusion process: awareness, influence and communication networks

The themes of awareness and influence within the innovation diffusion process are addressed. The innovation diffusion process is typically represented as stages, yet awareness and influence are somewhat under-represented in the literature. Awareness and influence are situated within the contextual setting of individual actors but also within the broader institutional forces. Understanding how actors become aware of an innovation and then how their opinion is influenced is important for creating a more innovation-active UK construction sector. Social network analysis is proposed as one technique for mapping how awareness and influence occur and what they look like as a network. Empirical data are gathered using two modes of enquiry. This is done through a pilot study consisting of chartered professionals and then through a case study organization as it attempted to diffuse an innovation. The analysis demonstrates significant variations across actors’ awareness and influence networks. It is argued that social network analysis can complement other research methods in order to present a richer picture of how actors become aware of innovations and where they draw their influences regarding adopting innovations. In summarizing the findings, a framework for understanding awareness and influence associated with innovation within the UK construction sector is presented. Finally, with the UK construction sector continually being encouraged to be innovative, understanding and managing an actor’s awareness and influence network will be beneficial. The overarching conclusion thus describes the need not only to build research capacity in this area but also to push the boundaries related to the research methods employed.

Bistable systems with stochastic noise: virtues and limits of effective one-dimensional Langevin equations

The understanding of the statistical properties and of the dynamics of multistable systems is gaining more and more importance in a vast variety of scientific fields. This is especially relevant for the investigation of the tipping points of complex systems. Sometimes, in order to understand the time series of given observables exhibiting bimodal distributions, simple one-dimensional Langevin models are fitted to reproduce the observed statistical properties, and used to investing-ate the projected dynamics of the observable. This is of great relevance for studying potential catastrophic changes in the properties of the underlying system or resonant behaviours like those related to stochastic resonance-like mechanisms. In this paper, we propose a framework for encasing this kind of studies, using simple box models of the oceanic circulation and choosing as observable the strength of the thermohaline circulation. We study the statistical properties of the transitions between the two modes of operation of the thermohaline circulation under symmetric boundary forcings and test their agreement with simplified one-dimensional phenomenological theories. We extend our analysis to include stochastic resonance-like amplification processes. We conclude that fitted one-dimensional Langevin models, when closely scrutinised, may result to be more ad-hoc than they seem, lacking robustness and/or well-posedness. They should be treated with care, more as an empiric descriptive tool than as methodology with predictive power.

Corporate real estate management in the retail sector: a study of the relationship between the management of the corporate real estate and corporate performance

Retail organisations have often been cited as being at the forefront of corporate real estate management. This research found that the retail sector can be characterised by diversity both in terms of the degree to which organisations are vertically integrated and in terms of the range of modes of retailing they engage in. This in turn led to highly diverse real estate portfolios. Given this diversity it may be surprising that the over riding strategy which the vast majority of sample firms adopted was focused on supporting the core retail activity. However the way in which they implement this strategy, again reflected the diversity in the sector. In terms of the future, the senior real estate managers were focusing on the medium term particularly looking at the way change would impact their functional strategy. This study provides a snap-shot of current practice and contributes to the debate however it also recognised that there is a need to answer the more fundamental questions.

Formal theory building for the avalanche game: explaining counter-intuitive behaviour of a complex system using geometrical and human behavioural/physiological effects

In 'Avalanche', an object is lowered, players staying in contact throughout. Normally the task is easily accomplished. However, with larger groups counter-intuitive behaviours appear. The paper proposes a formal theory for the underlying causal mechanisms. The aim is to not only provide an explicit, testable hypothesis for the source of the observed modes of behaviour-but also to exemplify the contribution that formal theory building can make to understanding complex social phenomena. Mapping reveals the importance of geometry to the Avalanche game; each player has a pair of balancing loops, one involved in lowering the object, the other ensuring contact. For more players, sets of balancing loops interact and these can allow dominance by reinforcing loops, causing the system to chase upwards towards an ever-increasing goal. However, a series of other effects concerning human physiology and behaviour (HPB) is posited as playing a role. The hypothesis is therefore rigorously tested using simulation. For simplicity a 'One Degree of Freedom' case is examined, allowing all of the effects to be included whilst rendering the analysis more transparent. Formulation and experimentation with the model gives insight into the behaviours. Multi-dimensional rate/level analysis indicates that there is only a narrow region in which the system is able to move downwards. Model runs reproduce the single 'desired' mode of behaviour and all three of the observed 'problematic' ones. Sensitivity analysis gives further insight into the system's modes and their causes. Behaviour is seen to arise only when the geometric effects apply (number of players greater than degrees of freedom of object) in combination with a range of HPB effects. An analogy exists between the co-operative behaviour required here and various examples: conflicting strategic objectives in organizations; Prisoners' Dilemma and integrated bargaining situations. Additionally, the game may be relatable in more direct algebraic terms to situations involving companies in which the resulting behaviours are mediated by market regulations. Finally, comment is offered on the inadequacy of some forms of theory building and the case is made for formal theory building involving the use of models, analysis and plausible explanations to create deep understanding of social phenomena.

Demand response — a different form of distributed storage?

Reduced flexibility of low carbon generation could pose new challenges for future energy systems. Both demand response and distributed storage may have a role to play in supporting future system balancing. This paper reviews how these technically different, but functionally similar approaches compare and compete with one another. Household survey data is used to test the effectiveness of price signals to deliver demand responses for appliances with a high degree of agency. The underlying unit of storage for different demand response options is discussed, with particular focus on the ability to enhance demand side flexibility in the residential sector. We conclude that a broad range of options, with different modes of storage, may need to be considered, if residential demand flexibility is to be maximised.

Harringtonian virtue: Harrington, Machiavelli, and the method of the 'Moment'

This article presents a reinterpretation of James Harrington's writings. It takes issue with J. G. A. Pocock's reading, which treats him as importing into England a Machiavellian ‘language of political thought’. This reading is the basis of Pocock's stress on the republicanism of eighteenth-century opposition values. Harrington's writings were in fact a most implausible channel for such ideas. His outlook owed much to Stoicism. Unlike the Florentine, he admired the contemplative life; was sympathetic to commerce; and was relaxed about the threat of ‘corruption’ (a concept that he did not understand). These views can be associated with his apparent aims: the preservation of a national church with a salaried but politically impotent clergy; and the restoration of the royalist gentry to a leading role in English politics. Pocock's hypothesis is shown to be conditioned by his method; its weaknesses reflect some difficulties inherent in the notion of ‘languages of thought’.