The cell cycle and drug discovery: The promise and the hope

In recent years, there have been major developments in the understanding of the cell cycle. It is now known that normal cellular proliferation is tightly regulated by the activation and deactivation of a series of proteins that constitute the cell cycle machinery. The expression and activity of components of the cell cycle can be altered during the development of a variety of diseases where aberrant proliferation contributes to the pathology of the illness. Apart from yielding a new source of untapped therapeutic targets, it is likely that manipulating the activity of such proteins in diseased states will provide an important route for treating proliferative disorders, and the opportunity to develop a novel class of future medicines.

Nocturnal ranging behaviour of urban hedgehogs, Erinaceus europaeus, in relation to risk and reward

Urban areas have both positive and negative influences on wildlife. For terrestrial mammals, one of the principle problems is the risk associated with moving through the environment whilst foraging. In this study, we examined nocturnal patterns of movement of urban-dwelling hedgehogs (Erinaceus europaeus) in relation to (i) the risks posed by predators and motor vehicles and (ii) nightly weather patterns. Hedgehogs preferentially utilised the gardens of semi-detached and terraced houses. However, females, but not males, avoided the larger back gardens of detached houses, which contain more of the habitat features selected by badgers. This difference in the avoidance of predation risk is probably associated with sex differences in breeding behaviour. Differences in nightly movement patterns were consistent with strategies associated with mating behaviour and the accumulation of fat reserves for hibernation. Hedgehogs also exhibited differences in behaviour associated with the risks posed by humans; they avoided actively foraging near roads and road verges, but did not avoid crossing roads per se. They were, however, significantly more active after midnight when there was a marked reduction in vehicle and foot traffic. In particular, responses to increased temperature, which is associated with increased abundance of invertebrate prey, were only observed after midnight. This variation in the timing of bouts of activity would reduce the risks associated with human activities. There were also profound differences in both area ranged and activity with chronological year which warrant further investigation.

the implication of social cognition for experimental economics From the issue entitled "Special issue on Experimental economics and the social embedding of economic behavior and cognition"

Can human social cognitive processes and social motives be grasped by the methods of experimental economics? Experimental studies of strategic cognition and social preferences contribute to our understanding of the social aspects of economic decisions making. Yet, papers in this issue argue that the social aspects of decision-making introduce several difficulties for interpreting the results of economic experiments. In particular, the laboratory is itself a social context, and in many respects a rather distinctive one, which raises questions of external validity.

Application of molecular biological methods for studying probiotics and the gut flora

Increasingly, the microbiological scientific community is relying on molecular biology to define the complexity of the gut flora and to distinguish one organism from the next. This is particularly pertinent in the field of probiotics, and probiotic therapy, where identifying probiotics from the commensal flora is often warranted. Current techniques, including genetic fingerprinting, gene sequencing, oligonucleotide probes and specific primer selection, discriminate closely related bacteria with varying degrees of success. Additional molecular methods being employed to determine the constituents of complex microbiota in this area of research are community analysis, denaturing gradient gel electrophoresis (DGGE)/temperature gradient gel electrophoresis (TGGE), fluorescent in situ hybridisation (FISH) and probe grids. Certain approaches enable specific aetiological agents to be monitored, whereas others allow the effects of dietary intervention on bacterial populations to be studied. Other approaches demonstrate diversity, but may not always enable quantification of the population. At the heart of current molecular methods is sequence information gathered from culturable organisms. However, the diversity and novelty identified when applying these methods to the gut microflora demonstrates how little is known about this ecosystem. Of greater concern is the inherent bias associated with some molecular methods. As we understand more of the complexity and dynamics of this diverse microbiota we will be in a position to develop more robust molecular-based technologies to examine it. In addition to identification of the microbiota and discrimination of probiotic strains from commensal organisms, the future of molecular biology in the field of probiotics and the gut flora will, no doubt, stretch to investigations of functionality and activity of the microflora, and/or specific fractions. The quest will be to demonstrate the roles of probiotic strains in vivo and not simply their presence or absence.

Actors and objects: A socio-technical networks approach for construction management research

We explore the contribution of socio-technical networks approaches to construction management research. These approaches are distinctive for their analysis of actors and objects as mutually constituted within socio-technical networks. They raise questions about the ways in which the content, meaning and use of technology is negotiated in practice, how particular technical configurations are elaborated in response to specific problems and why certain paths or solutions are adopted rather than others. We illustrate this general approach with three case studies: a historical study of the development of reinforced concrete in France, the UK and the US, the recent introduction of 3D-CAD software into four firms and an analysis of the uptake of environmental assessment technologies in the UK since 1990. In each we draw out the ways in which various technologies shaped and were shaped by different socio-technical networks. We conclude with a reflection on the contributions of socio-technical network analysis for more general issues including the study of innovation and analyses of context and power.

Sulforaphane protects cortical neurons against 5-S-cysteinyl-dopamine-induced toxicity through the activation of ERK1/2, Nrf-2 and the upregulation of detoxification enzymes

The degeneration of dopaminergic neurons in the substantia nigra has been linked to the formation of the endogenous neurotoxin 5-S-cysteinyl-dopamine. Sulforaphane (SFN), an isothiocyanate derived from the corresponding precursor glucosinolate found in cruciferous vegetables has been observed to exert a range of biological activities in various cell populations. In this study, we show that SFN protects primary cortical neurons against 5-S-cysteinyl-dopamine induced neuronal injury. Pre-treatment of cortical neurons with SFN (0.01-1 microM) resulted in protection against 5-S-cysteinyl-dopamine-induced neurotoxicity, which peaked at 100 nM. This protection was observed to be mediated by the ability of SFN to modulate the extracellular signal-regulated kinase 1 and 2 and the activation of Kelch-like ECH-associated protein 1/NF-E2-related factor-2 leading to the increased expression and activity of glutathione-S-transferase (M1, M3 and M5), glutathione reductase, thioredoxin reductase and NAD(P)H oxidoreductase 1. These data suggest that SFN stimulates the NF-E2-related factor-2 pathway of antioxidant gene expression in neurons and may protect against neuronal injury relevant to the aetiology of Parkinson's disease.

Television and the popular: viewing from the British perspective

The academic discipline of television studies has been constituted by the claim that television is worth studying because it is popular. Yet this claim has also entailed a need to defend the subject against the triviality that is associated with the television medium because of its very popularity. This article analyses the many attempts in the later twentieth and twenty-first centuries to constitute critical discourses about television as a popular medium. It focuses on how the theoretical currents of Television Studies emerged and changed in the UK, where a disciplinary identity for the subject was founded by borrowing from related disciplines, yet argued for the specificity of the medium as an object of criticism. Eschewing technological determinism, moral pathologization and sterile debates about television's supposed effects, UK writers such as Raymond Williams addressed television as an aspect of culture. Television theory in Britain has been part of, and also separate from, the disciplinary fields of media theory, literary theory and film theory. It has focused its attention on institutions, audio-visual texts, genres, authors and viewers according to the ways that research problems and theoretical inadequacies have emerged over time. But a consistent feature has been the problem of moving from a descriptive discourse to an analytical and evaluative one, and from studies of specific texts, moments and locations of television to larger theories. By discussing some historically significant critical work about television, the article considers how academic work has constructed relationships between the different kinds of objects of study. The article argues that a fundamental tension between descriptive and politically activist discourses has confused academic writing about ›the popular‹. Television study in Britain arose not to supply graduate professionals to the television industry, nor to perfect the instrumental techniques of allied sectors such as advertising and marketing, but to analyse and critique the medium's aesthetic forms and to evaluate its role in culture. Since television cannot be made by ›the people‹, the empowerment that discourses of television theory and analysis aimed for was focused on disseminating the tools for critique. Recent developments in factual entertainment television (in Britain and elsewhere) have greatly increased the visibility of ›the people‹ in programmes, notably in docusoaps, game shows and other participative formats. This has led to renewed debates about whether such ›popular‹ programmes appropriately represent ›the people‹ and how factual entertainment that is often despised relates to genres hitherto considered to be of high quality, such as scripted drama and socially-engaged documentary television. A further aspect of this problem of evaluation is how television globalisation has been addressed, and the example that the issue has crystallised around most is the reality TV contest Big Brother. Television theory has been largely based on studying the texts, institutions and audiences of television in the Anglophone world, and thus in specific geographical contexts. The transnational contexts of popular television have been addressed as spaces of contestation, for example between Americanisation and national or regional identities. Commentators have been ambivalent about whether the discipline's role is to celebrate or critique television, and whether to do so within a national, regional or global context. In the discourses of the television industry, ›popular television‹ is a quantitative and comparative measure, and because of the overlap between the programming with the largest audiences and the scheduling of established programme types at the times of day when the largest audiences are available, it has a strong relationship with genre. The measurement of audiences and the design of schedules are carried out in predominantly national contexts, but the article refers to programmes like Big Brother that have been broadcast transnationally, and programmes that have been extensively exported, to consider in what ways they too might be called popular. Strands of work in television studies have at different times attempted to diagnose what is at stake in the most popular programme types, such as reality TV, situation comedy and drama series. This has centred on questions of how aesthetic quality might be discriminated in television programmes, and how quality relates to popularity. The interaction of the designations ›popular‹ and ›quality‹ is exemplified in the ways that critical discourse has addressed US drama series that have been widely exported around the world, and the article shows how the two critical terms are both distinct and interrelated. In this context and in the article as a whole, the aim is not to arrive at a definitive meaning for ›the popular‹ inasmuch as it designates programmes or indeed the medium of television itself. Instead the aim is to show how, in historically and geographically contingent ways, these terms and ideas have been dynamically adopted and contested in order to address a multiple and changing object of analysis.

Cognitive and bodily selves: how do they interact following brain lesion?

Dualism has long distinguished between the mental and the body experiences. Probing the structure and organisation of the self traditionally calls for a distinction between these two sides of the self coin. It is far beyond the scope of this chapter to address these philosophical issues, and our starting point will be the simple distinction between reflective processes involved in the elaboration of body image, self awareness and self-recognition (i.e. ‘the self’) and the sensori-motor dialogues involved in action control, reactions and automatisms (i.e. ‘the body’ schema). This oversimplification does not take into account the complex interactions taking place between these two levels of description, but our initial aim will be to distinguish between them, before addressing the question of their interactions. Cognitive and sensori-motor processes have frequently been distinguished (review: Rossetti and Revonsuo 2000), and it may be proposed that a similar dissociation can be put forward, a priori, between a central representation of self and a bodily representation corresponding to body schema (Figure 1).

Demand response experience in Europe: policies, programmes and implementation

Over the last few years, load growth, increases in intermittent generation, declining technology costs and increasing recognition of the importance of customer behaviour in energy markets have brought about a change in the focus of Demand Response (DR) in Europe. The long standing programmes involving large industries, through interruptible tariffs and time of day pricing, have been increasingly complemented by programmes aimed at commercial and residential customer groups. Developments in DR vary substantially across Europe reflecting national conditions and triggered by different sets of policies, programmes and implementation schemes. This paper examines experiences within European countries as well as at European Union (EU) level, with the aim of understanding which factors have facilitated or impeded advances in DR. It describes initiatives, studies and policies of various European countries, with in-depth case studies of the UK, Italy and Spain. It is concluded that while business programmes, technical and economic potentials vary across Europe, there are common reasons as to why coordinated DR policies have been slow to emerge. This is because of the limited knowledge on DR energy saving capacities; high cost estimates for DR technologies and infrastructures; and policies focused on creating the conditions for liberalising the EU energy markets.

A framework of brand value in B2B markets: the contributing role of functional and emotional components

The creation of value is admittedly a critical task for marketers regardless of industry. This paper focuses on a type of value that has traditionally been perceived as irrelevant to industrial markets and argues that brand value facilitates the progression from goods and services value to relationship value. To address the limited amount of research on B2B branding from the suppliers' point of view, we complement insights gained from a literature review with ten exploratory interviews with B2B supplier managers, and develop a framework of brand value applicable to industrial markets. This identifies both the functional (i.e., quality, technology, capacity, infrastructure, after sales service, capabilities, reliability, innovation) and emotional qualities (i.e., risk reduction, reassurance, trust) important for the development of industrial brand equity. Situational (e.g. nature of the purchase) and environmental factors (e.g. the economic situation) affecting suppliers' perceptions of the importance of brand in a B2B context and the role of functional versus emotional brand qualities are discussed. The value of the brand as a driver for the development of business to business relationships is also highlighted. The framework provides a basis for B2B practitioners to build their brands in such a way as to make a functional as well as an emotional connection with buyers that is more likely to lead to a supplier–buyer relationship.

Supranutritional selenium induces alterations in molecular targets related to energy metabolism in skeletal muscle and visceral adipose tissue of pigs

While selenium (Se) is an essential micronutrient for humans, epidemiological studies have raised concern that supranutritional Se intake may increase the risk to develop Type 2 diabetes mellitus (T2DM). We aimed to determine the impact of Se at a dose and source frequently ingested by humans on markers of insulin sensitivity and signalling. Male pigs were fed either a Se-adequate (0.17 mg Se/kg) or a Se-supranutritional (0.50 mg Se/kg; high-Se) diet. After 16 weeks of intervention, fasting plasma insulin and cholesterol levels were non-significantly increased in the high-Se pigs, whereas fasting glucose concentrations did not differ between the two groups. In skeletal muscle of high-Se pigs, glutathione peroxidase activity was increased, gene expression of forkhead box O1 transcription factor and peroxisomal proliferator-activated receptor- coactivator 1 were increased and gene expression of the glycolytic enzyme pyruvate kinase was decreased. In visceral adipose tissue of high-Se pigs, mRNA levels of sterol regulatory element-binding transcription factor 1 were increased, and the phosphorylation of Akt, AMP-activated kinase and mitogen-activated protein kinases was affected. In conclusion, dietary Se oversupply may affect expression and activity of proteins involved in energy metabolism in major insulin target tissues, though this is probably not sufficient to induce diabetes.

Research review: reading comprehension in developmental disorders of language and communication

Background: Deficits in reading airment (SLI), Down syndrome (DS) and autism spectrum disorders (ASD). Methods: In this review (based on a search of the ISI Web of Knowledge database to 2011), the Simple View of Reading is used as a framework for considering reading comprehension in these groups. Conclusions: There is substantial evidence for reading comprehension impairments in SLI and growing evidence that weaknesses in this domain are common in DS and ASD. Further, in these groups reading comprehension is typically more impaired than word recognition. However, there is also evidence that some children and adolescents with DS, ASD and a history of SLI develop reading comprehension and word recognition skills at or above the age appropriate level. This review of the literature indicates that factors including word recognition, oral language, nonverbal ability and working memory may explain reading comprehension difficulties in SLI, DS and ASD. In addition, it highlights methodological issues, implications of poor reading comprehension and fruitful areas for future research.

Prebiotics and the health benefits of fiber: current regulatory status, future research, and goals.

First defined in the mid-1990s, prebiotics, which alter the composition and activity of gastrointestinal (GI) microbiota to improve health and well-being, have generated scientific and consumer interest and regulatory debate. The Life Sciences Research Organization, Inc. (LSRO) held a workshop, Prebiotics and the Health Benefits of Fiber: Future Research and Goals, in February 2011 to assess the current state of the science and the international regulatory environment for prebiotics, identify research gaps, and create a strategy for future research. A developing body of evidence supports a role for prebiotics in reducing the risk and severity of GI infection and inflammation, including diarrhea, inflammatory bowel disease, and ulcerative colitis as well as bowel function disorders, including irritable bowel syndrome. Prebiotics also increase the bioavailability and uptake of minerals and data suggest that they reduce the risk of obesity by promoting satiety and weight loss. Additional research is needed to define the relationship between the consumption of different prebiotics and improvement of human health. New information derived from the characterization of the composition and function of different prebiotics as well as the interactions among and between gut microbiota and the human host would improve our understanding of the effects of prebiotics on health and disease and could assist in surmounting regulatory issues related to prebiotic use.

Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint?

Hydrogen sulfide (H(2)S) has recently been proposed as an endogenous mediator of inflammation and is present in human synovial fluid. This study determined whether primary human articular chondrocytes (HACs) and mesenchymal progenitor cells (MPCs) could synthesize H(2)S in response to pro-inflammatory cytokines relevant to human arthropathies, and to determine the cellular responses to endogenous and pharmacological H(2)S. HACs and MPCs were exposed to IL-1β, IL-6, TNF-α and lipopolysaccharide (LPS). The expression and enzymatic activity of the H(2)S synthesizing enzymes cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) were determined by Western blot and zinc-trap spectrophotometry, respectively. Cellular oxidative stress was induced by H(2)O(2), the peroxynitrite donor SIN-1 and 4-hydroxynonenal (4-HNE). Cell death was assessed by 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (DCm) was determined in situ by flow cytometry. Endogenous H(2) S synthesis was inhibited by siRNA-mediated knockdown of CSE and CBS and pharmacological inhibitors D,L-propargylglycine and aminoxyacetate, respectively. Exogenous H(2)S was generated using GYY4137. Under basal conditions HACs and MPCs expressed CBS and CSE and synthesized H(2)S in a CBS-dependent manner, whereas CSE expression and activity was induced by treatment of cells with IL-1β, TNF-α, IL-6 or LPS. Oxidative stress-induced cell death was significantly inhibited by GYY4137 treatment but increased by pharmacological inhibition of H(2)S synthesis or by CBS/CSE-siRNA treatment. These data suggest CSE is an inducible source of H(2)S in cultured HACs and MPCs. H(2)S may represent a novel endogenous mechanism of cytoprotection in the inflamed joint, suggesting a potential opportunity for therapeutic intervention.

Housing supply and brownfield regeneration in a post-Barker world: is there enough brownfield land in England and Scotland?

The findings of the Barker review, which examined the reasons for the undersupply of UK housing, have important implications for the devolved constituents of the UK, including Scotland. This paper traces the emergence of the brownfi eld regeneration policy agenda across the UK and examines how the Barker review connects with this brownfi eld policy focus. The paper compares housing and brownfi eld policies and practices in England and Scotland, places them in an international context and elicits wider lessons for devolved governance in relation to housing policy, in terms of ‘centrist–local’ tensions. Estimates based on published data suggest that Barker’s emphasis on increased housing supply cannot easily be reconciled with the current emphasis on brownfi eld development and is likely to require a return to greenfield development in both countries.