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The University of Edinburgh , founded in 1583, is the sixth-oldest university in the English-speaking world and one of Scotland's ancient universities. The university is deeply embedded in the fabric of the city, with many of the buildings in the historic Old Town belonging to the university.The University of Edinburgh is ranked 17th in the world by the 2013–14 and 2014–15 QS rankings. The Research Excellence Framework, a research ranking used by the UK government to determine future research funding, ranked Edinburgh 4th in the UK in 2014. It is ranked 12th in the world in arts and humanities by the 2014–15 Times Higher Education Ranking. It is ranked the 15th most employable university in the world by the 2013 Global Employability University Ranking. It is a member of both the Russell Group, and the League of European Research Universities, a consortium of 21 research universities in Europe. It has the third largest endowment of any university in the United Kingdom, after the universities of Cambridge and Oxford.The university played an important role in leading Edinburgh to its reputation as a chief intellectual centre during the Age of Enlightenment, and helped give the city the nickname of the Athens of the North. Alumni of the university include some of the major figures of modern history, including the physicist James Clerk Maxwell, naturalist Charles Darwin, philosopher David Hume, mathematician Thomas Bayes, surgeon Joseph Lister, signatories of the American declaration of independence John Witherspoon and Benjamin Rush, inventor Alexander Graham Bell, first president of Tanzania Julius Nyerere, and a host of famous authors such as Sir Arthur Conan Doyle, Robert Louis Stevenson, J.M. Barrie and Sir Walter Scott. Associated people include 20 Nobel Prize winners, 2 Turing Award winners, 1 Abel Prize winner, 1 Fields Medal winner, 1 Pulitzer Prize winner, 3 Prime Ministers of the United Kingdom, 2 currently-sitting UK Supreme Court Justices, and several Olympic gold medallists. It continues to have links to the British Royal Family, having had the Duke of Edinburgh as its Chancellor from 1953 to 2010 and Princess Anne since 2011.Edinburgh receives approximately 47,000 applications every year, making it the third most popular university in the UK by volume of applicants. Entrance is competitive, with 2012–2013 having an acceptance rate of 11.5% and offer rate of 38.6%. Wikipedia.

Miller W.R.,University of Edinburgh | Larionov A.A.,Edinburgh Breakthrough Breast Research Unit
Breast Cancer Research | Year: 2012

Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment. © 2012 BioMed Central Ltd.

Hill W.G.,University of Edinburgh
Genetics research | Year: 2011

Although the expected relationship or proportion of genome shared by pairs of relatives can be obtained from their pedigrees, the actual quantities deviate as a consequence of Mendelian sampling and depend on the number of chromosomes and map length. Formulae have been published previously for the variance of actual relationship for a number of specific types of relatives but no general formula for non-inbred individuals is available. We provide here a unified framework that enables the variances for distant relatives to be easily computed, showing, for example, how the variance of sharing for great grandparent-great grandchild, great uncle-great nephew, half uncle-nephew and first cousins differ, even though they have the same expected relationship. Results are extended in order to include differences in map length between sexes, no recombination in males and sex linkage. We derive the magnitude of skew in the proportion shared, showing the skew becomes increasingly large the more distant the relationship. The results obtained for variation in actual relationship apply directly to the variation in actual inbreeding as both are functions of genomic coancestry, and we show how to partition the variation in actual inbreeding between and within families. Although the variance of actual relationship falls as individuals become more distant, its coefficient of variation rises, and so, exacerbated by the skewness, it becomes increasingly difficult to distinguish different pedigree relationships from the actual fraction of the genome shared.

Sarkisov L.,University of Edinburgh
Physical Chemistry Chemical Physics | Year: 2012

A simple protocol based on a lattice representation of the porous space is proposed to locate and characterize the free energy bottle-necks in rigid metal organic frameworks. As an illustration we apply this method to HKUST-1 to demonstrate that there are impassable free energy barriers for molecules of trinitrotoluene in this structure. © 2012 the Owner Societies.

Cockell C.S.,University of Edinburgh
Astrobiology | Year: 2014

Beginning from two plausible starting points - an uninhabited or inhabited Mars - this paper discusses the possible trajectories of martian habitability over time. On an uninhabited Mars, the trajectories follow paths determined by the abundance of uninhabitable environments and uninhabited habitats. On an inhabited Mars, the addition of a third environment type, inhabited habitats, results in other trajectories, including ones where the planet remains inhabited today or others where planetary-scale life extinction occurs. By identifying different trajectories of habitability, corresponding hypotheses can be described that allow for the various trajectories to be disentangled and ultimately a determination of which trajectory Mars has taken and the changing relative abundance of its constituent environments. © 2014, Mary Ann Liebert, Inc. 2014.

Brenn T.,University of Edinburgh
Advances in Anatomic Pathology | Year: 2014

Pleomorphic neoplasms are typically associated with high-grade malignant behavior, but this does not readily apply to primary cutaneous tumors. Despite morphologic features suggestive of malignancy, atypical fibroxanthoma, the classic example of a pleomorphic dermal neoplasm, is characterized by indolent clinical behavior. Atypical fibroxanthoma is a distinctive clinicopathologic disease affecting sun-damaged skin of elderly males. Histologically, it is often ulcerated and dermal based with pushing growth, characterized by a sheet-like and fascicular growth of pleomorphic epithelioid, spindled, and multinucleated tumor cells with brisk and atypical mitotic activity. However, no positive discriminatory histologic or immunohistochemical features exist. Its diagnosis is one exclusion with a wide differential diagnosis, mainly including other mesenchymal, melanocytic, and epithelial neoplasms. Particular considerations are pleomorphic dermal sarcoma, invasive melanoma, squamous cell carcinoma, metaplastic carcinoma, poorly differentiated cutaneous angiosarcoma, cutaneous leiomyosarcoma, myxofibrosarcoma, variants of fibrous histiocytoma (FH), pleomorphic fibroma, and non-neural granular cell tumor. The behavior of these tumors is varied and ranges from outright malignant to entirely benign, requiring confident diagnosis to reliably predict behavior and guide treatment. Although challenging, because of significant clinical and pathologic overlap, it is usually possible to establish a definitive diagnosis when attention is paid to the often subtle differentiating features. This requires careful tumor sampling, recognition of the subtle distinguishing morphologic features, judicious use and analysis of immunohistochemistry, and interpretation of the findings in the appropriate clinical setting. © 2014 by Lippincott Williams & Wilkins.

Despite the fact that much of the global microbial biosphere is believed to exist in high pressure environments, the effects of hydrostatic pressure on microbial physiology remain poorly understood. We use a genome-wide screening approach, combined with a novel high-throughput high-pressure cell culture method, to investigate the effects of hydrostatic pressure on microbial physiology in vivo. The Keio collection of single-gene deletion mutants in Escherichia coli K-12 was screened for growth at a range of pressures from 0.1 MPa to 60 MPa. This led to the identification of 6 genes, rodZ, holC, priA, dnaT, dedD and tatC, whose products were required for growth at 30 MPa and a further 3 genes, tolB, rffT and iscS, whose products were required for growth at 40 MPa. Our results support the view that the effects of pressure on cell physiology are pleiotropic, with DNA replication, cell division, the cytoskeleton and cell envelope physiology all being potential failure points for cell physiology during growth at elevated pressure.

Ruhsam M.,University of Edinburgh
Heredity | Year: 2011

Although often considered as evolutionary dead ends, selfing taxa may make an important contribution to plant evolution through hybridization with related outcrossing lineages. However, there is a shortage of studies examining the evolutionary dynamics of hybridization between outcrossing and selfing taxa. On the basis of differential pollinator attractiveness, production and competitive ability of pollen, as well as levels of inbreeding depression, we predict that the early products of hybridization between outcrossing and selfing lineages will be F1s and first-generation backcrosses sired mainly by the outcrossing lineage, together with selfed F2s containing a limited genetic contribution from the outcrosser. These predictions were tested using amplified fragment length polymorphism and chloroplast markers to analyze the composition of a recent hybrid swarm between predominantly outcrossing Geum rivale and predominantly selfing Geum urbanum. In line with predictions, the hybrid swarm comprised both parental species together with F1s and first-generation backcrosses to G. rivale alone. Chloroplast data suggested that G. rivale was the pollen parent for both observed hybrid classes. However, there was no evidence for F2 individuals, despite the fact that the F1 was fully self-compatible and able to auto-pollinate. The pollen fertility of F1s was only 30% lower than that of the parental taxa, and was fully restored in backcross hybrids. Predicting future evolution in the hybrid swarm will require an understanding of the mating patterns within and among the mix of parental, F1 and backcross genotypes that are currently present. However, these results support the hypothesis that introgression is likely to be asymmetrical from selfing to outcrossing lineages.

Chen W.-T.,National Taiwan University | Sheu H.-S.,National Synchrotron Radiation Research Center | Liu R.-S.,National Taiwan University | Attfield J.P.,University of Edinburgh
Journal of the American Chemical Society | Year: 2012

Red or yellow phosphors excited by a blue light-emitting diode are an efficient source of white light for everyday applications. Many solid oxides and nitrides, particularly silicon nitride-based materials such as M 2Si 5N 8 and MSi 2O 2N 2 (M = Ca, Sr, Ba), CaAlSiN 3, and SiAlON, are useful phosphor hosts with good thermal stabilities. Both oxide/nitride and various cation substitutions are commonly used to shift the emission spectrum and optimize luminescent properties, but the underlying mechanisms are not always clear. Here we show that size-mismatch between host and dopant cations tunes photoluminescence shifts systematically in M 1.95Eu 0.05Si 5-xAl xN 8-xO x lattices, leading to a red shift when the M = Ba and Sr host cations are larger than the Eu 2+ dopant, but a blue shift when the M = Ca host is smaller. Size-mismatch tuning of thermal quenching is also observed. A local anion clustering mechanism in which Eu 2+ gains excess nitride coordination in the M = Ba and Sr structures, but excess oxide in the Ca analogues, is proposed for these mismatch effects. This mechanism is predicted to be general to oxynitride materials and will be useful in tuning optical and other properties that are sensitive to local coordination environments. © 2012 American Chemical Society.

Evangelisti M.,University of Zaragoza | Brechin E.K.,University of Edinburgh
Dalton Transactions | Year: 2010

Molecular nanomagnets are considered valid candidates for magnetic refrigeration at low temperatures. Designing these materials for enhanced cooling requires the control and optimization of the quantum properties at the molecular level, in particular: spin ground state, magnetic anisotropy, and presence of low-lying excited spin states. Herein, we present the theoretical framework together with a critical review of recent results, and perspectives for future developments. © The Royal Society of Chemistry 2010.

Saunders D.S.,University of Edinburgh
Physiological Entomology | Year: 2012

This review examines the spectral sensitivities of photoperiodic responses in insects and mites in relation to circadian-based models for the photoperiodic clock. It concludes that there are probably a number of different photoreceptors at both the organ and molecular levels. These latter probably fall into two classes: (i) a blue-light sensitive photoreceptor and (ii) a range of opsins (i.e. opsin proteins conjugated with a vitamin A based pigment) absorbing light at a range of wavelengths. In flesh flies (Sarcophaga spp. and possibly other higher Diptera), which are considered to exemplify the 'external coincidence' model, entrainment of the photoperiodic oscillator probably involves a blue-light photoreceptor of Drosophila-type CRYPTOCHROME (CRY1) absorbing maximally at approximately 470 nm, whereas opsins absorbing at longer wavelengths may be involved in the photo-inductive process (diapause/nondiapause regulation) that occurs when dawn light coincides with the photo-inducible phase. In the parasitic wasp Nasonia vitripennis, on the other hand, a species that lacks CRY1 but expresses the nonphotosensitive 'mammalian-type' CRY2, and is considered to exemplify 'internal coincidence', entrainment of the dawn and dusk oscillators may involve opsin-based photoreceptors absorbing light at longer wavelengths as far as the red end of the spectrum. In the Lepidoptera, which express both CRY1 and CRY2, properties of both external and internal coincidence may be evident. The presence or absence of cry1 in the genome may thus emerge as a key to the photoperiodic mechanism on its light input pathway. © 2012 The Author. Physiological Entomology © 2012 The Royal Entomological Society.

Andrews P.J.,University of Edinburgh
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2010

purpose of review: There is considerable interest in glutamine and selenium in critical care as both offer the potential to enhance host defences, through different but complimentary mechanisms and may reduce subsequent infections and mortality. The SIGNET trial (randomized controlled factorial trial) is the largest, critical care study of both supplements. The data have been presented publicly, but the data are not published or available for review and will therefore not be discussed fully in this update. In the present review I will explore the recently available (past 1-2 years) published literature. Recent findings: The current literature demonstrates that there are currently insufficient data to enable confident recommendations on the optimal route, timing, duration and dosage of each of these nutritional supplements. The pending results of SIGNET, the largest critical care trial of parenteral nutrition supplemented by glutamine and or selenium promises to clarify some of the current ambiguities and inform future practice. Summary: To be able to confidently establish or refute the hypothesis that either glutamine or selenium alone or in combination improves outcome in critical care requires a well designed prospective randomized controlled trial. To design such a trial we require the optimal dose and duration of the nutritional supplement (balancing efficacy and toxicity, ease of administration and cost) and then conduct an adequately powered trial. Such a trial is still lacking for these two agents. There are some supportive data for selenium but the case is less strong for parenteral glutamine and weakest for enteral glutamine. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Clark A.,University of Edinburgh
Behavioral and Brain Sciences | Year: 2013

The target article sketched and explored a mechanism (action-oriented predictive processing) most plausibly associated with core forms of cortical processing. In assessing the attractions and pitfalls of the proposal we should keep that element distinct from larger, though interlocking, issues concerning the nature of adaptive organization in general. © 2013 Cambridge University Press.

Del Debbio L.,University of Edinburgh
International Journal of Modern Physics A | Year: 2014

The existence of strongly-interacting infrared (IR) fixed points in gauge theories can be studied using field theories defined on a lattice. Besides their academic interest, it has been argued that these theories could be used as a starting point to construct viable models of electroweak symmetry breaking (EWSB). A quantitative description of the large-distance dynamics is mandatory in order to develop predictive models for phenomenology. In these notes, we discuss the theoretical foundations of IR conformality, and present possible ways to study the problem using the lattice formulation of gauge theories. An overview of current results and methods is discussed. © 2014 World Scientific Publishing Company.

Hobley L.,University of Dundee | Harkins C.,University of Dundee | MacPhee C.E.,University of Edinburgh | Stanley-Wall N.R.,University of Dundee
FEMS Microbiology Reviews | Year: 2015

Biofilms are communities of microbial cells that underpin diverse processes including sewage bioremediation, plant growth promotion, chronic infections and industrial biofouling. The cells resident in the biofilm are encased within a self-produced exopolymeric matrix that commonly comprises lipids, proteins that frequently exhibit amyloid-like properties, eDNA and exopolysaccharides. This matrix fulfils a variety of functions for the community, from providing structural rigidity and protection from the external environment to controlling gene regulation and nutrient adsorption. Critical to the development of novel strategies to control biofilm infections, or the capability to capitalize on the power of biofilm formation for industrial and biotechnological uses, is an in-depth knowledge of the biofilm matrix. This is with respect to the structure of the individual components, the nature of the interactions between the molecules and the three-dimensional spatial organization. We highlight recent advances in the understanding of the structural and functional role that carbohydrates and proteins play within the biofilm matrix to provide three-dimensional architectural integrity and functionality to the biofilm community. We highlight, where relevant, experimental techniques that are allowing the boundaries of our understanding of the biofilm matrix to be extended using Escherichia coli, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis as exemplars. © FEMS 2015. All rights reserved.

Hedge J.,University of Edinburgh
Biology letters | Year: 2013

Early characterization of the epidemiology and evolution of a pandemic is essential for determining the most appropriate interventions. During the 2009 H1N1 influenza A pandemic, public databases facilitated widespread sharing of genetic sequence data from the outset. We use Bayesian phylogenetics to simulate real-time estimates of the evolutionary rate, date of emergence and intrinsic growth rate (r0) of the pandemic from whole-genome sequences. We investigate the effects of temporal range of sampling and dataset size on the precision and accuracy of parameter estimation. Parameters can be accurately estimated as early as two months after the first reported case, from 100 genomes and the choice of growth model is important for accurate estimation of r0. This demonstrates the utility of simple coalescent models to rapidly inform intervention strategies during a pandemic.

Essery R.,University of Edinburgh
Geophysical Research Letters | Year: 2013

Comparisons between climate models have found large differences in predictions for the albedo of forested regions with snow cover, leading to uncertainty in the strength of snow albedo feedbacks on climate change predicted by these models. To explore this uncertainty, three commonly used methods for calculating the albedo of vegetated surfaces are compared, taking observed snow and vegetation distributions as inputs. Surprisingly, all three methods produce similar results and compare reasonably well with observations over seasonally snow-covered regions of the Northern Hemisphere. It appears that some climate models use unrealistic parameter values, and snow albedo masking need not be as large a source of uncertainty as it is in current climate projections. Key Points Climate model comparisons have shown wide range in albedo of snow-covered forest Models of widely differing complexity can compare well with albedo observations Good land cover data required, and optimal model parameters depend on data used ©2013 The Authors. Geophysical Research Letters published by Wiley on behalf of the American Geophysical Union.

Ness R.W.,University of Edinburgh
G3 (Bethesda, Md.) | Year: 2012

Although the brown rat (Rattus norvegicus) is widely used as a model mammal throughout biological sciences, little is known about genetic variation in wild rat populations or the relationship of commonly used inbred strains to their wild relatives. We sampled wild brown rats from the species' presumed ancestral range in NW China and from a derived population in the UK and estimated nucleotide diversity and population subdivision, based on the sequences of 30 autosomal protein-coding loci. Neutral genetic diversity was close to 0.2% in both populations, which is about five times lower than diversity at the orthologous sites in a population of wild house mice from the species' putative ancestral range in India. We found significant population differentiation between UK and Chinese populations, as assessed by F(st) and the program STRUCTURE. Based on synonymous diversity and divergence between the brown rat and house mouse, we estimate that the recent effective population size in brown rats is approximately 130,000 (approximate 95% confidence interval 85,000-184,000), about fivefold lower than wild house mice.

I review theoretical models for the evolution of supergenes in the cases of Batesian mimicry in butterflies, distylous plants and sex chromosomes. For each of these systems, I outline the genetic evidence that led to the proposal that they involve multiple genes that interact during 'complex adaptations', and at which the mutations involved are not unconditionally advantageous, but show advantages that trade-off against some disadvantages. I describe recent molecular genetic studies of these systems and questions they raise about the evolution of suppressed recombination. Nonrecombining regions of sex chromosomes have long been known, but it is not yet fully understood why recombination suppression repeatedly evolved in systems in distantly related taxa, but does not always evolve. Recent studies of distylous plants are tending to support the existence of recombination-suppressed genome regions, which may include modest numbers of genes and resemble recently evolved sex-linked regions. For Batesian mimicry, however, molecular genetic work in two butterfly species suggests a new supergene scenario, with a single gene mutating to produce initial adaptive phenotypes, perhaps followed by modifiers specifically refining and perfecting the new phenotype. © 2016 John Wiley & Sons Ltd.

Chapman B.P.,University of Edinburgh
Medical Care | Year: 2015

BACKGROUND:: Predicting risk of premature death is one of the most basic tasks in medicine and public health, but has proven to be difficult over the long term even with the best prognostic models. One popular strategy has been to improve prognostic models with candidate genes and other novel biomarkers. However, the gains in predictive power have been modest and the costs have been high, leading to a demand for cost-effective alternatives. We conducted a proof-of-principle investigation to examine whether simple, cheap, and noninvasive paper-and-pencil measures of social class and personality phenotype could improve the performance of one of the most widely used prediction models for all-cause mortality, the Charlson Comorbidity Index (CCI). METHODS:: We used data from baseline and 25-year mortality follow-up of the UK Health and Lifestyle Study cohort. In a subset of the cohort, we first identified 5 psychosocial factors highly predictive of mortality: income, education, type A personality, communalism (preference for the company of others), and “lie” scale (a measure of denial, putatively associated with ill health). We then examined the predictive performance of the CCI with and without these measures in a validation subsample. RESULTS:: Across 5-, 10-, 15-, 20-, and 25-year time horizons, the psychosocially augmented CCI showed substantially better discrimination [area under the receiver-operating curves (95% confidence interval) from 0.83 (0.81–0.85) to 0.84 (0.83–0.86)] than the CCI [area under the receiver-operating curves from 0.74 (0.71–0.76) to 0.77 (0.76–0.79)]. These translated into net reclassification improvements from 27% (23%–31%) to 35% (32%–38%) of survivors and from 23% (17%–30%) to 34% (17%–30%) of decedents; and 23%–42% reductions in the Number Needed to Screen. Calibration improved at all time horizons except 25 years, where it was decreased. CONCLUSION:: Widespread attempts to improve prognostic models might consider not only novel biomarkers, but also psychosocial questionnaire measures. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Walker A.R.,University of Edinburgh
Parasitology | Year: 2011

Comparisons of successful and failed attempts to eradicate livestock ticks reveal that the social context of farming and management of the campaigns have greater influence than techniques of treatment. The biology of ticks is considered principally where it has contributed to control of ticks as practiced on farms. The timing of treatments by life cycle and season can be exploited to reduce numbers of treatments per year. Pastures can be managed to starve and desiccate vulnerable larvae questing on vegetation. Immunity to ticks acquired by hosts can be enhanced by livestock breeding. The aggregated distribution of ticks on hosts with poor immunity can be used to select animals for removal from the herd. Models of tick population dynamics required for predicting outcomes of control methods need better understanding of drivers of distribution, aggregation, stability, and density-dependent mortality. Changing social circumstances, especially of land-use, has an influence on exposure to tick-borne pathogens that can be exploited for disease control. © 2011 Cambridge University Press.

Jung H.,Yonsei University | Gkogkas C.G.,University of Edinburgh | Sonenberg N.,McGill University | Holt C.E.,University of Cambridge
Cell | Year: 2014

The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function. © 2014 The Authors.

Boswell C.,University of Edinburgh
British Journal of Politics and International Relations | Year: 2011

The dynamics of migration are incredibly complex, creating immense problems for governments attempting to steer immigration. These challenges are well elucidated in literature on societal steering, and especially Luhmann's analysis of the impediments to steering by the political and legal systems. Politics and the law develop highly simplifying models of the dynamics they are seeking to steer, resulting in various problems of distortion and counterproductive effects. We can see examples of this in the case of migration control, where attempts to prevent irregular labour or stay have led to numerous unintended effects. However, it is far from evident how such problems of steering can be addressed. A number of cognitive, social and political factors place pressure on policy-makers to adopt highly simplifying models of these processes. The implication is that policy interventions have a structural tendency to 'short-circuit' the complexity of the migratory processes they are attempting to steer. © 2011 The Author. British Journal of Politics and International Relations © 2011 Political Studies Association.

Howell R.A.,University of Edinburgh
Global Environmental Change | Year: 2011

The film The Age of Stupid depicts the world in 2055 devastated by climate change, combining this with documentary footage which illustrates many facets of the problems of climate change and fossil-fuel dependency. This study investigates the effects of the film on UK viewers' attitudes and behaviour through a three-stage survey. Analysis of changes in attitudes focussed particularly on respondents' concern about climate change, motivation to act, fear about the potential for catastrophe, beliefs about responsibility for action, and sense of agency. The film increased concern about climate change, motivation to act, and viewers' sense of agency, although these effects had not persisted 10-14 weeks after seeing it. It was also successful in promoting some mitigation actions and behavioural change, although respondents reported barriers to further action, such as limited options for improving home energy efficiency among those in rented accommodation. However, filmgoers were atypical of the general public in that they exhibited very high levels of concern about climate change, knowledge about how to reduce their carbon emissions, and contact with organisations campaigning about climate change, before they saw the film. The paper considers how these factors may have enabled viewers to respond to the film as they did, as well as policy implications for those seeking to develop effective climate change communications. © 2010 Elsevier Ltd.

Nightingale A.J.,University of Edinburgh
Society and Natural Resources | Year: 2011

Common property debates are dominated by approaches that seek to demonstrate how cooperation is "rational"; by working together under appropriate institutions, the commons becomes a viable management strategy. This article seeks to expand the commons debate by arguing that more attention is needed on the emotional and "ir-rational" reasons people cooperate. Drawing from feminist theory, subjectivity, and power, I explore how subjectivity is bound up in kinship and community obligations, such that people draw from alternative rationalities to develop informal modes of cooperation. These affective relations are important for people's willingness (or not) to cooperate in more organized contexts, demonstrating the importance of thinking about gender, community, and space as productive of subjectivity, rather than roles or structures in order to understand how particular forms of cooperation emerge. The result is a new understanding of cooperation that incorporates new feminist research on emotion and subjectivity with institutional studies. © 2011 Taylor & Francis Group, LLC.

Gastrointestinal nematode parasitism is the most important disease affecting livestock production systems in developing countries, particularly small ruminant production systems. Of particular importance are infections with the strongyle Haemonchus contortus. Integrated disease control strategies are required, including improved management, nutrition and wise use of anthelmintic chemicals. Increasingly, selection of sheep or goats for improved nematode resistance is viewed as a valuable option to complement other control measures. Breeding for resistance is possible because of the existence of extensive genetic variation in resistance, both within and between breeds of sheep and goats. Such breeding schemes are most likely to be based on choice of appropriate breeds adapted to the local environmental conditions, followed by phenotypic selection for resistance. Goal and selection objective traits are likely to include performance (e.g. growth rate) under conditions of parasite challenge, faecal egg count (FEC) and measures of anaemia. With current technologies, genetic markers are likely to be too expensive and logistically difficult to incorporate into breeding schemes in tropical or developing countries. Genotype by environment interactions may be expected, particularly when comparing animals in environments that differ in the extent of parasite challenge or differ in the quality of available nutrition. However, there is no reason to expect antagonistic genetic relationships between performance and resistance, and selection indices should be readily constructed that improve both performance and resistance. If FEC is decreased, then pasture contamination should also decrease, leading to additional benefits for all sheep grazing the same pasture. Finally, breeding for nematode resistance should lead to lasting and sustained improvements in resistance or tolerance. There is no empirical evidence to suggest that nematodes will evolve rapidly in response to resistant hosts, and mathematical models based on genetic and biological principles also suggest that resistance should be sustainable. © 2011 The Animal Consortium.

MacDonald F.,University of Edinburgh
Environment and Planning D: Society and Space | Year: 2011

Amid a resurgence of interest in histories of scientific fieldwork and in the geographies of the Cold War, this paper presents a comparative history of field practice across the distinct epistemic traditions of geography, archaeology, and folklore. The paper follows the intellectual practices of three research teams attempting to 'rescue' Gaelic culture from the development of a missile-testing station in the Scottish Hebrides. The aims of the paper are fivefold: to extend insights from the histories of scientific fieldwork to understand the production of social knowledge, to consider the coconstitution of fieldwork and the region, to expand recent histories of geography in the mid-20th century, to draw out the lingering significance of the 'salvage paradigm' in geography and other social sciences, and to reconceptualise this salvage fieldwork as a way of constructing social life as much as rescuing it.

Charlesworth D.,University of Edinburgh
New Phytologist | Year: 2015

A minority of angiosperms have male and female flowers separated in distinct individuals (dioecy), and most dioecious plants do not have cytologically different (heteromorphic) sex chromosomes. Plants nevertheless have several advantages for the study of sex chromosome evolution, as genetic sex determination has evolved repeatedly and is often absent in close relatives. I review sex-determining regions in non-model plant species, which may help us to understand when and how (and, potentially, test hypotheses about why) recombination suppression evolves within young sex chromosomes. I emphasize high-throughput sequencing approaches that are increasingly being applied to plants to test for non-recombining regions. These data are particularly illuminating when combined with sequence data that allow phylogenetic analyses, and estimates of when these regions evolved. Together with comparative genetic mapping, this has revealed that sex-determining loci and sex-linked regions evolved independently in many plant lineages, sometimes in closely related dioecious species, and often within the past few million years. In reviewing recent progress, I suggest areas for future work, such as the use of phylogenies to allow the informed choice of outgroup species suitable for inferring the directions of changes, including testing whether Y chromosome-like regions are undergoing genetic degeneration, a predicted consequence of losing recombination. © 2015 New Phytologist Trust.

Children's perspectives literature repositions children and young people as active participants in surviving domestic abuse, protecting their family, opposing the violence and recovering from abuse. However, key tenets of safeguarding in relation to domestic abuse, both in practice and childhood research ethics, struggle to fully recognise children's agency and the need to empower children and young people as well as women. Children's right to participation now extends to national policy-making in many countries, yet has not been explored in relation to the interdependency of women and children's rights, safety and wellbeing where both have been subject to abuse. This paper challenges the current exclusion of young voices from the development of ethical praxis. It outlines a participatory ethical approach that promotes the inclusion and empowerment of young survivors in research and policy. Young expert advisors on Scottish domestic abuse policy (2009-11) co-develop the approach (participatory action research) which is informed by a wider study (2004-11) about children's help-seeking and solutions for practice. Mullender et al.'s accepted model of three Cs and Ds (consent, confidentiality, child protection: danger, distress, disclosure) are adapted to focus on children's agency. Three Es are added focusing on children's power and impact: enjoyment, empowerment and emancipation. © 2015 John Wiley & Sons, Ltd.

Morris N.J.,University of Edinburgh
Cultural Geographies | Year: 2011

Human sensory orders are recalibrated when faced with the reduced illumination levels of the night; it is harder to judge depth and distance, details are obscured, colours muted, and one is obliged to compensate for this loss of visual acuity by drawing on the other senses. Darkness also forces one to question how one's body is in relation to that which surrounds, challenging one's human sense of bodily presence and boundary. Focusing on The Storr: Unfolding Landscape, a temporary night-time installation by the environmental arts charity NVA (Nacionale Vite Activa) on the Isle of Skye in 2005, this article draws together contemporary art theory on installation art and recent post-phenomenological work in geography to explore the ways in which individuals experience the nocturnal landscape. In so doing, the article highlights the close connections between these two bodies of work and how they might be usefully employed to advance traditional geographical understandings of landscape in art. At the same time, however, it raises both an empirical concern and a methodological question. First, regarding the uncritical way in which visibility is incorporated into many post-phenomenological accounts of landscape. Second, regarding the validity of focusing on isolated narratives in instances such as this when so much of what the individuals experienced was caused by, or shared with, others. © The Author(s) 2011.

Saunders D.H.,University of Edinburgh
The Cochrane database of systematic reviews | Year: 2013

Levels of physical fitness are low after stroke. It is unknown whether improving physical fitness after stroke reduces disability. To determine whether fitness training after stroke reduces death, dependence, and disability. The secondary aims were to determine the effects of training on physical fitness, mobility, physical function, quality of life, mood, and incidence of adverse events. We searched the Cochrane Stroke Group Trials Register (last searched January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12: searched January 2013), MEDLINE (1966 to January 2013), EMBASE (1980 to January 2013), CINAHL (1982 to January 2013), SPORTDiscus (1949 to January 2013), and five additional databases (January 2013). We also searched ongoing trials registers, handsearched relevant journals and conference proceedings, screened reference lists, and contacted experts in the field. Randomised trials comparing either cardiorespiratory training or resistance training, or both, with no intervention, a non-exercise intervention, or usual care in stroke survivors. Two review authors independently selected trials, assessed quality, and extracted data. We analysed data using random-effects meta-analyses. Diverse outcome measures limited the intended analyses. We included 45 trials, involving 2188 participants, which comprised cardiorespiratory (22 trials, 995 participants), resistance (eight trials, 275 participants), and mixed training interventions (15 trials, 918 participants). Nine deaths occurred before the end of the intervention and a further seven at the end of follow-up. No dependence data were reported. Diverse outcome measures made data pooling difficult. Global indices of disability show a tendency to improve after cardiorespiratory training (standardised mean difference (SMD) 0.37, 95% confidence interval (CI) 0.10 to 0.64; P = 0.007); benefits at follow-up and after mixed training were unclear. There were insufficient data to assess the effects of resistance training.Cardiorespiratory training involving walking improved maximum walking speed (mean difference (MD) 7.37 metres per minute, 95% CI 3.70 to 11.03), preferred gait speed (MD 4.63 metres per minute, 95% CI 1.84 to 7.43), walking capacity (MD 26.99 metres per six minutes, 95% CI 9.13 to 44.84), and Berg Balance scores (MD 3.14, 95% CI 0.56 to 5.73) at the end of the intervention. Mixed training, involving walking, increased preferred walking speed (MD 4.54 metres per minute, 95% CI 0.95 to 8.14), walking capacity (MD 41.60 metres per six minutes, 95% CI 25.25 to 57.95), and also pooled balance scores but the evidence is weaker (SMD 0.26 95% CI 0.04 to, 0.49). Some mobility benefits also persisted at the end of follow-up. The variability and trial quality hampered the assessment of the reliability and generalisability of the observed results. The effects of training on death and dependence after stroke are unclear. Cardiorespiratory training reduces disability after stroke and this may be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programs to improve the speed and tolerance of walking; improvement in balance may also occur. There is insufficient evidence to support the use of resistance training. Further well-designed trials are needed to determine the optimal content of the exercise prescription and identify long-term benefits.

Wardlaw J.M.,University of Edinburgh
The Cochrane database of systematic reviews | Year: 2013

Stroke is a leading cause of death and disability world wide. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is licensed for treatment of acute ischaemic stroke in the early hours after symptom onset. It has been shown in randomised controlled trials (RCTs) and the 2009 Cochrane review of thrombolysis for acute ischaemic stroke to reduce dependency but at the increased risk of intracranial haemorrhage. Methods to reduce the risk of haemorrhage while retaining or enhancing the benefit could increase the use of thrombolytic treatment. While most available information comes from RCTs of intravenous rt-PA at 0.9 mg/kg, it is possible that other doses, drugs and other routes of administration might increase benefit and reduce the hazard. To assess the risks and benefits of different thrombolytic agents, doses and routes of administration for the treatment of acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (May 2012), MEDLINE (1966 to May 2012) and EMBASE (1980 to May 2012). We handsearched journals and conference proceedings, searched ongoing trials registers and contacted pharmaceutical companies and researchers. Unconfounded randomised and quasi-randomised trials of different doses of a thrombolytic agent, or different agents, or the same agent given by different routes, in people with confirmed acute ischaemic stroke. Two review authors independently assessed trial eligibility and quality, and extracted the data using a structured proforma. We cross-checked and resolved discrepancies by discussion to reach consensus. We obtained translations and additional information from study authors where required. We included 20 trials involving 2527 patients. Concealment of allocation was poorly described. Different doses (of tissue plasminogen activator, urokinase, desmoteplase or tenecteplase) were compared in 13 trials (N = 1433 patients). Different agents (tissue plasminogen activator versus urokinase, tissue-cultured urokinase versus conventional urokinase, tenecteplase versus tissue plasminogen activator) were compared in five trials (N = 875 patients). Five trials (N = 485) compared different routes of administration. As some trials compared different agents and different doses, some patients contributed to two analyses. There was an approximately three-fold increase in fatal intracranial haemorrhages in patients allocated to higher than to lower doses of the same thrombolytic drug (odds ratio (OR) 2.71, 95% confidence interval (CI) 1.22 to 6.04). There was no difference in the number of patients who were dead or dependent at the end of follow-up between those allocated higher or lower doses of thrombolytic drug (OR 0.86, 95% CI 0.62 to 1.19). Higher versus lower doses of desmoteplase were associated with more deaths at the end of follow-up (OR 3.21, 95% CI 1.23 to 8.39). There was no evidence of any benefit for intra-arterial over intravenous treatment. These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.

Pickersgill M.,University of Edinburgh
Sociology of Health and Illness | Year: 2011

Neuroscientific research into mental health commands generous funding, suggesting neuroscience is understood by a variety of actors and institutions as having significant potential to enhance the therapeutic practices of psychiatrists. This article interrogates this 'therapeutic promise' of neuroscience through the case study of the psychiatric condition personality disorder. Specifically, the focus is on the promissory discourse of clinicians specialising in the management of two variants of personality disorder - antisocial personality disorder and psychopathy - and researchers investigating the neurobiology of these constructs. The article discusses the respondents' ambivalent expectations regarding the therapeutic promise of brain research, and shows how these are structured by understandings of the ontology of personality disorder. In turn, these ambivalences direct our attention to practical issues surrounding the potential of neuroscience to translate into and enhance clinical practice, as well as theoretical concerns revolving around the place and role of the biological within contemporary neuroscience, psychiatry and psychology. In sum, the necessity of large material and symbolic investments in neuroscience should, perhaps, be reflected upon more critically, and analytic encounters with this discipline must keep in mind it's at times surprising commitment to the realms of the social and the psychological. © 2011 The Authors. Sociology of Health & Illness © 2011 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.

Marshall I.,University of Edinburgh
Journal of Magnetic Resonance Imaging | Year: 2010

Purpose: To evaluate the use of computational fluid dynamic (CFD)-based magnetic resonance imaging (MRI) simulations to predict the image appearance and velocity measurement of fluid flow in human carotid bifurcation geometries, and to compare the results with images from experimental MRI studies. Materials and Methods: Simulated particle paths were calculated from available CFD datasets of normal and moderately stenosed carotid bifurcation geometries. An MRI simulator based on the spin isochromat method was used to generate images corresponding to a 3D phasecontrast sequence with velocity encoding in three orthogonal directions. The resulting images were compared qualitatively with experimental MRI scans of the corresponding physical models. Results: The simulations predicted the main features observed in experimental studies, such as the low image intensity in regions of complex flow and the position and bright appearance of the jet in the stenosed bifurcation. Simulated velocity images also agreed well with experimental results. The effects of sequence parameters such as repetition time (TR) and echo time (TE) were readily demonstrated by the simulations. Conclusion: CFD-based MRI simulations can be used to predict the appearance of MRI images of regions of physiological flow, and may be useful in the development of improved pulse sequences for flow measurement. © 2010 Wiley-Liss, Inc.

Campbell A.,University of Edinburgh
The Cochrane database of systematic reviews | Year: 2013

Omega-3 fatty acids have been used in the treatment and prevention of coronary artery disease although current evidence suggests they may be of limited benefit. Peripheral arterial disease and coronary artery disease share a similar pathogenesis so omega-3 fatty acids may have a similar effect on both conditions. This is an update of a review first published in 2004 and updated in 2007. To determine the clinical and haematological effects of omega-3 supplementation in people with intermittent claudication. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched September 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9). Randomised controlled trials of omega-3 fatty acids versus placebo or non-omega-3 fatty acids in people with intermittent claudication. One review author identified potential trials. Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information if necessary. Nine studies were included representing 425 participants. All studies compared omega-3 fatty acid supplementation with placebo lasting from four weeks to two years. Three studies with long treatment periods administered additional substances, making any observed effects impossible to attribute to omega-3 fatty acids and were excluded from the statistical analyses. One study did not express any mean values and, therefore, could not be included in statistical analyses.No significant differences between intervention and control groups were observed in pain-free walking distance (mean difference (MD) 11.62 m, 95% confidence interval (CI) -67.74 to 90.98), maximal walking distance (MD 16.99 m, 95% CI -72.14 to 106.11), ankle brachial pressure index (MD -0.02, 95% CI -0.09 to 0.05), total cholesterol levels (MD 0.27 mmol/L, 95% CI -0.48 to 1.01), high-density lipoprotein cholesterol levels (MD 0.00 mmol/L, 95% CI -0.16 to 0.15), low-density lipoprotein cholesterol levels (MD 0.44 mmol/L, 95% CI -0.31 to 1.19), triglyceride levels (MD -0.39 mmol/L, 95% CI -1.10 to 0.33), systolic blood pressure (MD 5.00 mmHg, 95% CI -11.59 to 21.59) or plasma viscosity (MD 0.03 mPa/s, 95% CI -0.02 to 0.08).There was some limited evidence that blood but not plasma viscosity levels decreased with treatment and gastrointestinal side effects such as nausea, diarrhoea and flatulence were observed in two studies. Omega-3 fatty acids appear to have little haematological benefit in people with intermittent claudication and there is no evidence of consistently improved clinical outcomes (quality of life, walking distance, ankle brachial pressure index or angiographic findings). Supplementation may also cause adverse effects such as nausea, diarrhoea and flatulence. Further research is needed to evaluate fully short- and long-term effects of omega-3 fatty acids on the most clinically relevant outcomes in people with intermittent claudication before they can be recommended for routine use.

Sharp P.M.,University of Edinburgh
Cold Spring Harbor perspectives in medicine | Year: 2011

Acquired immunodeficiency syndrome (AIDS) of humans is caused by two lentiviruses, human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2). Here, we describe the origins and evolution of these viruses, and the circumstances that led to the AIDS pandemic. Both HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M-the principal cause of the AIDS pandemic. We discuss how host restriction factors have shaped the emergence of new SIV zoonoses by imposing adaptive hurdles to cross-species transmission and/or secondary spread. We also show that AIDS has likely afflicted chimpanzees long before the emergence of HIV. Tracing the genetic changes that occurred as SIVs crossed from monkeys to apes and from apes to humans provides a new framework to examine the requirements of successful host switches and to gauge future zoonotic risk.

Wardlaw J.M.,University of Edinburgh
Journal of the Neurological Sciences | Year: 2010

Increasing evidence from neuro and retinal imaging, neuropathology, epidemiology and experimental models suggests that the primary underlying initiating cause of cerebral small vessel disease is the derangement of the blood-brain barrier. This may start some years before the first symptoms, leads to the small vessel structural changes (vessel wall thickening, disorganisation and eventual breakdown) and perivascular changes (oedema, enlarged perivascular spaces, tissue damage interpreted as "infarcts") and is fundamentally different to traditional "ischaemic" mechanisms, although small vessel occlusion due to thrombus formation on damaged vessel walls may be a late secondary phenomenon. Space limits a detailed discussion of the epidemiology and experimental evidence, so this brief review will focus on neuroimaging evidence and summarise the appearances, risk factors and associations of different components of cerebral small vessel disease as identified on imaging, discuss potential causes and, in particular, the evidence that disordered blood-brain barrier precipitates or worsens progression of cerebral small vessel disease. This mechanism may also play a role in other common disorders of ageing such as Alzheimer's disease. © 2010 Elsevier B.V. All rights reserved.

Bednar J.A.,University of Edinburgh
Journal of Physiology Paris | Year: 2012

Researchers have used a very wide range of different experimental and theoretical approaches to help understand mammalian visual systems. These approaches tend to have quite different assumptions, strengths, and weaknesses. Computational models of the visual cortex, in particular, have typically implemented either a proposed circuit for part of the visual cortex of the adult, assuming a very specific wiring pattern based on findings from adults, or else attempted to explain the long-term development of a visual cortex region from an initially undifferentiated starting point. Previous models of adult V1 have been able to account for many of the measured properties of V1 neurons, while not explaining how these properties arise or why neurons have those properties in particular. Previous developmental models have been able to reproduce the overall organization of specific feature maps in V1, such as orientation maps, but are generally formulated at an abstract level that does not allow testing with real images or analysis of detailed neural properties relevant for visual function. In this review of results from a large set of new, integrative models developed from shared principles and a set of shared software components, I show how these models now represent a single, consistent explanation for a wide body of experimental evidence, and form a compact hypothesis for much of the development and behavior of neurons in the visual cortex. The models are the first developmental models with wiring consistent with V1, the first to have realistic behavior with respect to visual contrast, and the first to include all of the demonstrated visual feature dimensions. The goal is to have a comprehensive explanation for why V1 is wired as it is in the adult, and how that circuitry leads to the observed behavior of the neurons during visual tasks. © 2012.

Heggie D.C.,University of Edinburgh
Monthly Notices of the Royal Astronomical Society | Year: 2014

This paper describes an N-body model for the dynamical evolution of the nearby globular cluster M4. The initial conditions,with N=484 710 particles, were generated from a published study of this cluster with a Monte Carlo code. With the Monte Carlo code, these initial conditions led, after 12 Gyr of dynamical and stellar evolution, to a model which resembles M4 in terms of its surface brightness and velocity dispersion profiles, and its local luminosity function. Though the N-body model reported here is marred by some errors, its evolution can be compared with that of the published Monte Carlo model, with a result from the synthetic evolution code EMACSS, and with M4 itself. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Millar A.J.,University of Edinburgh
Annual Review of Plant Biology | Year: 2016

A major challenge for biology is to extend our understanding of molecular regulation from the simplified conditions of the laboratory to ecologically relevant environments. Tractable examples are essential to make these connections for complex, pleiotropic regulators and, to go further, to link relevant genome sequences to field traits. Here, I review the case for the biological clock in higher plants. The gene network of the circadian clock drives pervasive, 24-hour rhythms in metabolism, behavior, and physiology across the eukaryotes and in some prokaryotes. In plants, the scope of chronobiology is now extending from the most tractable, intracellular readouts to the clock's many effects at the whole-organism level and across the life cycle, including biomass and flowering. I discuss five research areas where recent progress might be integrated in the future, to understand not only circadian functions in natural conditions but also the evolution of the clock's molecular mechanisms. Copyright © 2016 by Annual Reviews. All rights reserved.

Harkin D.M.,University of Edinburgh
Theoretical Criminology | Year: 2015

This article argues that police studies should draw on the sociology of punishment to better understand state pain-delivery. Whereas penal theorists commonly assess the pain and punishment of inmates in relation to wider social sentiments, police theory has yet to regard police violence and harm in the same fashion. As a result, police scholars often fail to address why the damage caused by public constabularies, even when widely publicized, is accommodated and accepted. Adapting the idea of ‘punitiveness’ from penal theory allows some explanation of how the public views injury and suffering caused by the police by illuminating the emotions and sentiments their actions generate. © The Author(s) 2014.

Morling J.R.,University of Edinburgh
The Cochrane database of systematic reviews | Year: 2013

Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. To determine the effectiveness and safety of rutosides for treatment of PTS in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9). Clinical trials databases were searched for details of ongoing and unpublished studies. Two authors (JM and DNK) independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two authors (JM and SEY) extracted information from the trials. Disagreements were resolved by discussion. Data were extracted using designated data extraction forms. The Cochrane risk of bias tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of deep venous thrombosis or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. One study compared rutoside with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was a 29% odds of an improvement in PTS in the rutoside treated group versus placebo or no treatment, and lower rates of improvement in PTS in the rutoside treated group when compared with ECS, however these were statistically non-significant. Lower rates of improvement in PTS were shown in the rutoside treated group when compared with an alternative venoactive remedy. More PTS deterioration was shown in the placebo or no treatment group when compared with rutosides but this was not statistically significant. Compared with ECS, rutosides showed higher odds of PTS deterioration but this was also not statistically significant. One study reported on adverse effects showing higher odds of mild adverse effects in the rutoside treated group compared to placebo but this was not statistically significant. There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence for the use of rutosides in the treatment of PTS.

Essery R.,University of Edinburgh
Geoscientific Model Development | Year: 2015

A model for the coupled mass and energy balances of snow on the ground requires representations of absorption of solar radiation by snow, heat conduction in snow, compaction of snow, transfer of heat to snow from the air and retention and refreezing of meltwater in snow. Many such models exist, but it has proven hard to relate their relative performances to the complexity of their process representations. This paper describes the systematic development of an open-source snowpack model with two levels of representation for each of the five processes mentioned above, allowing factorial experimental designs with 32 different model configurations. The model is demonstrated using driving and evaluation data recorded over one winter at an alpine site. © 2015 Author(s).

Cates M.E.,University of Edinburgh | Tailleur J.,University Paris Diderot
Annual Review of Condensed Matter Physics | Year: 2015

Self-propelled particles include both self-phoretic synthetic colloids and various microorganisms. By continually consuming energy, they bypass the laws of equilibrium thermodynamics. These laws enforce the Boltzmann distribution in thermal equilibrium: The steady state is then independent of kinetic parameters. In contrast, self-propelled particles tend to accumulate where they move more slowly. They may also slow down at high density for either biochemical or steric reasons. This creates positive feedback, which can lead to motility-induced phase separation (MIPS) between dense and dilute fluid phases. At leading order in gradients, a mapping relates variable-speed, self-propelled particles to passive particles with attractions. This deep link to equilibrium phase separation is confirmed by simulations but generally breaks down at higher order in gradients: New effects, with no equilibrium counterpart, then emerge. We give a selective overview of the fast-developing field of MIPS, focusing on theory and simulation but including a brief speculative survey of its experimental implications. © 2015 by Annual Reviews.

Heal M.R.,University of Edinburgh
Analytical and Bioanalytical Chemistry | Year: 2013

Organic carbon (OC) and elemental carbon (EC) together constitute a substantial proportion of airborne particulate matter (PM). Insight into the sources of this major contributor to PM is important for policies to mitigate the impact of PM on human health and climate change. In recent years measurement of the abundance of the radioisotope of carbon (14C) in samples of PMby accelerator mass spectrometry has been used to help quantify the relative contributions from sources of fossil carbon and contemporary carbon. This review provides an introduction to the different sources of carbon within PM and the role of 14C measurements, a description of the preparation of PM samples and of the instrumentation used to quantify 14C, and a summary of the results and source apportionment methods reported in published studies since 2004. All studies report a sizable fraction of the carbonaceous PM as of non-fossil origin. Even for PM collected in urban locations, the proportions of non-fossil carbon generally exceed 30 %; typically the proportion in urban background locations is around 40-60 % depending on the local influence of biomass burning. Where values have been measured directly, proportions of non-fossil carbon in EC are lower than in OC, reflecting the greater contribution of fossilfuel combustion to EC and the generally small sources of contemporary EC. Detailed source apportionment studies point to important contributions from biogenic-derived secondary OC, consistent with other evidence of a ubiquitous presence of heavily oxidized background secondary OC. The review concludes with some comments on current issues and future prospects, including progress towards compound-class and individual-compound- specific 14C analyses. © Springer-Verlag Berlin Heidelberg 2013.

Fearon K.C.H.,University of Edinburgh | Glass D.J.,Novartis | Guttridge D.C.,Ohio State University
Cell Metabolism | Year: 2012

Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. © 2012 Elsevier Inc.

Dostie J.,McGill University | Bickmore W.A.,University of Edinburgh
Current Opinion in Genetics and Development | Year: 2012

For more than a century, developments in light microscopy drove forward our understanding of how chromosomes are organized in the cell nucleus. Now, derivatives of the chromosome conformation capture (3C) technique have harnessed the power of molecular biology to provide more genome-wide perspectives on the spatial relationships of DNA sequences, both within and between chromosomes. Here we consider what new insights into chromosome territory organization and mechanisms of gene regulation these innovative tools are providing, and the extent to which the visual and the molecular approaches give consistent or differing views of chromosome territory organization. © 2012 Elsevier Ltd.

Deary I.J.,University of Edinburgh
Gerontology | Year: 2012

Background: In the last decade, an increasing body of empirical evidence has gathered to establish an association between higher cognitive ability in youth and later mortality, less morbidity and better health. This field of research is known as cognitive epidemiology. The causes of these associations are not understood. Objective: Among the possible explanations for the associations is the suggestion that they might, in part, be accounted for by general bodily 'system integrity'. That is, scoring well on cognitive ability tests might be an indicator of a more general tendency for complex systems in the body to be efficient. The construct of system integrity is critically assessed. Method: This viewpoint provides a critical presentation and an empirical and theoretical evaluation of the construct of system integrity as it is used in cognitive epidemiology. Results: A precedent of the system integrity suggestion is discovered. The empirical tests of the system integrity idea to date are critically evaluated. Other possible routes to testing system integrity are suggested. There is a critical re-evaluation of the idea and other, related concepts. Conclusion: The construct of system integrity is distinct from related constructs. It is still underdeveloped theoretically, and undertested empirically within cognitive epidemiology. Copyright © 2012 S. Karger AG, Basel.

Shah P.J.,University of Edinburgh | Morton M.J.S.,Royal Hospital for Sick Children
British Journal of Psychiatry | Year: 2013

Attention-deficit hyperactivity disorder in adults evokes extreme responses within British psychiatrists, because its diagnostic validity and pharmacological treatments are heavily contested. We propose a model that accommodates apparently divergent evidence, and provides a clinical framework for clinicians and patients, allowing safe, responsible and ethically balanced clinical practice.

Rao D.N.,Indian Institute of Science | Rao D.N.,University of Edinburgh | Dryden D.T.F.,Indian Institute of Science | Bheemanaik S.,Indian Institute of Science
Nucleic Acids Research | Year: 2014

Restriction endonucleases interact with DNA at specific sites leading to cleavage of DNA. Bacterial DNA is protected from restriction endonuclease cleavage by modifying the DNA using a DNA methyltransferase. Based on their molecular structure, sequence recognition, cleavage position and cofactor requirements, restriction-modification (R-M) systems are classified into four groups. Type III R-M enzymes need to interact with two separate unmethylated DNA sequences in inversely repeated head-to-head orientations for efficient cleavage to occur at a defined location (25-27 bp downstream of one of the recognition sites). Like the Type I R-M enzymes, Type III R-M enzymes possess a sequence-specific ATPase activity for DNA cleavage. ATP hydrolysis is required for the long-distance communication between the sites before cleavage. Different models, based on 1D diffusion and/or 3D-DNA looping, exist to explain how the long-distance interaction between the two recognition sites takes place. Type III R-M systems are found in most sequenced bacteria. Genome sequencing of many pathogenic bacteria also shows the presence of a number of phase-variable Type III R-M systems, which play a role in virulence. A growing number of these enzymes are being subjected to biochemical and genetic studies, which, when combined with ongoing structural analyses, promise to provide details for mechanisms of DNA recognition and catalysis. © The Author(s) 2013. Published by Oxford University Press.

Dransfield I.,University of Edinburgh
Blood | Year: 2014

In this issue of Blood, Vaughan et al demonstrate that certain antibodies that are used therapeutically in lymphoma treatment (eg, rituximab) undergo Fcg receptor IIb (FcgRIIb)-mediated internalization from the B-cell surface in a manner that is independent of activation of FcgRIIb with important implications for the design of antibody-based therapeutics (see figure). © 2014 by The American Society of Hematology.

Rees J.L.,University of Edinburgh | Harding R.M.,University of Oxford
Journal of Investigative Dermatology | Year: 2012

Variation in human skin and hair color is one of the most striking aspects of human variability, and explaining this diversity is one of the central questions of human biology. Only in the last decade or so has it been realistically possible to address this question experimentally using population genetic approaches. On the basis of earlier studies in mice, and on studies in humans with various Mendelian disorders, many of the genes underpinning population variation in skin color have been identified. More recently, genome-wide approaches have identified other loci that appear to contribute to pigmentary variation. The ability to study sequence diversity from world populations has allowed examination of whether the observed variability is due to random genetic drift or is a result of natural selection. The genetic evidence taken as a whole provides strong evidence for natural selection, functioning so as to increase pigment diversity across the world's populations. Future larger studies are likely to provide more details of this process and may provide evidence for exactly which mechanistic pathways have mediated selection. © 2012 The Society for Investigative Dermatology.

Keightley P.D.,University of Edinburgh
Genetics | Year: 2012

The human mutation rate per nucleotide site per generation (m) can be estimated from data on mutation rates at loci causing Mendelian genetic disease, by comparing putatively neutrally evolving nucleotide sequences between humans and chimpanzees and by comparing the genome sequences of relatives. Direct estimates from genome sequencing of relatives suggest that m is about 1.1 · 1028, which is about twofold lower than estimates based on the human-chimp divergence. This implies that an average of ~70 new mutations arise in the human diploid genome per generation. Most of these mutations are paternal in origin, but the male:female mutation rate ratio is currently uncertain and might vary even among individuals within a population. On the basis of a method proposed by Kondrashov and Crow, the genome-wide deleterious mutation rate (U) can be estimated from the product of the number of nucleotide sites in the genome, m, and the mean selective constraint per site. Although the presence of many weakly selected mutations in human noncoding DNA makes this approach somewhat problematic, estimates are U ≈ 2.2 for the whole diploid genome per generation and ~0.35 for mutations that change an amino acid of a protein-coding gene. A genome-wide deleterious mutation rate of 2.2 seems higher than humans could tolerate if natural selection is "hard," but could be tolerated if selection acts on relative fitness differences between individuals or if there is synergistic epistasis. I argue that in the foreseeable future, an accumulation of new deleterious mutations is unlikely to lead to a detectable decline in fitness of human populations. © 2012 by the Genetics Society of America.

Shipston M.J.,University of Edinburgh
Biochemical Society Transactions | Year: 2013

BK (large conductance calcium- and voltage-activated potassium) channels are important determinants of physiological control in the nervous, endocrine and vascular systems with channel dysfunction associated with major disorders ranging from epilepsy to hypertension and obesity. Thus the mechanisms that control channel surface expression and/or activity are important determinants of their (patho)physiological function. BK channels are S-acylated (palmitoylated) at two distinct sites within the N- and C-terminus of the pore-forming α-subunit. Palmitoylation of the N-terminus controls channel trafficking and surface expression whereas palmitoylation of the C-terminal domain determines regulation of channel activity by AGC-family protein kinases. Recent studies are beginning to reveal mechanistic insights into how palmitoylation controls channel trafficking and cross-talk with phosphorylation-dependent signalling pathways. Intriguingly, each site of palmitoylation is regulated by distinct zDHHCs (palmitoyl acyltransferases) and APTs (acyl thioesterases). This supports that different mechanisms may control substrate specificity by zDHHCs and APTs even within the same target protein. As palmitoylation is dynamically regulated, this fundamental post-translational modification represents an important determinant of BK channel physiology in health and disease. © 2013 Biochemical Society.

In 2005, Scotland became the first nation to make breastfeeding in public a legal right, but current breastfeeding targets and maternity leave allowance do not acknowledge the conflicting demands women face when juggling employment and motherhood. This paper explores how employment and maternity leave relate to breastfeeding duration among mothers in Scotland. The Growing Up in Scotland national longitudinal cohort study of 5,217 babies born in 2004-2005 was used. Multivariate proportional hazards regression models were specified using one cross-sectional wave of data to predict breastfeeding duration. Mothers working as employees, full-time (Hazard Ratio 1.6) or part-time (HR1.3), had a higher risk of earlier breastfeeding cessation than non-working mothers. However, self-employed mothers did not differ significantly from non-working mothers in their breastfeeding patterns. Mothers who took longer maternity leave breastfed for longer. The relationships between employment, maternity leave and breastfeeding duration were significant when controlling for known predictors of breastfeeding. Younger mothers, those with less formal education, single mothers, those of white ethnic background, and first-time mothers were more likely to stop breastfeeding sooner, as has been noted in previous research. Employment and early return to work are both factors associated with a shorter duration of breastfeeding. More flexible working conditions and more generous employment leave could help to prolong breastfeeding among working mothers. Current health and employment policy in Scotland and the UK could be better coordinated so that working mothers have the adequate support to meet the conflicting demands of employment and motherhood. © Springer Science+Business Media, LLC 2011.

Harley M.E.,University of Edinburgh
Nature Genetics | Year: 2015

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions. © 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Stone J.,University of Edinburgh | Edwards M.,University College London
Neurology | Year: 2012

Functional (psychogenic) motor symptoms are diagnosed on the basis of positive signs of inconsistency or incongruity with known neurologic disease. These signs, such as Hoover sign or tremor entrainment, are often regarded by neurologists as 'tricks of the trade,' to 'catch the patient out, ' and certainly not to be shared with them. In this reflective article, the authors suggest that showing the patient with functional motor symptoms their physical signs, if done in the right way, is actually one of the most useful things a neurologist can do for these patients in persuading them of the accuracy of their diagnosis and the potential reversibility of their symptoms. Copyright © 2012 by AAN Enterprises, Inc.

Jiang J.,Tongji University | Usmani A.,University of Edinburgh
Computers and Structures | Year: 2013

The OpenSees framework has been extended to deal with frame structures under fire conditions. OpenSees is an object-oriented, open source software framework developed at UC Berkeley and has so far been focused on providing an advanced computational tool for analyzing the non-linear response of structural frames subjected to seismic excitations. New classes defining time-dependent temperature distributions in the cross-section of members have been created and OpenSees material classes have been modified to include temperature dependent properties based on the Eurocode. New functions and interfaces have been added into existing element and section classes to calculate the member actions due to arbitrary thermal loading taking into account material degradation with increasing temperature for non-linear analyses. This paper reports on a number of benchmark tests to ascertain the performance of the new codes implemented in OpenSees for beams, frames, and plate structures. The analysis procedures being developed for structures exposed to fire in OpenSees will make it easier for users to define temperature-dependent material properties and allow for arbitrary non-uniform temperature distributions across and along an element by interfacing a fire and heat transfer analysis module also being developed for OpenSees. This work will also enable the modeling of earthquake damaged structural frames subjected to a subsequent fire. © 2012 Published by Elsevier Ltd. All rights reserved.

Cates M.E.,University of Edinburgh
Nature Materials | Year: 2013

Open crystalline configurations self-assembled from colloids with sticky patches have recently been shown to be unexpectedly stable. A theory that accounts for the entropy of the colloids' thermal fluctuations now explains why. Entropy can be a subtle and elusive concept. Although in some sense it is the quantification of disorder, it has long been known that for hard spheres at high density an ordered crystal has higher entropy than a disordered fluid. The existence of a bond between two particles in contact requires that the two involved patches cover the contact point, whose position is known. Each particle can therefore fluctuate independently within an angular domain set purely by the constraint that its patches cover all contact points with its bondable neighbors. Building on this simplification, Mao and co-authors construct an effective description of the interactions in a system of patchy particles with fluctuating lattice positions, and compare it with experimental data on the mode structure of lattice vibrations for triblock Janus spheres.

Morton S.,University of Edinburgh
Evidence and Policy | Year: 2015

An impact assessment of research into children's concerns about their families and relationships found many ways research had been used in different sectors by different actors. Specific impacts from the research were harder to identify. However, instances where there were clear impacts highlighted the ways research users had adapted research to fit the context for research use in order to create impact. Research users continued to draw on the research for many years after publication, creating further impact as new policy or practice agendas arose. © Policy Press 2015.

Di Renzo M.,Supelec | Haas H.,University of Edinburgh
IEEE Transactions on Vehicular Technology | Year: 2013

In this paper, we contribute to the theoretical understanding, analysis, and design of spatial modulation multiple-input-multiple-output (SM-MIMO) systems for transmit diversity without channel state information at the transmitter. The contribution is threefold: 1) The achievable transmit diversity of SM-MIMO is analytically studied by analyzing the impact of various design parameters, notably spatial constellation diagram and shaping filters at the transmitter; 2) the design of SM-MIMO providing transmit diversity and maximum-likelihood (ML) optimum single-stream decoding is investigated; and 3) via Monte Carlo simulations, a comprehensive performance assessment of SM-MIMO against state-of-the-art MIMO (e.g., spatial multiplexing, orthogonal space-time block codes, Golden code, and double space-time transmit diversity) is conducted. It is shown that, for many system setups, a properly designed SM-MIMO outperforms, with lower decoding complexity, state-of-the-art MIMO. In particular, SM-MIMO is particularly useful in the downlink, where many antenna elements (with only few of them active) are available at the transmitter, and few antenna elements are available at the receiver. © 1967-2012 IEEE.

Sheikh A.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2012

Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may cause death. Adrenaline (epinephrine) auto-injectors are recommended as the initial, potentially life-saving treatment of choice for anaphylaxis in the community, but they are not universally available and have limitations in their use. To assess the effectiveness of adrenaline (epinephrine) auto-injectors in relieving respiratory, cardiovascular, and other symptoms during episodes of anaphylaxis that occur in the community. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (Ovid SP) (1950 to January 2012), EMBASE (Ovid SP) (1980 to January 2012 ), CINAHL (EBSCO host) (1982 to January 2012 ), AMED (EBSCO host) (1985 to January 2012 ), LILACS, (BIREME) (1980 to January 2012 ), ISI Web of Science (1950 to January 2012 ). We adapted our search terms for other databases. We also searched websites listing on-going trials: the World Health Organization International Clinical Trials Registry Platform, the UK Clinical Research Network Study Portfolio, and the meta Register of Controlled Trials; and contacted pharmaceutical companies who manufacture adrenaline auto-injectors in an attempt to locate unpublished material. Randomized and quasi-randomized controlled trials comparing auto-injector administration of adrenaline with any control including no intervention, placebo, or other adrenergic agonists were eligible for inclusion. Two authors independently assessed articles for inclusion. None of the 1328 studies that were identified satisfied the inclusion criteria. Based on this review, we cannot make any new recommendations on the effectiveness of adrenaline auto-injectors for the treatment of anaphylaxis. Although randomized, double-blind, placebo-controlled clinical trials of high methodological quality are necessary to define the true extent of benefits from the administration of adrenaline in anaphylaxis via an auto-injector, such trials are unlikely to be performed in individuals experiencing anaphylaxis because of ethical concerns associated with randomization to placebo. There is, however, a need to consider trials in which, for example, auto-injectors of different doses of adrenaline and differing devices are compared in order to provide greater clarity on the dose and device of choice. Such trials would be practically challenging to conduct. In the absence of appropriate trials, we recommend that adrenaline administration by auto-injector should still be regarded as the most effective first-line treatment for the management of anaphylaxis in the community. In countries where auto-injectors are not commonly used, it may be possible to conduct trials to compare administration of adrenaline via auto-injector with adrenaline administered by syringe and ampoule, or comparing the effectiveness of two different types of auto-injector.

Stevens P.,University of Edinburgh
Software and Systems Modeling | Year: 2013

The QVT Relations (QVT-R) transformation language allows the definition of bidirectional model transformations, which are required in cases where two (or more) models must be kept consistent in the face of changes to either or both. A QVT-R transformation can be used either in checkonly mode, to determine whether a target model is consistent with a given source model, or in enforce mode, to change the target model. A precise understanding of checkonly mode transformations is prerequisite to a precise understanding of enforce mode transformations, and this is the focus of this paper. In order to give semantics to checkonly QVT-R transformations, we need to consider the overall structure of the transformation as given by when and where clauses, and the role of trace classes. In the standard, the semantics of QVT-R are given both directly, and by means of a translation to QVT Core, a language which is intended to be simpler. In this paper, we argue that there are irreconcilable differences between the intended semantics of QVT-R and those of QVT Core, so that no translation from QVT-R to QVT Core can be semantics-preserving, and hence no such translation can be helpful in defining the semantics of QVT-R. Treating QVT-R directly, we propose a simple game-theoretic semantics. We demonstrate its behaviour on examples and show how it can be used to prove an example result comparing two QVT-R transformations. We demonstrate that consistent models may not possess a single trace model whose objects can be read as traceability links in either direction. We briefly discuss the effect of variations in the rules of the game, to elucidate some design choices available to the designers of the QVT-R language. © 2011 Springer-Verlag.

Marsland R.,University of Edinburgh
Medical Anthropology Quarterly | Year: 2012

This article addresses life on antiretroviral therapy in rural Tanzania. It argues that a nuanced understanding of theories of biosociality requires us to take sociality and locality as seriously as we do "bio." People living with HIV associate on the basis of preexisting social relations, not just on the basis of their biological status. Their CD4 counts do not only measure immunological processes but also index social conditions of hunger. The pharmaceutical that gives them life insists that they eat and rest more than austere financial circumstances allow. Many join HIV groups, but these do not enable the kinds of "citizenship" that have been described elsewhere. Patient activism is stifled by bureaucratic antipolitics mechanisms inherited from postcolonial restrictions on political association. Instead, they enter an NGO economy that values their biological status because they attract income from donors, but does little to enable the living that they need. © 2012 by the American Anthropological Association.

Ralph A.R.,University of Sydney | Lucas R.M.,Australian National University | Norval M.,University of Edinburgh
The Lancet Infectious Diseases | Year: 2013

Improved understanding of the association between tuberculosis and vitamin D is needed to inform clinical practice. Vitamin D has both immunostimulatory and immunosuppressive effects relevant to human antimycobacterial responses. Ultraviolet radiation, the main source of vitamin D, also induces immunomodulation and could affect the relation between vitamin D and tuberculosis. Clinical trials of vitamin D supplementation in patients with tuberculosis have produced largely negative results, prompting the review of dosing regimens-an explanation for low 25-hydroxyvitamin D status in patients with active tuberculosis is also needed. The reporting of vitamin D deficiency needs to address assay inaccuracies, rising thresholds to define sufficiency, and scarce knowledge of the concentrations needed for optimum immune responses. Future research to measure the effect of the inflammatory setting on serum concentrations of 25-hydroxyvitamin D, at tuberculosis diagnosis and during recovery, could help to account for 25-hydroxyvitamin D changes in these concentrations in patients with tuberculosis. Studies into the role of vitamin D supplementation in latent tuberculosis justify clinical trials in this population, but pose methodological challenges. Vitamin D trials in patients with active tuberculosis should be done in well selected populations using adequate vitamin D doses, although such doses remain undefined. © 2013 Elsevier Ltd.

Goldstein L.H.,Kings College London | Abrahams S.,University of Edinburgh
The Lancet Neurology | Year: 2013

Increased awareness of cognitive and behavioural change in amyotrophic lateral sclerosis has been driven by various clinic-based and population-based studies. A frontotemporal syndrome occurs in a substantial proportion of patients, a subgroup of whom present with frontotemporal dementia. Deficits are characterised by executive and working-memory impairments, extending to changes in language and social cognition. Behaviour and social cognition abnormalities are closely similar to those reported in behavioural variant frontotemporal dementia, implying a clinical spectrum linking amyotrophic lateral sclerosis and frontotemporal dementia. Cognitive impairment should be considered in clinical management, but few specialist assessment resources are available, and thus the cognitive status of most patients is unknown. Standard assessment procedures are not appropriate to detect dysfunction due to progressive physical disability; techniques that better measure the problems encountered by this group of patients are needed to further establish disease effects. Screening instruments are needed that are validated specifically for amyotrophic lateral sclerosis, encompass the heterogeneity of impairment, and accommodate physical disability. © 2013 Elsevier Ltd.

Jenkins S.J.,University of Edinburgh | Hume D.A.,Roslin Institute
Trends in Immunology | Year: 2014

The mononuclear phagocyte system (MPS) is a family of functionally related cells including bone marrow precursors, blood monocytes, and tissue macrophages. We review the evidence that macrophages and dendritic cells (DCs) are separate lineages and functional entities, and examine whether the traditional view that monocytes are the immediate precursors of tissue macrophages needs to be refined based upon evidence that macrophages can extensively self-renew and can be seeded from yolk sac/foetal liver progenitors with little input from monocytes thereafter. We review the role of the growth factor colony-stimulating factor (CSF)1, and present a model consistent with the concept of the MPS in which local proliferation and monocyte recruitment are connected to ensure macrophages occupy their well-defined niche in most tissues. © 2014 Elsevier Ltd.

Background: Few data are available from randomised trials about the effect of thrombolysis with alteplase on long-term functional outcome in patients who have had acute ischaemic stroke and no trial has reported effects on health-related quality of life. A secondary objective of the third International Stroke Trial (IST-3) was to assess the effect of thrombolysis on such outcomes at 18 months. Methods: In this open-label, international, multicentre, randomised, controlled trial, 3035 patients with ischaemic stroke from 12 countries were randomly allocated within 6 h of onset via a secure central system to either intravenous alteplase (0·9 mg/kg; n=1515) plus standard care or standard care alone (control; n=1520). 2348 patients were scheduled for 18-month follow-up. For our main analysis, survivors were assessed at 18 months with the Oxford handicap scale (OHS; the primary outcome was the adjusted odds of OHS score 0-2). We also used the EuroQoL (EQ) instrument and asked questions about overall functioning and living circumstances. We analysed the OHS and the five EQ domains by ordinal logistic regression and calculated the mean difference between treatment groups in EQ utility index and visual analogue scale score. Analyses were adjusted for key baseline prognostic factors. This study is registered with controlled-trials.com, number ISRCTN25765518. Findings: At 18 months, 408 (34·9%) of 1169 patients in the alteplase group versus 414 (35·1%) of 1179 in the control group had died (p=0·85). 391 (35·0%) of 1117 patients versus 352 (31·4%) of 1122 had an OHS score of 0-2 (adjusted odds ratio [OR] 1·28, 95% CI 1·03-1·57; p=0·024). Treatment was associated with a favourable shift in the distribution of OHS grades (adjusted common OR 1·30, 95% CI 1·10-1·55; p=0·002). Alteplase treatment was associated with significantly higher overall self-reported health (adjusted mean difference in EQ utility index 0·060; p=0·019). The differences between the groups in visual analogue scale score and the proportion living at home were not significant. Interpretation: IST-3 provides evidence that thrombolysis with intravenous alteplase for acute ischaemic stroke does not affect survival, but does lead to statistically significant, clinically relevant improvements in functional outcome and health-related quality of life that are sustained for at least 18 months. © 2013 The IST-3 collaborative group. Open Access article distributed under the terms of CC BY.

Wardlaw J.M.,University of Edinburgh
Journal of Internal Medicine | Year: 2010

Wardlaw JM (Western General Hospital, Edinburgh, UK). Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology (Review). J Intern Med 2010; 267: 172-190. The treatment of acute ischaemic stroke is based on the principle that there is ischaemic but still potentially salvageable tissue that could be rescued if blood flow could be restored quickly. It is assumed that salvage might only be possible in the first few hours, and that infarct expansion is a direct result of failed recanalization of the main artery. This concept arose from experimental work in the 1970s, supported more recently by studies using imaging to identify penumbral tissue. However, although magnetic resonance diffusion and perfusion imaging is a way of imaging penumbral tissue and has been around for over a decade, it is not an easy technique to apply in practice and its use has produced conflicting results. Computed tomography perfusion, and any other tissue perfusion imaging technique, is likely to encounter the same difficulties. Indeed many factors, other than the presence of a diffusion-perfusion mismatch acutely, may determine or influence ultimate tissue fate even days after the stroke, and in turn, clinical outcome. Many of these potential influences are beginning to emerge from studies using different forms of imaging at later times after stroke. This review will explore the information now emerging from imaging studies in large artery ischaemic stroke to summarize knowledge to date and indicate unresolved issues for the future. © 2010 Blackwell Publishing Ltd.

Chandler A.,University of Edinburgh
Medical Humanities | Year: 2014

Illness narratives have traditionally been used as a conceptual tool for exploring experiences of chronic illness or disease. In this paper, I suggest that Frank’s typology of illness narratives (chaos, restitution and quest) also offers an illuminating approach to analysing accounts of self-injury, demonstrating the diverse ways in which self-injury is practiced, experienced and narrated. Drawing on 24 narrative interviews with 12 people who had self-injured, I focus on participants’ accounts of their self-injured bodies. The approach is phenomenological, and concerned with talk about the experience of living with and in a body that has been marked by self-injury. Thus, the act of self-injury is not the sole focus, and particular attention is paid to accounts of the bodily aftermath: scars, marks and wounds. Scars left by selfinjury can be seen as communicative, and the analysis developed here demonstrates some of the various ways that these marks may be read. Attending to these diverse narratives can contribute to the provision of  compassionate, non-judgemental care for patients who have self-injured. Further, highlighting the existence of  different ways of narrating the self-injured body may offer an optimistic resource for people who have self-injured. © 2014, BMJ Publishing Group. All rights reserved.

Simpson T.C.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Glycaemic control is a key issue in the care of people with diabetes mellitus (DM). Some studies have suggested a bidirectional relationship between glycaemic control and periodontal disease. OBJECTIVES: To investigate the relationship between periodontal therapy and glycaemic control in people with diabetes and to identify the appropriate future strategy for this question. SEARCH STRATEGY: A comprehensive approach was adopted employing handsearching; searching of electronic databases including the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL, ZETOC, ISI Web of Knowledge and LILACS; contact with appropriate non-English language healthcare professionals; authors and organisations. The final date for searching for studies was 24th March 2010. SELECTION CRITERIA: This review studied randomised controlled trials of people with Type 1 or 2 diabetes mellitus (DM) with a diagnosis of periodontitis. Suitable interventions included mechanical periodontal therapy with or without adjunctives and oral hygiene education. DATA COLLECTION AND ANALYSIS: The titles and abstracts of 690 papers were examined by two review authors independently. Ultimately, seven studies were included and 19 excluded after full text scrutiny. All trials were assessed for risk of bias. MAIN RESULTS: Three studies had results pooled into a meta-analysis. The effect for the mean percentage difference in HbA1c for scaling/root planing and oral hygiene (+/- antibiotic therapy) versus no treatment/usual treatment after 3/4 months was -0.40% (95% confidence interval (CI) fixed effect -0.78% to -0.01%), representing a statistically significant reduction in HbA1c (P = 0.04) for scaling/root planing. One study was assessed as being at low risk of bias with the other two at moderate to high risk of bias. A subgroup analysis examined studies without adjunctive antibiotics -0.80% (one study: 95% CI -1.73% to 0.13%; P = 0.09), with adjunctive antibiotics in the test group -0.36% (one study: 95% CI -0.83% to 0.11%; P = 0.14), and with antibiotics in both test and control groups after 3/4 months -0.15% (one study: 95% CI -1.04% to 0.74%; P = 0.74). AUTHORS' CONCLUSIONS: There is some evidence of improvement in metabolic control in people with diabetes, after treating periodontal disease. There are few studies available and individually these lacked the power to detect a significant effect. Most of the participants in the study had poorly controlled Type 2 DM with little data from randomised trials on the effects on people with Type 1 DM.Improving periodontal health is an important objective in itself. However, in order to understand the potential of this treatment to improve glycaemic control among people with diabetes, larger, carefully conducted and reported studies are needed.

Choo K.J.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2012

Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. Anaphylaxis guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis. We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis. In our previous version we searched the literature until September 2009. In this version we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (Ovid) (1956 to September 2011), EMBASE (Ovid) (1982 to September 2011), CINAHL (EBSCOhost) (to September 2011). We also searched the UK National Research Register and websites listing ongoing trials, and contacted international experts in anaphylaxis in an attempt to locate unpublished material. We planned to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these). Two authors independently assessed articles for inclusion. We found no studies that satisfied the inclusion criteria. We are, based on this review, unable to make any recommendations for the use of glucocorticoids in the treatment of anaphylaxis.

Pickersgill M.,University of Edinburgh
Sociology of Health and Illness | Year: 2012

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is one of the most influential and controversial terminological standards ever produced. As such, it continues to provide a valuable case study for sociologists of health and illness. In this article I take as my focus one particular DSM category: antisocial personality disorder (ASPD). The analysis charts the shifting understandings of personality disorders associated with antisocial behaviour in the DSM and in US psychiatry more broadly from 1950 to the present day. Memos, letters and minutes produced by the DSM-III committee and held in the American Psychiatric Association (APA) archives ground the discussion. Finally, the article explores more recent constructions of antisocial personality disorder and examines the anticipatory discourse pertaining to the rewriting of this category expected in the forthcoming DSM-5. In presenting an in-depth socio-historical narrative of the development - and potential future - of standards for pathological antisociality, this analysis casts new light on the ASPD construct. In particular, by considering it as a technology, I elaborate how processes of path dependency constrain innovation and how imaginaries of users and publics are implicated in the APA debates constitutive of this. © 2011 The Authors. Sociology of Health & Illness © 2011 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.

Mendelow A.D.,Northumbria University | Gregson B.A.,Northumbria University | Rowan E.N.,Northumbria University | Murray G.D.,University of Edinburgh | And 2 more authors.
The Lancet | Year: 2013

Background The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. Methods In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. Findings 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). Interpretation The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. © 2013 Mendelow et al. Open Access article distributed under the terms of CC BY-NC-ND.

Ralston S.H.,University of Edinburgh
New England Journal of Medicine | Year: 2013

A 73-year-old man presents with a 5-year history of low back pain that is exacerbated by standing. During the past year, pain has developed in his buttocks and legs when he walks, and it is not relieved by acetaminophen. The neurologic examination is unremarkable. Radiographs of the spine show coarsening of the trabecular pattern in several lumbar and lower thoracic vertebrae and expansion of several lumbar vertebral bodies. The total serum alkaline phosphatase level is 350 U per liter (reference range, 40 to 125); the results of liver-function tests and other routine laboratory tests are normal. How should he be further evaluated and treated? Copyright © 2013 Massachusetts Medical Society.

Biro A.,University of Edinburgh
Preventive Medicine | Year: 2013

Objective: This study aims to investigate which individual characteristics influenced the uptake of the 2009 H1N1 vaccination in England. The vaccination was provided for free to a specified target group who also received invitation letters, but the coverage rate was still far from universal among them. Methods: Data from the 2010 edition of the Health Survey for England are used (size of the estimation sample: 7211). In order to partial out the effect of unobservable time costs, attitudes or access to vaccinations, immunisations against the seasonal and pandemic influenza are jointly estimated. Results: Health risks, health behaviours and preferences, and exposure to various information help explain the immunisation decision. Receiving the seasonal flu vaccine increases the probability of H1N1 vaccination uptake by 20 percentage points. Conclusions: The widespread refusal of the vaccination can be worrying for the control of potential future pandemics. Providing clear, well targeted information, ensuring that high risk groups are contacted, and raising the level of health consciousness can increase the coverage rate with vaccinations. © 2013 Elsevier Inc.

Smith C.,University of Edinburgh
Neuropathology and Applied Neurobiology | Year: 2013

The brain is vulnerable to a number of acute insults, with traumatic brain injury being among the commonest. Neuroinflammation is a common response to acute injury and microglial activation is a key component of the inflammatory response. In the acute and subacute phase it is likely that this response is protective and forms an important part of the normal tissue reaction. However, there is considerable literature demonstrating an association between acute traumatic brain injury to the brain and subsequent cognitive decline. This article will review the epidemiological literature relating to both single and repetitive head injury. It will focus on the neuropathological features associated with long-term complications of a single blunt force head injury, repetitive head injury and blast head injury, with particular reference to chronic traumatic encephalopathy, including dementia pugilistica. Neuroinflammation has been postulated as a key mechanism linking acute traumatic brain injury with subsequent neurodegenerative disease, and this review will consider the response to injury in the acute phase and how this may be detrimental in the longer term, and discuss potential genetic factors which may influence this cellular response. Finally, this article will consider future directions for research and potential future therapies. © 2012 The Author Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.

McMillan T.M.,University of Edinburgh
Journal of neurology, neurosurgery, and psychiatry | Year: 2014

OBJECTIVE: To investigate mortality rate in a population of adults admitted to hospital with mild head injury (MHI) 15 years later.DESIGN: A prospective case control, record linkage study.PARTICIPANTS: 2428 adults with MHI and an equal number of community controls (CC) were case-matched for age, gender and social deprivation. A further control group admitted with a non-head injury was in addition matched for duration of hospital admission. Controls with a history of head injury prior to study entry were excluded.MAIN OUTCOME MEASURES: Death or survival 15 years poststudy entry.RESULTS: Mortality per 1000 per year after MHI (24.49; 95% CI 23.21 to 25.79) was higher than in CC (13.34; 95% CI 12.29 to 14.44; p<0.0001) or 'other injury' controls (OIC) (19.63; 95% CI 18.43 to 20.87; p<0.0001). Age at injury was important: younger adults (15-54 years) with MHI had a 4.2-fold greater risk of death than CC; in adults aged over 54, the risk was 1.4 times higher. Gender and social deprivation showed a similar association with death in the MHI and control groups. Repeated head injury was a risk factor for death in the MHI group. The frequency of hospital admission with systemic disease preinjury and postinjury was higher in both injury groups than in CC and higher in MHI than OIC. Prospective data in the MHI group suggest an association between preinjury lifestyle and mortality. Causes of death after MHI were similar to those of the control groups.CONCLUSIONS: Adults hospitalised with MHI had greater risk of death in the following 15 years than matched controls. The extent to which lifestyle and potential chronic changes in neuropathology explain these findings is unclear. Lifestyle factors do contribute to risk of death after MHI and this finding has implications for lifestyle management interventions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Del Debbio L.,University of Edinburgh | Zwicky R.,University of Southampton
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

We consider mass-deformed conformal gauge theories (mCGT) and investigate the scaling behaviour of hadronic observables as a function of the fermion mass. Applying renormalization group arguments directly to matrix elements, we find mH~m1/(1+γ) and F~mηF(γ*) for given ηF(γ*), for the hadronic masses and the decay constants respectively, thereby generalizing our results from a previous paper to the entire spectrum. Applying the Hellmann-Feynman theorem to the trace anomaly we obtain the hadron mass scaling independent of renormalization group arguments. From the trace anomaly we obtain a relation reminiscent of the Gell-Mann-Oakes-Renner relation in QCD. Using the new results we discuss the scaling of the S-parameter inside the conformal window. Finally, we discuss how spectral representations can be used to relate the mass and decay constant trajectories. © 2011 Elsevier B.V.

Studying ethnic differences in health not only benefits minority groups but is a powerful tool for scientific analysis and for social action in the wider field of health inequalities. Coronary mortality in developed countries is well-known to be higher for men and women born in south Asia compared to other ethnic groups. The aim of this review is to examine how the knowledge of ethnic differences in coronary health in south Asians has advanced in the last decade. We set out to answer the following: Is the high rate of coronary mortality in south Asians a result of high incidence or high case fatality? Why are there ethnic differences, and are they the result of biology, healthcare or social circumstances? Is the cardiovascular health future for south Asians (and especially the UK-born second generation) any brighter than in their parents?

Hadfield J.D.,University of Edinburgh
Ecology Letters | Year: 2016

The distribution of phenotypes in space will be a compromise between adaptive plasticity and local adaptation increasing the fit of phenotypes to local conditions and gene flow reducing that fit. Theoretical models on the evolution of quantitative characters on spatially explicit landscapes have only considered scenarios where optimum trait values change as deterministic functions of space. Here, these models are extended to include stochastic spatially autocorrelated aspects to the environment, and consequently the optimal phenotype. Under these conditions, the regression of phenotype on the environmental variable becomes steeper as the spatial scale on which populations are sampled becomes larger. Under certain deterministic models – such as linear clines – the regression is constant. The way in which the regression changes with spatial scale is informative about the degree of phenotypic plasticity, the relative scale of effective gene flow and the environmental dependency of selection. Connections to temporal models are discussed. © 2016 John Wiley & Sons Ltd/CNRS

Bagchi A.,University of Edinburgh
Journal of High Energy Physics | Year: 2011

The Galilean Conformal Algebra (GCA) arises from the conformal algebra in the non-relativistic limit. In two dimensions, one can view it as a limit of linear combinations of the two copies Virasoro algebra. Recently, it has been argued that Topologically Massive Gravity (TMG) realizes the quantum 2d GCA in a particular scaling limit of the gravitational Chern-Simons term. To add strength to this claim, we demonstrate a matching of correlation functions on both sides of this correspondence. A priori looking for spatially dependent correlators seems to force us to deal with high spin operators in the bulk. We get around this difficulty by constructing the non-relativistic Energy-Momentum tensor and considering its correlation functions. On the gravity side, our analysis makes heavy use of recent results of Holographic Renormalization in Topologically Massive Gravity. © SISSA 2011.

Klironomos F.D.,University of Cologne | Berg J.,University of Cologne | Collins S.,University of Edinburgh
BioEssays | Year: 2013

We hypothesize that heritable epigenetic changes can affect rates of fitness increase as well as patterns of genotypic and phenotypic change during adaptation. In particular, we suggest that when natural selection acts on pure epigenetic variation in addition to genetic variation, populations adapt faster, and adaptive phenotypes can arise before any genetic changes. This may make it difficult to reconcile the timing of adaptive events detected using conventional population genetics tools based on DNA sequence data with environmental drivers of adaptation, such as changes in climate. Epigenetic modifications are frequently associated with somatic cell differentiation, but recently epigenetic changes have been found that can be transmitted over many generations. Here, we show how the interplay of these heritable epigenetic changes with genetic changes can affect adaptive evolution, and how epigenetic changes affect the signature of selection in the genetic record. © 2013 WILEY Periodicals, Inc.

Osborne N.,University of Edinburgh
Annals of the New York Academy of Sciences | Year: 2012

Recent developments in music neuroscience are considered a source for reflection on, and evaluation and development of, musical therapeutic practice in the field, in particular, in relation to traumatized children and postconflict societies. Music neuroscience research is related to practice within a broad biopsychosocial framework. Here, examples are detailed of work from North Uganda, Palestine, and South Thailand. © 2012 New York Academy of Sciences.

Overy K.,University of Edinburgh
Annals of the New York Academy of Sciences | Year: 2012

To consider the full impact of musical learning on the brain, it is important to study the nature of everyday, non-expert forms of musical behavior alongside expert instrumental training. Such informal forms of music making tend to include social interaction, synchronization, body movements, and positive shared experiences. Here, I propose that when designing music intervention programs for scientific purposes, such features may have advantages over instrumental training, depending on the specific research aims, contexts, and measures. With reference to a selection of classroom approaches to music education and to the shared affective motion experience (SAME) model of emotional responses to music, I conclude that group learning may be particularly valuable in music pedagogy. © 2012 New York Academy of Sciences.

Forgan D.,University of Edinburgh
Monthly Notices of the Royal Astronomical Society | Year: 2012

The α Cen AB system is an attractive one for radial velocity observations to detect potential exoplanets. The high metallicity of both α Cen A and B suggests that they could have possessed circumstellar discs capable of forming planets. As the closest star system to the Sun, with well over a century of accurate astrometric measurements (and α Cen B exhibiting low chromospheric activity), high-precision surveys of α Cen B's potential exoplanetary system are possible with relatively cheap instrumentation. Authors studying habitability in this system typically adopt habitable zones (HZs) based on global radiative balance models that neglect the radiative perturbations of α Cen A. We investigate the habitability of planets around α Cen B using one-dimensional latitudinal energy balance models (LEBMs), which fully incorporate the presence of α Cen A as a means of astronomically forcing terrestrial planet climates. We find that the extent of the HZ is relatively unchanged by the presence of α Cen A, but there are variations in fractional habitability for planets orbiting at the boundaries of the zone due to α Cen A, even in the case of zero eccentricity. Temperature oscillations of a few K can be observed at all planetary orbits, the strength of which varies with the planet's ocean fraction and obliquity. © 2012 The Author Monthly Notices of the Royal Astronomical Society © 2012 RAS.

Morelli X.,Aix - Marseille University | Hupp T.,University of Edinburgh
EMBO Reports | Year: 2012

The first EMBO workshop on 'Protein-Protein Interaction Analysis & Modulation' took place in June 2012 in Roscoff, France. It brought together researchers to discuss the growing field of protein network analysis and the modulation of protein-protein interactions, as well as outstanding related issues including the daunting challenge of integrating interactomes in systems biology and in the modelling of signalling networks. © 2012 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION.

Charlesworth B.,University of Edinburgh
Genetics | Year: 2013

Genomic traits such as codon usage and the lengths of noncoding sequences may be subject to stabilizing selection rather than purifying selection. Mutations affecting these traits are often biased in one direction. To investigate the potential role of stabilizing selection on genomic traits, the effects of mutational bias on the equilibrium value of a trait under stabilizing selection in a finite population were investigated, using two different mutational models. Numerical results were generated using a matrix method for calculating the probability distribution of variant frequencies at sites affecting the trait, as well as by Monte Carlo simulations. Analytical approximations were also derived, which provided useful insights into the numerical results. A novel conclusion is that the scaled intensity of selection acting on individual variants is nearly independent of the effective population size over a wide range of parameter space and is strongly determined by the logarithm of the mutational bias parameter. This is true even when there is a very small departure of the mean from the optimum, as is usually the case. This implies that studies of the frequency spectra of DNA sequence variants may be unable to distinguish between stabilizing and purifying selection. A similar investigation of purifying selection against deleterious mutations was also carried out. Contrary to previous suggestions, the scaled intensity of purifying selection with synergistic fitness effects is sensitive to population size, which is inconsistent with the general lack of sensitivity of codon usage to effective population size. © 2013 by the Genetics Society of America.

Melchior P.,Ohio State University | Viola M.,University of Edinburgh
Monthly Notices of the Royal Astronomical Society | Year: 2012

Weak-lensing shear estimates show a troublesome dependence on the apparent brightness of the galaxies used to measure the ellipticity: in several studies, the amplitude of the inferred shear falls sharply with decreasing source significance. This dependence limits the overall ability of upcoming large weak-lensing surveys to constrain cosmological parameters. We seek to provide a concise overview of the impact of pixel noise on weak-lensing measurements, covering the entire path from noisy images to shear estimates. We show that there are at least three distinct layers, where pixel noise not only obscures but also biases the outcome of the measurements: (1) the propagation of pixel noise to the non-linear observable ellipticity; (2) the response of the shape-measurement methods to limited amount of information extractable from noisy images and (3) the reaction of shear estimation statistics to the presence of noise and outliers in the measured ellipticities. We identify and discuss several fundamental problems and show that each of them is able to introduce biases in the range of a few tens to a few per cent for galaxies with typical significance levels. Furthermore, all of these biases do not only depend on the brightness of galaxies but also depend on their ellipticity, with more elliptical galaxies often being harder to measure correctly. We also discuss existing possibilities to mitigate and novel ideas to avoid the biases induced by pixel noise. We present a new shear estimator that shows a more robust performance for noisy ellipticity samples. Finally, we release the open-source python code to predict and efficiently sample from the noisy ellipticity distribution and the shear estimators used in this work at https://github.com/pmelchior/epsnoise. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.

Scott P.R.,University of Edinburgh
Small Ruminant Research | Year: 2010

Lumbar cerebrospinal fluid (CSF) collection and subsequent analysis are particularly useful with respect to confirming the presence of an inflammatory lesion involving the leptomeninges, such as bacterial meningo-encephalitis, and investigating potential compressive lesions of the spinal cord. When correctly performed under local anaesthesia, lumbar CSF collection in sheep is a safe procedure. Familiarity with the technique aids high extradural injection of lidocaine and/or xylazine which has many applications in sheep clinical practice. There are no indications for cisternal CSF collection. © 2010 Elsevier B.V.

Lawrence A.,University of Edinburgh
Monthly Notices of the Royal Astronomical Society | Year: 2012

I summarize and analyse key problems with observations of the UV bump in active galactic nuclei (AGN), and especially the accretion disc interpretation - the temperature problem, the ionization problem, the time-scale problem and the co-ordination problem - and suggest that all these problems can be solved if, in addition to the accretion disc, there is a population of cold, thick clouds at approximately 30R S which reprocess the intrinsic continuum. Exploring cloud parameter space, I find that clouds with density n∼ 10 12cm -3 and column N H > 4 × 10 24cm -2 reflect most of the intrinsic continuum, but convert a substantial fraction of the EUV luminosity into lines, dominated by Lyβ and Heii Lyα. When velocity-blurred, this makes a false continuum peak at ∼1100Å which fits the observed spectral energy distribution (SED) well, but turns back up in the FUV to make a hard EUV SED, as required by ionization models. I argue that the observed UV variability is dominated by this component of fixed shape, possibly due to changes of covering factor. The amount of mass required is small, so it is not necessary to disrupt the disc, but only to make an unstable and inhomogeneous atmosphere. The proposed clouds may be related to those suggested by several X-ray phenomena (X-ray reflection components, high-velocity outflows, Compton thick partial covering) but are not the same, leading to a picture with a wide range of inhomogeneous structures at different radii. © 2012 The Author Monthly Notices of the Royal Astronomical Society © 2012 RAS.

Fukagawa T.,Graduate University for Advanced Studies | Earnshaw W.C.,University of Edinburgh
Developmental Cell | Year: 2014

Since discovery of the centromere-specific histone H3 variant CENP-A, centromeres have come to be defined as chromatin structures that establish the assembly site for the complex kinetochore machinery. In most organisms, centromere activity is defined epigenetically, rather than by specific DNA sequences. In this review, we describe selected classic work and recent progress in studies of centromeric chromatin with a focus on vertebrates. We consider possible roles for repetitive DNA sequences found at most centromeres, chromatin factors and modifications that assemble and activate CENP-A chromatin for kinetochore assembly, plus the use of artificial chromosomes and kinetochores to study centromere function. © 2014 The Authors.

Although animal breeding was practiced long before the science of genetics and the relevant disciplines of population and quantitative genetics were known, breeding programs have mainly relied on simply selecting and mating the best individuals on their own or relatives' performance. This is based on sound quantitative genetic principles, developed and expounded by Lush, who attributed much of his understanding to Wright, and formalized in Fisher's infinitesimal model. Analysis at the level of individual loci and gene frequency distributions has had relatively little impact. Now with access to genomic data, a revolution in which molecular information is being used to enhance response with "genomic selection" is occurring. The predictions of breeding value still utilize multiple loci throughout the genome and, indeed, are largely compatible with additive and specifically infinitesimal model assumptions. I discuss some of the history and genetic issues as applied to the science of livestock improvement, which has had and continues to have major spin-offs into ideas and applications in other areas. © 2014 by the Genetics Society of America.

Blumensath T.,University of Southampton | Davies M.E.,University of Edinburgh
IEEE Journal on Selected Topics in Signal Processing | Year: 2010

Sparse signal models are used in many signal processing applications. The task of estimating the sparsest coefficient vector in these models is a combinatorial problem and efficient, often suboptimal strategies have to be used. Fortunately, under certain conditions on the model, several algorithms could be shown to efficiently calculate near-optimal solutions. In this paper, we study one of these methods, the so-called Iterative Hard Thresholding algorithm. While this method has strong theoretical performance guarantees whenever certain theoretical properties hold, empirical studies show that the algorithm's performance degrades significantly, whenever the conditions fail. What is more, in this regime, the algorithm also often fails to converge. As we are here interested in the application of the method to real world problems, in which it is not known in general, whether the theoretical conditions are satisfied or not, we suggest a simple modification that guarantees the convergence of the method, even in this regime. With this modification, empirical evidence suggests that the algorithm is faster than many other state-of-the-art approaches while showing similar performance. What is more, the modified algorithm retains theoretical performance guarantees similar to the original algorithm. © IEEE.

Cooney G.,Royal Edinburgh Hospital | Dwan K.,University of Liverpool | Mead G.,University of Edinburgh
JAMA - Journal of the American Medical Association | Year: 2014

CLINICAL QUESTION: Is exercise an effective treatment for depression? BOTTOM LINE: Exercise is associated with a greater reduction in depression symptoms compared with no treatment, placebo, or active control interventions, such as relaxation or meditation. However, analysis of high-quality studies alone suggests only small benefits. Copyright 2014 American Medical Association. All rights reserved.

Gondzio J.,University of Edinburgh
SIAM Journal on Optimization | Year: 2013

In this paper we will discuss two variants of an inexact feasible interior point algorithm for convex quadratic programming. We will consider two different neighborhoods: a small one induced by the use of the Euclidean norm which yields a short-step algorithm nd a symmetric one induced by the use of the infinity norm which yields a (practical) long-step algorithm. Both algorithms allow for the Newton equation system to be solved inexactly. For both algorithms we will provide conditions for the level of error acceptable in the Newton equation and establish the worst-case complexity results. © 2013 Society for Industrial and Applied Mathematics.

Baker J.C.T.,University of Edinburgh
Environment and Planning D: Society and Space | Year: 2015

Scholars have written and theorised landscape mainly by the light of day. Not only does such a perspective bypass a significant portion of human experience, it conflicts with some past diurnal routines of dwelling and mobility, such as mid-nineteenth century colonial travel in India. This article studies the interpretations of two English travellers - Emma Roberts and Charles Acland - under conditions of darkness and illumination: by campfire, torchlight and starlight. Specifically, it merges insights from a growing nightscape literature with the scenic sensibilities these travellers imported to India, such as the picturesque and notions of India as oriental and tropical. It argues that darkness and illumination amplified these travellers’ aesthetic impressions by fostering collective experience, optically altering colours and furnishing imaginative leeway. © SAGE Publications Ltd, 2015.

Shipston M.J.,University of Edinburgh
Journal of General Physiology | Year: 2014

Protein S-acylation, the reversible covalent fatty-acid modification of cysteine residues, has emerged as a dynamic posttranslational modification (PTM) that controls the diversity, life cycle, and physiological function of numerous ligand-and voltage-gated ion channels. S-acylation is enzymatically mediated by a diverse family of acyltransferases (zDHHCs) and is reversed by acylthioesterases. However, for most ion channels, the dynamics and subcellular localization at which S-acylation and deacylation cycles occur are not known. S-acylation can control the two fundamental determinants of ion channel function: (1) the number of channels resident in a membrane and (2) the activity of the channel at the membrane. It controls the former by regulating channel trafficking and the latter by controlling channel kinetics and modulation by other PTMs. Ion channel function may be modulated by S-acylation of both pore-forming and regulatory subunits as well as through control of adapter, signaling, and scaffolding proteins in ion channel complexes. Importantly, cross-talk of S-acylation with other PTMs of both cysteine residues by themselves and neighboring sites of phosphorylation is an emerging concept in the control of ion channel physiology. In this review, I discuss the fundamentals of protein S-acylation and the tools available to investigate ion channel S-acylation. The mechanisms and role of S-acylation in controlling diverse stages of the ion channel life cycle and its effect on ion channel function are highlighted. Finally, I discuss future goals and challenges for the field to understand both the mechanistic basis for S-acylation control of ion channels and the functional consequence and implications for understanding the physiological function of ion channel S-acylation in health and disease. © 2014 Shipston.

Lubbock A.L.,University of Edinburgh
Nucleic acids research | Year: 2013

Tissue microarrays (TMAs) allow multiplexed analysis of tissue samples and are frequently used to estimate biomarker protein expression in tumour biopsies. TMA Navigator (www.tmanavigator.org) is an open access web application for analysis of TMA data and related information, accommodating categorical, semi-continuous and continuous expression scores. Non-biological variation, or batch effects, can hinder data analysis and may be mitigated using the ComBat algorithm, which is incorporated with enhancements for automated application to TMA data. Unsupervised grouping of samples (patients) is provided according to Gaussian mixture modelling of marker scores, with cardinality selected by Bayesian information criterion regularization. Kaplan-Meier survival analysis is available, including comparison of groups identified by mixture modelling using the Mantel-Cox log-rank test. TMA Navigator also supports network inference approaches useful for TMA datasets, which often constitute comparatively few markers. Tissue and cell-type specific networks derived from TMA expression data offer insights into the molecular logic underlying pathophenotypes, towards more effective and personalized medicine. Output is interactive, and results may be exported for use with external programs. Private anonymous access is available, and user accounts may be generated for easier data management.

Hayward T.,University of Edinburgh
Nature Climate Change | Year: 2012

What does it matter if the climate changes? This kind of question does not admit of a scientific answer. Natural science can tell us what some of its biophysical effects are likely to be; social scientists can estimate what consequences such effects could have for human lives and livelihoods. But how should we respond? The question is, at root, about how we think we should live - and different people have myriad different ideas about this. The distinctive task of ethics is to bring some clarity and order to these ideas.

Sheikh A.,University of Edinburgh
Current Opinion in Allergy and Clinical Immunology | Year: 2013

PURPOSE OF REVIEW: To review recent evidence on the effectiveness of glucocorticosteroids in the treatment and prevention of anaphylaxis. RECENT FINDINGS: Glucocorticosteroids are often used in the management of anaphylaxis in an attempt to reduce the severity of the acute reaction and decrease the risk of biphasic/protracted reactions. A recent Cochrane systematic review failed to identify any randomized controlled or quasi-randomized trials investigating the effectiveness of glucocorticosteroids in the emergency management of anaphylaxis. In contrast, randomized controlled trials have been undertaken of glucocorticosteroids, given individually or in combination with other drugs, in preventing anaphylaxis. Systematic reviews of these prophylactic approaches undertaken in patients being investigated with iodinated contrast media and treated with snake anti-venom therapy have found routine prophylaxis to be of questionable value. Trials of a combination of glucocorticosteroids and H1/H2-antihistamine premedication for preventing allergen immunotherapy- triggered anaphylaxis have yielded mixed results. SUMMARY: Glucocorticosteroids should be regarded, at best, as a second-line agent in the emergency management of anaphylaxis, and administration of epinephrine should therefore not be delayed whilst glucocorticosteroids are drawn up and administered. Routine premedication with glucocorticosteroids in patients receiving iodinated contrast media, snake anti-venom therapy or allergen immunotherapy is unlikely to confer clinical benefit. © 2013 Wolters Kluwer Health | Lippincott Williams and Wilkins.

Elgala H.,Jacobs Engineering | Mesleh R.,University of Tabuk | Haas H.,University of Edinburgh
IEEE Communications Magazine | Year: 2011

In recent years, interest in optical wireless (OW) as a promising complementary technology for RF technology has gained new momentum fueled by significant deployments in solid state lighting technology. This article aims at reviewing and summarizing recent advancements in OW communication, with the main focus on indoor deployment scenarios. This includes a discussion of challenges, potential applications, state of the art, and prospects. Related issues covered in this article are duplex transmission, multiple access, MAC protocols, and link capacity improvements. © 2011 IEEE.

Nussey D.H.,University of Edinburgh
Proceedings. Biological sciences / The Royal Society | Year: 2014

Despite our rapidly advancing mechanistic understanding of vertebrate immunity under controlled laboratory conditions, the links between immunity, infection and fitness under natural conditions remain poorly understood. Antibodies are central to acquired immune responses, and antibody levels circulating in vivo reflect a composite of constitutive and induced functional variants of diverse specificities (e.g. binding antigens from prevalent parasites, self tissues or novel non-self sources). Here, we measured plasma concentrations of 11 different antibody types in adult females from an unmanaged population of Soay sheep on St Kilda. Correlations among antibody measures were generally positive but weak, and eight of the measures independently predicted body mass, strongyle parasite egg count or survival over the subsequent winter. These independent and, in some cases, antagonistic relationships point to important multivariate immunological heterogeneities affecting organismal health and fitness in natural systems. Notably, we identified a strong positive association between anti-nematode immunoglobulin (Ig) G antibodies in summer and subsequent over-winter survival, providing rare evidence for a fitness benefit of helminth-specific immunity under natural conditions. Our results highlight both the evolutionary and ecological importance and the complex nature of the immune phenotype in the wild.

Prior S.,University of Edinburgh
Sociology of Health and Illness | Year: 2012

Increasing attention has been focused on adolescent help-seeking in relation to services aimed at promoting mental health and wellbeing. Much research reinforces the ubiquity of concerns about negative stigmatisation by peers as a barrier to young people accessing services. This paper draws on interviews conducted with young people, who completed a course of counselling in school, to investigate how they managed and negotiated this. Drawing on positioning theory from discourse analysis, young people's accounts are analysed with reference to the variety of positions they articulated and adopted. This demonstrates how they elaborated and reinforced virtuous problem-solver positions within broader discourses of individualisation and normalisation, and resisted positioning within a stigmatised mental illness discourse. Although focused on a small sample, the analysis offers potential insights into the ways other people may negotiate stigma concerns to access mental health resources, while also demonstrating the utility of positioning theory for understanding stigma and normalisation. © 2011 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.

Bhopal R.S.,University of Edinburgh
Journal of Public Health (United Kingdom) | Year: 2012

Reducing ethnic inequalities and inequities in health needs to become a higher priority for public health research. Active involvement of migrant and ethnic minority populations in European population health research is necessary, for data show important inequalities but evidence, particularly on effectiveness, is sparse and strategic overviews rarer still. Ethnically disaggregated health surveillance systems are developing slowly, and pragmatically, often using country of birth. The principles to adopt, given the gaps between the ideal and the current reality, need wider discussion. Ethics may provide both principles and impetus. Doing no harm, doing good, respecting the research participants autonomy are good starting points. More emphasis is needed on justice, fairness and equality, participation and communicating effectively. Ethnic minority groups are willing participants in trials once linguistic and trust-related barriers are overcome, though recruitment costs are higher. Guidelines and strategies by European bodies with research funding or enforcement responsibilities are needed. The research community needs an infrastructure within which to collect and utilize evidence. Research can help migrant and ethnic minority groups to participate more fully in our multi-ethnic societies. © 2012 The Author, Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved.

Sung K.-C.,Sungkyunkwan University | Wild S.H.,University of Edinburgh | Byrne C.D.,Endocrinology and Metabolism Unit
Journal of Hepatology | Year: 2014

Background & Aims Approximately 50% of hypertensive patients have non-alcoholic fatty liver disease (NAFLD), but whether change in fatty liver status over time modifies risk of developing hypertension is uncertain. Our aim was to determine whether a change in fatty liver status (either development of new fatty liver, or resolution of existing fatty liver) over five years modified risk of incident hypertension at five year follow-up. Methods 11,448 patients without hypertension were examined at baseline and at five year follow-up, using a retrospective cohort study design. Fatty liver status (absent or present) was assessed at baseline and follow-up using standard ultrasound criteria. Adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for incident hypertension at follow-up were estimated controlling for potential confounders, compared to the reference group (patients who did not have fatty liver at either baseline or follow-up). Results 911 patients developed incident hypertension. Incident fatty liver developed during follow-up in 1418 patients and fatty liver at baseline resolved during follow-up in 684 patients. Developing incident fatty liver was associated with incident hypertension, even after adjustment for multiple confounders (aOR = 1.60 (95% CI 1.30, 1.96; p <0.001). Further adjustment for change in body mass index between baseline and follow-up only slightly attenuated this association (aOR = 1.36 (95% CI 1.10, 1.67; p = 0.004). With resolution of fatty liver at follow-up, risk of incident hypertension was not different from the reference group (aOR = 1.21 (95% CI 0.90, 1.63; p = 0.21). Conclusions Development of incident fatty liver is associated with increased risk of hypertension. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The WHO Framework Convention on Tobacco Control (FCTC) demonstrates the international political will invested in combating the tobacco pandemic and a newfound prominence for tobacco control within the global health agenda. However, major difficulties exist in managing conflicts with foreign and trade policy priorities, and significant obstacles confront efforts to create synergies with development policy and avoid tensions with other health priorities. This paper uses the concept of policy coherence to explore congruence and inconsistencies in objectives, policy, and practice between tobacco control and trade, development and global health priorities. Following the inability of the FCTC negotiations to satisfactorily address the relationship between trade and health, several disputes highlight the challenges posed to tobacco control policies by multilateral and bilateral agreements. While the work of the World Bank has demonstrated the potential contribution of tobacco control to development, the absence of non-communicable diseases from the Millennium Development Goals has limited scope to offer developing countries support for FCTC implementation. Even within international health, tobacco control priorities may be hard to reconcile with other agendas. The paper concludes by discussing the extent to which tobacco control has been pursued via a model of governance very deliberately different from those used in other health issues, in what can be termed 'tobacco exceptionalism'. The analysis developed here suggests that noncommunicable disease (NCD) policies, global health, development and tobacco control would have much to gain from re-examining this presumption of difference.

Slater T.,University of Edinburgh
Antipode | Year: 2012

This article takes on the challenge of what Robert Proctor calls "agnotology" (the study of ignorance) to analyse the current assault on the British welfare state by think tanks, policy elites and conservative politicians. The assault is traced back to the emergence of the Centre for Social Justice think tank, founded in 2004 by the current Work and Pensions Secretary Iain Duncan-Smith. I argue that a familiar litany of social pathologies (family breakdown, worklessness, antisocial behaviour, personal responsibility, out-of-wedlock childbirth, dependency) is repeatedly invoked by the architects of welfare reform to manufacture ignorance of alternative ways of addressing poverty and social injustice. Structural causes of poverty have been strategically ignored in favour of a single behavioural explanation-"Broken Britain"-where "family breakdown" has become the central problem to be tackled by the philanthropic fantasy of a "Big Society". My agnotological approach critically explores the troubling relationship between (mis)information and state power. © 2012 Antipode Foundation Ltd.

Rees J.L.,University of Edinburgh
Acta Dermato-Venereologica | Year: 2013

The World Wide Web (www) and other internet-based technologies offer enormous potential for enhancing teaching in dermatology. There is also the possibility that if these technologies are adopted uncritically, either because of ignorance of how people learn, or because they are viewed primarily as ways to reduce institutional costs, that they might diminish learning, thereby reducing the value proposition that undergraduate students receive from Medical Schools. I review the history of recent technological change with a focus on what value such technologies bring to both student and institution. After summarising some of the core principles underpinning successful learning, and modern theories of medical expertise, I critically discuss some of the ways the Web and allied technologies might enhance the learning of dermatology. © 2013 The Authors.

Barz S.,University of Vienna | Fitzsimons J.F.,Singapore University of Technology and Design | Fitzsimons J.F.,National University of Singapore | Kashefi E.,University of Edinburgh | Walther P.,University of Vienna
Nature Physics | Year: 2013

Quantum computers are expected to offer substantial speed-ups over their classical counterparts and to solve problems intractable for classical computers. Beyond such practical significance, the concept of quantum computation opens up fundamental questions, among them the issue of whether quantum computations can be certified by entities that are inherently unable to compute the results themselves. Here we present the first experimental verification of quantum computation. We show, in theory and experiment, how a verifier with minimal quantum resources can test a significantly more powerful quantum computer. The new verification protocol introduced here uses the framework of blind quantum computing and is independent of the experimental quantum-computation platform used. In our scheme, the verifier is required only to generate single qubits and transmit them to the quantum computer. We experimentally demonstrate this protocol using four photonic qubits and show how the verifier can test the computer's ability to perform quantum computation. © 2013 Macmillan Publishers Limited.

Day P.L.,University of Canterbury | Pearce J.,University of Edinburgh
American Journal of Preventive Medicine | Year: 2011

Background The increasing prevalence of overweight and obesity in school-aged children is potentially linked to contextual influences such as the food environment around schools. The proximity of fast-food and convenience stores to schools may enhance access to unhealthy foods and have a negative impact on diet. Purpose This study used spatial cluster analysis to determine whether food outlets are clustered around schools and evaluated the extent of food outlet clustering by school and school neighborhood sociodemographic characteristics. Methods The locations in 2008 of all schools, fast-food outlets, and convenience stores in five urban regions across New Zealand were geocoded. Using GIS analysis conducted in 2009, the number and proportion of outlets within 400-m and 800-m road distance around each school was calculated. The spatial clustering of food outlets within 1.5 km of schools was determined using a multi-type K-function. Food outlet type, school level, SES, the degree of population density, and commercial land use zoning around each school were compared. Results Primary/intermediate schools had a total proportion of 19.3 outlets per 1000 students within 800 m compared to 6.6 for secondary schools. The most socially deprived quintile of schools had three times the number and proportion of food outlets compared to the least-deprived quintile. There was a high degree of clustering of food outlets around schools, with up to 5.5 times more outlets than might be expected. Outlets were most clustered up to 800 m from schools and around secondary schools, socially deprived schools, and schools in densely populated and commercially zoned areas. Conclusions Food environments in New Zealand within walking proximity to schools are characterized by a high density of fast-food outlets and convenience stores, particularly in moresocially deprived settings. These obesogenic environments provide ready access to obesity-promoting foods that may have a negative impact on student diet and contribute to inequalities in health. © 2011 American Journal of Preventive Medicine.

Williams A.,University of Edinburgh
QJM | Year: 2014

Until relatively recently, we thought that the human central nervous system (CNS) was unable to regenerate. However, with the initial discovery of remyelination within the brain and the spinal cord in cat (Bunge, Bunge and Ris. Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord. J Biophys Biochem Cytol 1961;10:67-94.) and later in human (Prineas and Connell. Remyelination in multiple sclerosis. Ann Neurol 1979;5:22-31.), we know that regeneration can be quite extensive. This review will concentrate on CNS remyelination, indicating why it is important for various human neurodegenerative diseases including multiple sclerosis and spinal cord injury, and relate how stem cells may be involved-both in endogenous repair and in proposed therapies. © The Author 2013. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved.

Fearon K.,University of Edinburgh | Arends J.,Albert Ludwigs University of Freiburg | Baracos V.,University of Alberta
Nature Reviews Clinical Oncology | Year: 2013

Cancer cachexia is a metabolic syndrome that can be present even in the absence of weight loss ('precachexia'). Cachexia is often compounded by pre-existing muscle loss, and is exacerbated by cancer therapy. Furthermore, cachexia is frequently obscured by obesity, leading to under-diagnosis and excess mortality. Muscle wasting (the signal event in cachexia) is associated not only with reduced quality of life, but also markedly increased toxicity from chemotherapy. Many of the primary events driving cachexia are likely mediated via the central nervous system and include inflammation-related anorexia and hypoanabolism or hypercatabolism. Treatment of cachexia should be initiated early. In addition to active management of secondary causes of anorexia (such as pain and nausea), therapy should target reduced food intake (nutritional support), inflammation-related metabolic change (anti-inflammatory drugs or nutrients) and reduced physical activity (resistance exercise). Advances in the understanding of the molecular biology of the brain, immune system and skeletal muscle have provided novel targets for the treatment of cachexia. The combination of therapies into a standard multimodal package coupled with the development of novel therapeutics promises a new era in supportive oncology whereby quality of life and tolerance to cancer therapy could be improved considerably.

Bowsher C.G.,University of Bristol | Swain P.S.,University of Edinburgh
Current Opinion in Biotechnology | Year: 2014

The recognition that gene expression can be substantially stochastic poses the question of how cells respond to dynamic environments using biochemistry that itself fluctuates. The study of cellular decision-making aims to solve this puzzle by focusing on quantitative understanding of the variation seen across isogenic populations in response to extracellular change. This behaviour is complex, and a theoretical framework within which to embed experimental results is needed. Here we review current approaches, with an emphasis on information theory, sequential data processing, and optimality arguments. We conclude by highlighting some limitations of these techniques and the importance of connecting both theory and experiment to measures of fitness. © 2014 Elsevier Ltd.

Garcia-Sancho M.,University of Edinburgh
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2016

In this paper, I propose a strategy for navigating newly available archives in the study of late-twentieth century genomics. I demonstrate that the alleged 'explosion of data' characteristic of genomics-and of contemporary science in general-is not a new problem and that historians of earlier periods have dealt with information overload by relying on the 'perspective of time': the filtering effect the passage of time naturally exerts on both sources and memories. I argue that this reliance on the selective capacity of time results in inheriting archives curated by others and, consequently, poses the risk of reifying ahistorical scientific discourses. Through a preliminary examination of archives documenting early attempts at mapping and sequencing the human genome, I propose an alternative approach, in which historians proactively problematize and improve available sources. This approach provides historians with a voice in the socio-political management of scientific heritage and advances methodological innovations in the use of oral histories. It also provides a narrative framework in which to address big science initiatives by following second order administrators, rather than individual scientists. The new genomic archives thus represent an opportunity for historians to take an active role in current debates concerning 'big data' and critically embed the humanities in pressing global problems. © 2015 Elsevier Ltd.

This review considers the effects of temperature on insect diapause induction and the photoperiodic response, and includes constant temperature, temperature cycles, pulses and steps in daily light-dark cycles, constant darkness and in constant light, all with reference to various circadian-based "clock" models. Although it is a comparative survey, it concentrates on two species, the flesh fly Sarcophaga argyrostoma and its pupal parasite Nasonia vitripennis, which possess radically different photoperiodic mechanisms, although both are based upon the circadian system. Particular attention is given to the effects of daily thermoperiod in darkness and to low and high temperature pulses in conjunction with a daily light-dark cycle, treatments that suggest that S.argyrostoma "measures" night length with a "clock" of the external coincidence type. However, N.vitripennis responds to seasonal changes in photoperiod with an internal coincidence device involving both "dawn" and "dusk" oscillators. Other species may show properties of both external and internal coincidence. Although the precepts of external coincidence have been well formulated and supported experimentally, those for internal coincidence remain obscure. © 2013 The Entomological Society of Japan.

Cheney J.,University of Edinburgh
Proceedings - IEEE Computer Security Foundations Symposium | Year: 2011

Provenance, or information about the origin, derivation, or history of data, is becoming an important topic especially for shared scientific or public data on the Web. It clearly has implications on security (and vice versa) yet these implications are not well-understood. A great deal of work has focused on mechanisms for recording, managing or using some kind of provenance information, but relatively little progress has been made on foundational models that define provenance and relate it to security goals such as availability, confidentiality or privacy. We argue that such foundations are essential to making meaningful progress on these problems and should be developed. In this paper, we outline a formal model of provenance, propose formalizations of security properties for provenance such as disclosure and obfuscation, and explore their implications in domains based on automata, database queries and workflow provenance graphs. © 2011 IEEE.

Miller M.R.,University of Edinburgh
Biochemical Society Transactions | Year: 2014

Air pollution has been estimated to be responsible for several millions of deaths worldwide per year, the majority of which have been attributed to cardiovascular causes. The particulate matter in air pollution has been shown impair vascular function, increase blood pressure, promote thrombosis and impair fibrinolysis, accelerate the development of atherosclerosis, increase the extent of myocardial ischaemia, and increase susceptibility to myocardial infarction. The pathways underlying these effects are complex and poorly understood; however, particulate-induced oxidative stress repeatedly emerges as a potential mechanism in all of these detrimental cardiovascular actions. The present mini-review will use diesel exhaust as an example of a pollutant rich in combustion-derived nanoparticles, to describe the potential bywhich oxidative stress could drive the cardiovascular effects of air pollution. © The Authors Journal compilation © 2014 Biochemical Society.

Venkatasubramanian S.,University of Edinburgh
Journal of the American Heart Association | Year: 2013

Urocortin 2 and urocortin 3 are endogenous peptides with an emerging role in cardiovascular pathophysiology. We assessed their pharmacodynamic profile and examined the role of the endothelium in mediating their vasomotor effects in vivo in man. Eighteen healthy male volunteers (23±4 years) were recruited into a series of double-blind, randomized crossover studies using bilateral forearm venous occlusion plethysmography during intra-arterial urocortin 2 (3.6 to 120 pmol/min), urocortin 3 (1.2 to 36 nmol/min), and substance P (2 to 8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole), and nitric oxide synthase (L-NMMA). Urocortins 2 and 3 evoked arterial vasodilatation (P<0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L-NMMA reduced vasodilatation to substance P and urocortin 2 (P≤0.001 for both) but had little effect on urocortin 3 (P>0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P>0.05 for all). In the presence of all 3 inhibitors, urocortin 2- and urocortin 3-induced vasodilatation was attenuated (P<0.001 for all) to a greater extent than with L-NMMA alone (P≤0.005). Urocortins 2 and 3 cause potent and prolonged arterial vasodilatation without tachyphylaxis. These vasomotor responses are at least partly mediated by endothelial nitric oxide and cytochrome P450 metabolites of arachidonic acid. The role of urocortins 2 and 3 remains to be explored in the setting of human heart failure, but they have the potential to have major therapeutic benefits. http://www.clinicaltrials.gov//. Unique identifier: NCT01096706 and NCT01296607.

Langrish J.P.,University of Edinburgh
Journal of the American Heart Association | Year: 2013

Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (NO) bioavailability in mediating these effects. In 2 randomized double-blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air. Study 1: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (ACh; 5 to 20 μg/min) and sodium nitroprusside (SNP; 2 to 8 μg/min) in the presence of the NO clamp (NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) 8 μg/min coinfused with the NO donor SNP at 90 to 540 ng/min to restore basal blood flow). Study 2: Blood pressure, arterial stiffness, and cardiac output were measured during systemic NO synthase inhibition with intravenous l-NMMA (3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68±48 versus 41±32 nmol/L; P=0.006) despite similar l-NMMA-induced reductions in basal blood flow (-20.6±14.7% versus -21.1±14.6%; P=0.559) compared to air. In the presence of the NO clamp, ACh and SNP caused dose-dependent vasodilatation that was not affected by diesel exhaust inhalation (P>0.05 for both). Following exposure to diesel exhaust, l-NMMA caused a greater increase in blood pressure (P=0.048) and central arterial stiffness (P=0.007), but reductions in cardiac output and increases in systemic vascular resistance (P>0.05 for both) were similar to those seen with filtered air. Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced NO generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced NO bioavailability. URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00845767 and NCT01060930.

Attfield J.P.,University of Edinburgh
Journal of Materials Chemistry | Year: 2011

Seven distinct families of superconductors with critical temperatures at ambient pressure that equal or surpass the historic 23 K limit for Nb 3Ge have been discovered in the last 25 years. Each family is reviewed briefly and their common chemical features are discussed. High temperature superconductors are distinguished by having a high (≥50%) content of nonmetallic elements and fall into two broad classes. 'Metal-nonmetal' superconductors require a specific combination of elements such as Cu-O and Fe-As which give rise to the highest known Tc's, probably through a magnetic pairing mechanism. 'Nonmetal-bonded' materials contain covalently bonded nonmetal anion networks and are BCS-like superconductors. Fitting an extreme value function to the distribution of Tc values for the known high-Tc families suggests that the probability of a newly discovered superconductor family having maximum Tc > 100 K is ∼0.1 to 1%, decreasing to ∼0.02 to 0.2% for room temperature superconductivity. © The Royal Society of Chemistry 2011.

The growing competition and "publish or perish" culture in academia might conflict with the objectivity and integrity of research, because it forces scientists to produce "publishable" results at all costs. Papers are less likely to be published and to be cited if they report "negative" results (results that fail to support the tested hypothesis). Therefore, if publication pressures increase scientific bias, the frequency of "positive" results in the literature should be higher in the more competitive and "productive" academic environments. This study verified this hypothesis by measuring the frequency of positive results in a large random sample of papers with a corresponding author based in the US. Across all disciplines, papers were more likely to support a tested hypothesis if their corresponding authors were working in states that, according to NSF data, produced more academic papers per capita. The size of this effect increased when controlling for state's per capita R&D expenditure and for study characteristics that previous research showed to correlate with the frequency of positive results, including discipline and methodology. Although the confounding effect of institutions' prestige could not be excluded (researchers in the more productive universities could be the most clever and successful in their experiments), these results support the hypothesis that competitive academic environments increase not only scientists' productivity but also their bias. The same phenomenon might be observed in other countries where academic competition and pressures to publish are high. © 2010 Daniele Fanelli.

Welburn J.P.I.,University of Edinburgh
Cytoskeleton | Year: 2013

Microtubule-based motor proteins play key roles during mitosis to assemble the bipolar spindle, define the cell division axis, and align and segregate the chromosomes. The majority of mitotic motors are members of the kinesin superfamily. Despite sharing a conserved catalytic core, each kinesin has distinct functions and localization, and is uniquely regulated in time and space. These distinct behaviors and functional specificity are generated by variations in the enzymatic domain as well as the non-conserved regions outside of the kinesin motor domain and the stalk. These flanking regions can directly modulate the properties of the kinesin motor through dimerization or self-interactions, and can associate with extrinsic factors, such as microtubule or DNA binding proteins, to provide additional functional properties. This review discusses the recently identified molecular mechanisms that explain how the control and functional specification of mitotic kinesins is achieved. © 2013 Wiley Periodicals, Inc.

Gambardella L.,Babraham Institute | Vermeren S.,University of Edinburgh
Journal of Leukocyte Biology | Year: 2013

Neutrophil chemotaxis is a process by which individual cells sense a gradient of chemoattractant, polarize, and then migrate toward the chemoattractant. Many features of chemotaxis are shared with other forms of cell migration. We continue to expand our understanding of the mechanisms governing these features. The rapid process through which neutrophils polarize when placed into a gradient of chemoattractant remains least well-understood. Several key molecular players involved in the regulation of polarization have been identified. However, crosstalk among the different molecular players is required to polarize the cell and to maintain cell polarity during directional migration. The mechanism(s) by which this occurs are the subject of current investigations using experimental and computational approaches. Here, we review progress in the field, putting recent observations into context with established findings. We concentrate on the signaling processes regulated by PI3Ks, their lipid products, the role of Rho-family small GTPases, and crosstalk between these important families of regulators. © Society for Leukocyte Biology.

Monteiro R.,University of Oxford | O'Connell D.,University of Edinburgh
Journal of High Energy Physics | Year: 2014

We study kinematic algebras associated to the recently proposed scattering equations, which arise in the description of the scattering of massless particles. In particular, we describe the role that these algebras play in the BCJ duality between colour and kinematics in gauge theory, and its relation to gravity. We find that the scattering equations are a consistency condition for a self-dual-type vertex which is associated to each solution of those equations. We also identify an extension of the anti-self-dual vertex, such that the two vertices are not conjugate in general. Both vertices correspond to the structure constants of Lie algebras. We give a prescription for the use of the generators of these Lie algebras in trivalent graphs that leads to a natural set of BCJ numerators. In particular, we write BCJ numerators for each contribution to the amplitude associated to a solution of the scattering equations. This leads to a decomposition of the determinant of a certain kinematic matrix, which appears naturally in the amplitudes, in terms of trivalent graphs. We also present the kinematic analogues of colour traces, according to these algebras, and the associated decomposition of that determinant. © The Authors.

Grant S.G.N.,University of Edinburgh
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

How the sophisticated vertebrate behavioural repertoire evolved remains a major question in biology. The behavioural repertoire encompasses the set of individual behavioural components that an organism uses when adapting and responding to changes in its external world. Although unicellular organisms, invertebrates and vertebrates share simple reflex responses, the fundamental mechanisms that resulted in the complexity and sophistication that is characteristic of vertebrate behaviours have only recently been examined. A series of behavioural genetic experiments in mice and humans support a theory that posited the importance of synapse proteome expansion in generating complexity in the behavioural repertoire. Genome duplication events, approximately 550 Ma, produced expansion in the synapse proteome that resulted in increased complexity in synapse signalling mechanisms that regulate components of the behavioural repertoire. The experiments demonstrate the importance to behaviour of the gene duplication events, the diversification of paralogues and sequence constraint. They also confirm the significance of comparative proteomic and genomic studies that identified the molecular origins of synapses in unicellular eukaryotes and the vertebrate expansion in proteome complexity. These molecular mechanisms have general importance for understanding the repertoire of behaviours in different species and for human behavioural disorders arising from synapse gene mutations. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Gardi E.,University of Edinburgh
Journal of High Energy Physics | Year: 2014

We compute a class of diagrams contributing to the multi-leg soft anomalous dimension through three loops, by renormalizing a product of semi-infinite non-lightlike Wilson lines in dimensional regularization. Using non-Abelian exponentiation we directly compute contributions to the exponent in terms of webs. We develop a general strategy to compute webs with multiple gluon exchanges between Wilson lines in configuration space, and explore their analytic structure in terms of α ij, the exponential of the Minkowski cusp angle formed between the lines i and j. We show that beyond the obvious inversion symmetry α ij → 1/α ij, at the level of the symbol the result also admits a crossing symmetry α ij → -α ij, relating spacelike and timelike kinematics, and hence argue that in this class of webs the symbol alphabet is restricted to α ij and α2 ij. We carry out the calculation up to three gluons connecting four Wilson lines, finding that the contributions to the soft anomalous dimension are remarkably simple: they involve pure functions of uniform weight, which are written as a sum of products of polylogarithms, each depending on a single cusp angle. We conjecture that this type of factorization extends to all multiple-gluon- exchange contributions to the anomalous dimension. © 2014 The Author(s).

Loenen W.A.M.,Leiden University | Dryden D.T.F.,University of Edinburgh | Raleigh E.A.,New England Biolabs | Wilson G.G.,New England Biolabs
Nucleic Acids Research | Year: 2014

In the early 1950's, 'host-controlled variation in bacterial viruses' was reported as a non-hereditary phenomenon: one cycle of viral growth on certain bacterial hosts affected the ability of progeny virus to grow on other hosts by either restricting or enlarging their host range. Unlike mutation, this change was reversible, and one cycle of growth in the previous host returned the virus to its original form. These simple observations heralded the discovery of the endonuclease and methyltransferase activities of what are now termed Type I, II, III and IV DNA restriction-modification systems. The Type II restriction enzymes (e.g. EcoRI) gave rise to recombinant DNA technology that has transformed molecular biology and medicine. This review traces the discovery of restriction enzymes and their continuing impact on molecular biology and medicine. © The Author(s) 2013. Published by Oxford University Press.

Schneider C.,Northumbria University | Tollervey D.,University of Edinburgh
Trends in Biochemical Sciences | Year: 2013

In eukaryotes, the exosome complex degrades RNA backbones and plays key roles in RNA processing and surveillance. It was predicted that RNA substrates are threaded through a central channel. This pathway is conserved between eukaryotic and archaeal complexes, even though nuclease activity was lost from the nine-subunit eukaryotic core (EXO-9) and transferred to associated proteins. The exosome cooperates with nuclear and cytoplasmic cofactors, including RNA helicases Mtr4 and Ski2, respectively. Structures of an RNA-bound exosome and both helicases revealed how substrates are channeled through EXO-9 to the associated nuclease Rrp44. Recent high-throughput analyses provided fresh insights relating exosome structure to its diverse in vivo functions. They also revealed surprisingly high degradation rates for newly synthesized RNAs, particularly RNA polymerase III transcripts. © 2013 Elsevier Ltd.

Butcher L.M.,University of Edinburgh
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

I prove that general relativity admits no asymptotically well-behaved static spherically symmetric traversable wormholes supported by classical scalar fields and nonexotic matter. The theorem holds for all values of the scalar field curvature coupling parameter ξ, even though fields with ξ>0 are capable of violating the average null energy condition. Good asymptotic behavior (the effective Newton's constant being positive and finite at both ends of the wormhole) can only be achieved by introducing additional exotic matter, which must itself violate the null energy condition over some region of nonzero volume. These results are insensitive to the number of scalar fields, the form of their potentials, and the coupling between the fields and the additional matter. © 2015 American Physical Society.

Jarman A.P.,University of Edinburgh | Groves A.K.,Baylor College of Medicine
Seminars in Cell and Developmental Biology | Year: 2013

Mechanosensation is an evolutionarily ancient sensory modality seen in all main animal groups. Mechanosensation can be mediated by sensory neurons or by dedicated receptor cells that form synapses with sensory neurons. Evidence over the last 15-20 years suggests that both classes of mechanosensory cells can be specified by the atonal class of basic helix-loop-helix transcription factors. In this review we discuss recent work addressing how atonal factors specify mechanosensitive cells in vertebrates and invertebrates, and how the redeployment of these factors underlies the regeneration of mechanosensitive cells in some vertebrate groups. © 2013 Elsevier Ltd.

Savaresi A.,University of Edinburgh
Ecology and Society | Year: 2013

The making of the REDD+ mechanism in the framework of the United Nations Framework Convention on Climate Change (UNFCCC) has raised specific concerns on how to reconcile incentives for forest carbon sequestration with the protection of the rights of the numerous communities that rely upon forests for their livelihood, shelter, and survival. Although the nascent REDD+ mechanism provides an opportunity to provide multiple benefits, the design of a framework to secure such benefits and avoid perverse outcomes has proven complex. I provide an overview of progress toward the establishment of such framework, arguing that concerns over the social impact of REDD+ activities may be addressed by resorting to clearer and stronger links with human rights instruments. © 2013 by the author(s).

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer. © 2013 David C.

The association between type 2 diabetes and some types of cancer is well established and the complexity of this association is receiving increasing recognition. Many factors influence the risk of both diabetes and cancer including age, sex, ethnicity, socioeconomic status, obesity/insulin resistance, diet (including alcohol intake), physical activity levels and smoking history. The presence of diabetes may influence the uptake of cancer screening. Using an experimental approach to investigate the effect of better control of diabetes is helpful in assessing whether hyperglycaemia has a causal relationship with cancer. Diabetes treatments may influence the risk of cancer independently of their effect on glycaemia and complicate investigation of the association between diabetes and cancer. This article discusses the complexity involved in attempting to clarify the factors that contribute to the associations between diabetes, hyperglycaemia, diabetes treatment and cancer. © 2011 Springer-Verlag.

With approximately 1.5 billion people at risk, the staggeringly high risk of Type 2 diabetes in South Asians comprises a global problem. The causes of this high risk are complex, with 23 major risk factors identified in a Lancet seminar. This paper proposes a four-stage explanatory model: (1) the birth of a small, adipose, lowlean mass South Asian baby-the phenotype tracking through life; (2) in childhood and early adulthood, the deposition of any excess energy intake preferentially in upper body and ectopic fat stores rather than in the lower body or superficial subcutaneous fat stores; (3) as a consequence of points 1 and 2, and exacerbated by an environment of low physical activity and excess calories, the accelerated appearance of high levels of plasma insulin, triglycerides and glucose, and the fatty-liver vicious cycle; (4) β-cell failure as a result of fewer β-cells at birth, exposure to apoptotic triggers such as fat in the pancreas, and high demand from insulin resistance, which causes diabetes. Other risk factors-especially energy-dense hyperglycaemic diet and low physical activity-play into this pathway. The recommended behavioural changes fit with this model, which brings clarity to guide future research, policy, practice and health promotion. © 2012 Diabetes UK.

Flors C.,University of Edinburgh
Current opinion in chemical biology | Year: 2011

Chromatin organization spans a wide range of structural complexity. Substructures at the 10-200nm scale are poorly characterized, especially in living cells, due to the limitations of electron microscopy and standard optical microscopy. Recently developed super-resolution fluorescence microscopy methods represent an exciting opportunity to access those substructures, and recent progress with these techniques has yielded insights into chromatin organization at different condensation stages. Recent studies have focused on confronting the challenges that are specific to chromatin super-resolution imaging, such as the high packing density of mitotic chromosomes and difficulties in interpreting interphase chromatin images. Building on these first results and with ongoing rapid technical advances in super-resolution fluorescence imaging there is great potential to uncover new features with unprecedented detail. Copyright © 2011 Elsevier Ltd. All rights reserved.

McMahon M.I.,University of Edinburgh
Topics in Current Chemistry | Year: 2012

The ability of pressure to change inter-atomic distances strongly leads to a wide range of pressure-induced phenomena at high pressures: for example metallisation, amorphisation, superconductivity and polymerisation. Key to understanding these phenomena is the determination of the crystal structure using X-ray or neutron diffraction. The tools necessary to compress matter above 1 million atmospheres (1 Megabar or 100 GPa) were established by the mid 1970s, but it is only since the early 1990s that we have been able to determine the detailed crystal structures of materials at such pressures. In this chapter I briefly review the history of high-pressure crystallography, and describe the techniques used to obtain and study materials at high pressure. Recent crystallographic studies of elements are then used to illustrate what is now possible using modern detectors and synchrotron sources. Finally, I speculate as to what crystallographic studies might become possible over the next decade. © 2011 Springer-Verlag Berlin Heidelberg.

Loenen W.A.M.,Leiden University | Dryden D.T.F.,University of Edinburgh | Raleigh E.A.,New England Biolabs | Wilson G.G.,New England Biolabs
Nucleic Acids Research | Year: 2014

Type I restriction enzymes (REases) are large pentameric proteins with separate restriction (R), methylation (M) and DNA sequence-recognition (S) subunits. They were the first REases to be discovered and purified, but unlike the enormously useful Type II REases, they have yet to find a place in the enzymatic toolbox of molecular biologists. Type I enzymes have been difficult to characterize, but this is changing as genome analysis reveals their genes, and methylome analysis reveals their recognition sequences. Several Type I REases have been studied in detail and what has been learned about them invites greater attention. In this article, we discuss aspects of the biochemistry, biology and regulation of Type I REases, and of the mechanisms that bacteriophages and plasmids have evolved to evade them. Type I REases have a remarkable ability to change sequence specificity by domain shuffling and rearrangements. We summarize the classic experiments and observations that led to this discovery, and we discuss how this ability depends on the modular organizations of the enzymes and of their S subunits. Finally, we describe examples of Type II restriction-modification systems that have features in common with Type I enzymes, with emphasis on the varied Type IIG enzymes. © The Author(s) 2013. Published by Oxford University Press.

Wallace W.H.B.,University of Edinburgh | Kelsey T.W.,University of St. Andrews
PLoS ONE | Year: 2010

The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50-51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained r2 correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). When restricted to ages up to 25 years, the ADC curve has r2 = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments. © 2010 Wallace, Kelsey.

Lewis G.J.,University of Edinburgh
Psychological science : a journal of the American Psychological Society / APS | Year: 2010

In-group favoritism is ubiquitous and associated with intergroup conflict, yet is little understood from a biological perspective. A fundamental question regarding the structure of favoritism is whether it is inflexibly directed toward distinct, "essentialist" categories, such as ethnicity and race, or is deployed in a context-sensitive manner. In this article, we report the first study (to our knowledge) of the genetic and environmental structure of in-group favoritism in the religious, ethnic, and racial domains. We contrasted a model of favoritism based on a single domain-general central affiliation mechanism (CAM) with a model in which each domain was influenced by specific mechanisms. In a series of multivariate analyses, utilizing a large, representative sample of twins, models containing only the CAM or essentialist domains fit the data poorly. The best-fitting model revealed that a biological mechanism facilitates affiliation with arbitrary groups and exists alongside essentialist systems that evolved to process salient cues, such as shared beliefs and ancestry.

Arnold P.L.,University of Edinburgh
Chemical Communications | Year: 2011

Molecular complexes of uranium are capable of activating a range of industrially and economically important small molecules such as CO, CO 2, and N 2; new and often unexpected reactions provide insight into an element that needs to be well-understood if future clean-energy solutions are to involve nuclear power. © 2011 The Royal Society of Chemistry.

Brenn T.,University of Edinburgh
Archives of Pathology and Laboratory Medicine | Year: 2011

Context.-Atypical genital nevus is rare and the only poorly documented melanocytic lesion in the spectrum of nevi of special sites. It is characterized by unique and reproducible histologic features, which may appear alarming and may raise significant concern for a diagnosis of melanoma. Objectives.-To present the clinical and histologic features of atypical genital nevus with emphasis on distinction from vulvar melanoma. Data Sources.-The findings are based on a review of the current literature. Conclusions.-Atypical genital nevus is most often found in the vulva of premenopausal women. Despite the alarming histologic features, its clinical behavior appears benign with only rare local recurrence after incomplete removal. Recognition of this unusual melanocytic lesion and its characteristic histologic features is important to avoid overdiagnosis of invasive melanoma, with subsequent wide excision or sentinel lymph node biopsy, especially in view of the sensitive anatomic location.

Heal M.R.,University of Edinburgh | Kumar P.,University of Surrey | Harrison R.M.,University of Birmingham | Harrison R.M.,King Abdulaziz University
Chemical Society Reviews | Year: 2012

The diversity of ambient particle size and chemical composition considerably complicates pinpointing the specific causal associations between exposure to particles and adverse human health effects, the contribution of different sources to ambient particles at different locations, and the consequent formulation of policy action to most cost-effectively reduce harm caused by airborne particles. Nevertheless, the coupling of increasingly sophisticated measurements and models of particle composition and epidemiology continue to demonstrate associations between particle components and sources (and at lower concentrations) and a wide range of adverse health outcomes. This article reviews the current approaches to source apportionment of ambient particles and the latest evidence for their health effects, and describes the current metrics, policies and legislation for the protection of public health from ambient particles. A particular focus is placed on particles in the ultrafine fraction. The review concludes with an extended evaluation of emerging challenges and future requirements in methods, metrics and policy for understanding and abating adverse health outcomes from ambient particles. © The Royal Society of Chemistry 2012.

Barran P.E.,University of Edinburgh
Angewandte Chemie - International Edition | Year: 2011

Who needs water? The gas phase may seem an esoteric place to examine the structures of proteins, but a new study reveals that the solution fold of the protein KIX can be retained for significant time periods in a mass spectrometer. Once in this ideal laboratory environment, details of the higher order fold can be elucidated at the single amino acid level. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Idris A.I.,University of Edinburgh
Current Neuropharmacology | Year: 2010

The central nervous system plays an important role in regulating bone metabolism in health and in disease with a number of neurotransmitters been reported to influence bone cell activity through a central relay. In keeping with this, recent studies demonstrated that endocannabinoids and their receptors are involved in the pathogenesis of osteoporosis. The endocannabinoids anandamide and 2-arachidonylglycerol are found in the skeleton and numerous studies also showed that bone cells express the cannabinoid receptors CB1 and CB2 and the orphan receptor GPR55. Pharmacological and genetic inactivation of CB1, CB2 and GPR55 in adult mice suppress bone resorption, increase bone mass and protect against bone loss, suggesting that inverse agonists/antagonists of these receptors may serve as anti-resorptive agents. In the ageing skeleton however CB1 and CB2 receptors have a protective effect against age-dependent bone loss in both male and female mice. CB1 receptor deficiency in aged mice results in accelerated age-dependent osteoporosis due to marked increase in bone resorption and significant reduction in bone formation coupled to enhanced adipocyte accumulation in the bone marrow compartment. Similar acceleration of bone loss was also reported in CB2 deficient mice of similar age but found to be associated with enhanced bone turnover. This review summarises in vitro and in vivo findings relating to the influence of cannabinoid ligands on bone metabolism and argues in favour of the exploitation of cannabinoid receptors as targets for both anabolic and anti-resorptive therapy for treatment of complex multifaceted bone diseases such as osteoporosis. © 2010 Bentham Science Publishers Ltd.

Vanneste J.,University of Edinburgh
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2010

We discuss several techniques for the evaluation of the generalized Lyapunov exponents which characterize the growth of products of random matrices in the large-deviation regime. A Monte Carlo algorithm that performs importance sampling using a simple random resampling step is proposed as a general-purpose numerical method which is both efficient and easy to implement. Alternative techniques complementing this method are presented. These include the computation of the generalized Lyapunov exponents by solving numerically an eigenvalue problem, and some asymptotic results corresponding to high-order moments of the matrix products. Taken together, the techniques discussed in this paper provide a suite of methods which should prove useful for the evaluation of the generalized Lyapunov exponents in a broad range of applications. Their usefulness is demonstrated on particular products of random matrices arising in the study of scalar mixing by complex fluid flows. © 2010 The American Physical Society.

Santhanam R.,University of Edinburgh
Proceedings - Annual IEEE Symposium on Foundations of Computer Science, FOCS | Year: 2010

We investigate the possibility of finding satisfying assignments to Boolean formulae and testing validity of quantified Boolean formulae (QBF) asymptotically faster than a brute force search. Our first main result is a simple deterministic algorithm running in time 2n-Ω(n) for satisfiability of formulae of linear size in n, where n is the number of variables in the formula. This algorithm extends to exactly counting the number of satisfying assignments, within the same time bound. Our second main result is a deterministic algorithm running in time 2n-Ω(n/log(n)) for solving QBFs in which the number of occurrences of any variable is bounded by a constant. For instances which are "structured", in a certain precise sense, the algorithm can be modified to run in time 2n-Ω(n). To the best of our knowledge, no non-trivial algorithms were known for these problems before. As a byproduct of the technique used to establish our first main result, we show that every function computable by linear-size formulae can be represented by decision trees of size 2n-Ω(n). As a consequence, we get strong superlinear average-case formula size lower bounds for the Parity function. © 2010 IEEE.

Smith K.E.,University of Edinburgh | Katikireddi S.V.,Medical Research Council
Journal of Epidemiology and Community Health | Year: 2013

Public health practitioners and researchers often seek to influence public policies in order to improve population health and/or reduce health inequalities. However, these efforts frequently appear to be uninformed by the many empirically-based theories about policymaking that have been developed within political science. This glossary provides a brief overview of some of the most popular of these theories, describing how each: frames the policymaking process; portrays the relationships and influence of specific policy actors; and depicts the potential for policy change (or inertia). Examples of their application to public health are provided to help improve understanding of the material presented. Throughout the article, the implications of the different theories for public health researchers and advocates seeking to inform policy decisions are emphasised. The glossary aims to provide an accessible overview to key theories about policy and decision-making, with a view to supporting public health efforts to achieve healthier public policies.

Adams R.R.,University of Edinburgh
Bioinformatics | Year: 2012

The simulation experiment description markup language (SED-ML) is a new community data standard to encode computational biology experiments in a computer-readable XML format. Its widespread adoption will require the development of software support to work with SED-ML files. Here, we describe a software tool, SED-ED, to view, edit, validate and annotate SEDML documents while shielding end-users from the underlying XML representation. SED-ED supports modellers who wish to create, understand and further develop a simulation description provided in SED-ML format. © The Author 2012. Published by Oxford University Press. All rights reserved.

Mitchard E.T.,University of Edinburgh
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

We review the literature and find 16 studies from across Africa's savannas and woodlands where woody encroachment dominates. These small-scale studies are supplemented by an analysis of long-term continent-wide satellite data, specifically the Normalized Difference Vegetation Index (NDVI) time series from the Global Inventory Modeling and Mapping Studies (GIMMS) dataset. Using dry-season data to separate the tree and grass signals, we find 4.0% of non-rainforest woody vegetation in sub-Saharan Africa (excluding West Africa) significantly increased in NDVI from 1982 to 2006, whereas 3.52% decreased. The increases in NDVI were found predominantly to the north of the Congo Basin, with decreases concentrated in the Miombo woodland belt. We hypothesize that areas of increasing dry-season NDVI are undergoing woody encroachment, but the coarse resolution of the study and uncertain relationship between NDVI and woody cover mean that the results should be interpreted with caution; certainly, these results do not contradict studies finding widespread deforestation throughout the continent. However, woody encroachment could be widespread, and warrants further investigation as it has important consequences for the global carbon cycle and land-climate interactions.

Wyart M.,New York University | Cates M.E.,University of Edinburgh
Physical Review Letters | Year: 2014

A consensus is emerging that discontinuous shear thickening (DST) in dense suspensions marks a transition from a flow state where particles remain well separated by lubrication layers, to one dominated by frictional contacts. We show here that reasonable assumptions about contact proliferation predict two distinct types of DST in the absence of inertia. The first occurs at densities above the jamming point of frictional particles; here, the thickened state is completely jammed and (unless particles deform) cannot flow without inhomogeneity or fracture. The second regime shows strain-rate hysteresis and arises at somewhat lower densities, where the thickened phase flows smoothly. DST is predicted to arise when finite-range repulsions defer contact formation until a characteristic stress level is exceeded. © 2014 American Physical Society.

Bickmore W.A.,University of Edinburgh | Van Steensel B.,Netherlands Cancer Institute
Cell | Year: 2013

The architecture of interphase chromosomes is important for the regulation of gene expression and genome maintenance. Chromosomes are linearly segmented into hundreds of domains with different protein compositions. Furthermore, the spatial organization of chromosomes is nonrandom and is characterized by many local and long-range contacts among genes and other sequence elements. A variety of genome-wide mapping techniques have made it possible to chart these properties at high resolution. Combined with microscopy and computational modeling, the results begin to yield a more coherent picture that integrates linear and three-dimensional (3D) views of chromosome organization in relation to gene regulation and other nuclear functions. © 2013 Elsevier Inc.

Deary I.J.,University of Edinburgh
Current Biology | Year: 2013

Some people are cleverer than others. I think it would be a good thing if more biologists began with that observation as the starting point for their research. Why? Because it is a prominent and consistent way in which people differ from each other; because the measurements we make of people's cleverness produce scores that are correlated with important life outcomes; because it is interesting to discover the mechanisms that produce these individual differences; and because understanding these mechanisms might help to ameliorate those states in which cognitive function is low or declining. © 2013 Elsevier Ltd.

Donoho D.L.,Stanford University | Tanner J.,University of Edinburgh
Proceedings of the IEEE | Year: 2010

Undersampling theorems state that we may gather far fewer samples than the usual sampling theorem while exactly reconstructing the object of interestprovided the object in question obeys a sparsity condition, the samples measure appropriate linear combinations of signal values, and we reconstruct with a particular nonlinear procedure. While there are many ways to crudely demonstrate such undersampling phenomena, we know of only one mathematically rigorous approach which precisely quantifies the true sparsity-undersampling tradeoff curve of standard algorithms and standard compressed sensing matrices. That approach, based on combinatorial geometry, predicts the exact location in sparsity-undersampling domain where standard algorithms exhibit phase transitions in performance. We review the phase transition approach here and describe the broad range of cases where it applies. We also mention exceptions and state challenge problems for future research. Sample result: one can efficiently reconstruct a k-sparse signal of length N from n measurements, provided n≥2k ̇ log(N/n), for (k,n,N) large, k ≥ N. AMS 2000 subject classifications. Primary: 41A46, 52A22, 52B05, 62E20, 68P30, 94A20; Secondary: 15A52, 60F10, 68P25, 90C25, 94B20. © 2010 IEEE.

Charlesworth B.,University of Edinburgh
Journal of Heredity | Year: 2013

The mutation process continually produces new deleterious variants at sites throughout the genome, which are then mostly eliminated by selection. This causes a reduction in variability at linked neutral or nearly neutral sites, as well as distortions of the genealogies of samples of alleles from a population. In regions of the genome where recombination is frequent, the effects of selection against deleterious mutations on variability and evolution at linked sites can be predicted under the assumption that most deleterious mutations have such large effects that their behavior in the population is effectively deterministic - this is background selection in the strict sense. But in genomic regions with little or no recombination, such as the Y chromosome, large departures from the predictions using deterministic models may occur, because of interference between different sites under selection. Evidence from Drosophila and human populations is discussed, which suggests that these processes play a major role in shaping patterns of DNA sequence variation and evolution, including the relative levels of variation on X chromosomes and autosomes, and the highly reduced variability seen in regions that lack crossing over. © 2013 © The American Genetic Association. 2013. All rights reserved.

Hawkins M.R.S.,University of Edinburgh
Monthly Notices of the Royal Astronomical Society | Year: 2010

In this paper we set out to measure time dilation in quasar light curves. In order to detect the effects of time dilation, sets of light curves from two monitoring programmes are used to construct Fourier power spectra covering time-scales from 50 d to 28 yr. Data from high- and low-redshift samples are compared to look for the changes expected from time dilation. The main result of the paper is that quasar light curves do not show the effects of time dilation. Several explanations are discussed, including the possibility that time dilation effects are exactly offset by an increase in time-scale of variation associated with black hole growth, or that the variations are caused by microlensing in which case time dilation would not be expected. © 2010 The Author. Journal compilation © 2010 RAS.

Knoblauch M.,Washington State University | Oparka K.,University of Edinburgh
Plant Journal | Year: 2012

Long-distance assimilate distribution in higher plants takes place in the enucleate sieve-tube system of the phloem. It is generally accepted that flow of assimilates is driven by an osmotically generated pressure differential, as proposed by Ernst Münch more than 80 years ago. In the period between 1960 and 1980, the pressure flow hypothesis was challenged when electron microscopic images suggested that sieve tubes contain obstructions that would prevent passive flow. This led to the proposal of alternative translocation mechanisms. However, most investigators came to the conclusion that obstructions in the sieve-tube path were due to preparation artifacts. New developments in bioimaging have vastly enhanced our ability to study the phloem. Unexpectedly, in vivo studies challenge the pressure-flow hypothesis once again. In this review we summarize current investigations of phloem structure and function and discuss their impact on our understanding of long-distance transport in the phloem. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

Mechanisms that control surface expression and/or activity of large conductance calcium-activated potassium (BK) channels are important determinants of their (patho)physiological function. Indeed, BK channel dysfunction is associated with major human disorders ranging from epilepsy to hypertension and obesity. Sacylation (S-palmitoylation) represents a major reversible, post-translational modification controlling the properties and function of many proteins including ion channels. Recent evidence reveals that both pore-forming and regulatory subunits of BK channels are S-acylated and control channel trafficking and regulation by AGCfamily protein kinases. The pore-forming a-subunit is S-acylated at two distinct sites within the N- and C-terminus, each site being regulated by different palmitoyl acyl transferases (zDHHCs) and acyl thioesterases. (APTs). S-acylation of the N-terminus controls channel trafficking and surface expression whereas S-acylation of the Cterminal domain determines regulation of channel activity by AGC-family protein kinases. S-acylation of the regulatory β4-subunit controls ER exit and surface expression of BK channels but does not affect ion channel kinetics at the plasma membrane. Furthermore, a significant number of previously identified BK-channel interacting proteins have been shown, or are predicted to be, S-acylated. Thus, the BK channel multi-molecular signalling complex may be dynamically regulated by this fundamental post-translational modification and thus S-acylation likely represents an important determinant of BK channel physiology in health and disease. © 2014 Shipston.

Pennacchio L.A.,Lawrence Berkeley National Laboratory | Bickmore W.,University of Edinburgh | Dean A.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Nobrega M.A.,University of Chicago | Bejerano G.,Stanford University
Nature Reviews Genetics | Year: 2013

It is estimated that the human genome contains hundreds of thousands of enhancers, so understanding these gene-regulatory elements is a crucial goal. Several fundamental questions need to be addressed about enhancers, such as how do we identify them all, how do they work, and how do they contribute to disease and evolution? Five prominent researchers in this field look at how much we know already and what needs to be done to answer these questions. © 2013 Macmillan Publishers Limited. All rights reserved.

Bickmore W.A.,University of Edinburgh
Annual Review of Genomics and Human Genetics | Year: 2013

In vivo, the human genome functions as a complex, folded, three-dimensional chromatin polymer. Understanding how the human genome is spatially organized and folded inside the cell nucleus is therefore central to understanding how genes are regulated in normal development and dysregulated in disease. Established light microscopy-based approaches and more recent molecular chromosome conformation capture methods are now combining to give us unprecedented insight into this fascinating aspect of human genomics. Copyright © 2013 by Annual Reviews. All rights reserved.

Buyx A.,Nuffield Council on Bioethics | Tait J.,University of Edinburgh
Science | Year: 2011

Biofuels policies must protect human rights and the environment.

This exploratory mixed-methods study uses in-depth interviews to investigate the values, motivations, and routes to engagement of UK citizens who have adopted lower-carbon lifestyles. Social justice, community, frugality, and personal integrity were common themes that emerged from the transcripts. Concern about 'the environment' per se is not the primary motivation for most interviewees' action. Typically, they are more concerned about the plight of poorer people who will suffer from climate change. Although biospheric values are important to the participants, they tended to score altruistic values significantly higher on a survey instrument. Thus, it may not be necessary to promote biospheric values to encourage lower-carbon lifestyles. Participants' narratives of how they became engaged with climate action reveal links to human rights issues and groups as much as environmental organisations and positive experiences in nature. Some interviewees offered very broad (positive) visions of what 'a low-carbon lifestyle' means to them. This, and the fact that 'climate change' is not necessarily seen as interesting even by these highly engaged people, reveals a need for climate change mitigation campaigns to promote a holistic view of a lower-carbon future, rather than simply offering a 'to do' list to 'combat climate change'. © 2012 Elsevier Ltd.

Pickering M.J.,University of Edinburgh | Garrod S.,University of Glasgow
Behavioral and Brain Sciences | Year: 2013

Currently, production and comprehension are regarded as quite distinct in accounts of language processing. In rejecting this dichotomy, we instead assert that producing and understanding are interwoven, and that this interweaving is what enables people to predict themselves and each other. We start by noting that production and comprehension are forms of action and action perception. We then consider the evidence for interweaving in action, action perception, and joint action, and explain such evidence in terms of prediction. Specifically, we assume that actors construct forward models of their actions before they execute those actions, and that perceivers of others' actions covertly imitate those actions, then construct forward models of those actions. We use these accounts of action, action perception, and joint action to develop accounts of production, comprehension, and interactive language. Importantly, they incorporate well-defined levels of linguistic representation (such as semantics, syntax, and phonology). We show (a) how speakers and comprehenders use covert imitation and forward modeling to make predictions at these levels of representation, (b) how they interweave production and comprehension processes, and (c) how they use these predictions to monitor the upcoming utterances. We show how these accounts explain a range of behavioral and neuroscientific data on language processing and discuss some of the implications of our proposal. Copyright © 2013 Cambridge University Press.

Bell K.F.S.,University of Edinburgh
Biochemical Society Transactions | Year: 2013

Neurons are more vulnerable to oxidative stress than astrocytes, the reasons for which have yet to be fully elucidated. Understanding the cellular and molecular mechanisms which contribute to this enhanced vulnerability is key to efforts aimed at ameliorating neuronal health and resilience to oxidative stress, particularly in the context of neurodegenerative disease, which is characterized by progressive dysfunction and loss of neurons specifically, and in which oxidative stress is considered a central aetiological contributor. Biological factors which may influence neuronal susceptibility to oxidative stress, in normal and neurodegenerative contexts, are reviewed in the present article, with a focus on properties intrinsic to the neuronal cell type and on properties related to neuronal reliance on surrounding astrocytes. © 2013 Biochemical Society.

Woolf A.S.,University of Manchester | Davies J.A.,University of Edinburgh
Journal of the American Society of Nephrology | Year: 2013

The mammalian ureter contains two main cell types: a multilayered water-tight epithelium called the urothelium, surrounded by smooth muscle layers that, by generating proximal to distal peristaltic waves, pump urine fromthe renal pelvis toward the urinary bladder. Here, we review the cellular mechanisms involved in the development of these tissues, and themolecules that control the process.We consider the relevance of these biologic findings for understanding the pathogenesis of human ureter malformations. Copyright © 2013 by the American Society of Nephrology.

Genzel L.,University of Edinburgh | Kroes M.C.W.,Radboud University Nijmegen | Dresler M.,Max Planck Institute of Psychiatry | Battaglia F.P.,Radboud University Nijmegen | Battaglia F.P.,NERF Neuroelectronics Research Flanders
Trends in Neurosciences | Year: 2014

Sleep is strongly involved in memory consolidation, but its role remains unclear. 'Sleep replay', the active potentiation of relevant synaptic connections via reactivation of patterns of network activity that occurred during previous experience, has received considerable attention. Alternatively, sleep has been suggested to regulate synaptic weights homeostatically and nonspecifically, thereby improving the signal:noise ratio of memory traces. Here, we reconcile these theories by highlighting the distinction between light and deep nonrapid eye movement (NREM) sleep. Specifically, we draw on recent studies to suggest a link between light NREM and active potentiation, and between deep NREM and homeostatic regulation. This framework could serve as a key for interpreting the physiology of sleep stages and reconciling inconsistencies in terminology in this field. © 2013 Elsevier Ltd.

Sharp P.M.,University of Edinburgh | Rayner J.C.,Wellcome Trust Sanger Institute | Hahn B.H.,University of Pennsylvania
Science | Year: 2013

Comparing the origins of AIDS and malaria may provide insight for gauging the prospect of future pathogen transmissions from apes to humans.

Chandler A.,University of Edinburgh
Sociology of Health and Illness | Year: 2013

The role of pain in the practice of self-injury is not straightforward. Existing accounts suggest that self-injury does not cause 'physical' pain, however self-injury is also said to alleviate 'emotional' pain by inflicting 'physical' pain. This article explores these tensions using sociological theories regarding the socio-cultural and subjective nature of pain. Analysis derives from in-depth, life-story interviews carried out in the UK with people who had self-injured. Findings contribute to on-going debates within social science regarding the nature of pain. Participants' narratives about pain and self-injury both drew on and challenged dualistic models of embodiment. I suggest that self-injury offers a unique case on which to extend existing theoretical work, which has tended to focus on pain as an unwanted and uninvited entity. In contrast, accounts of self-injury can feature pain as a central aspect of the practice, voluntarily invited into lived experience. © 2013 The Authors. Sociology of Health & Illness © 2013 Foundation for the Sociology of Health & Illness/John Wiley & Sons Ltd.

In recent years, a large number of studies have investigated the sociogeographical arrangements of health-related characteristics across urban areas. Drawing on theories of "environmental justice," researchers have been concerned with whether there is a social gradient in the spatial distribution of environmental "goods" and "bads." The accompanying article by King and Clarke (Am J Epidemiol. 2015;181(1):17-25) makes an important entry into these debates, as it describes the results of the first national-level US study to examine the relationship between urban form (particularly neighborhood walkability) and various area-level sociodemographic measures. Like many studies in this field, King and Clarke's work was constrained by the availability of certain area-level measures, and they had to rely on data from only a single point in time (2000-2001). For this reason, their results can provide few insights into the processes leading to the geographical arrangement of health-related resources across US cities. The emerging field of "historical geographic information systems" offers possibilities to researchers interested in relationships between place and health. Integrating spatial data from various historical sources can enable the reconstruction of past urban environments. These spatial data, accrued over time and appended with detailed cohort information, will offer analytical opportunities for better understanding how place-based factors influence health and well-being over the life course. © 2014 The Author.

The general consensus in the research to date is that family meals are linked to healthier eating habits in children, compared to not eating with the family. Yet, few studies explore what it is about commensality which leads to better food choices among children. Using a representative Scottish sample of five-year-old children, this research explores the extent to which family meal occurrence, meal patterns regarding where, when and with whom children eat and perceived meal enjoyment predict the quality of children's diets after controlling for indicators of maternal capital that influence both meal rituals and taste preferences. Eating the same food as parents is the aspect of family meals most strongly linked to better diets in children, highlighting the detrimental effect in the rise of 'children's food'. Although theoretical and empirical work pointed to the important health advantage in children eating together with parents, the results suggested that eating together was a far less important aspect of family meals. In evaluating the importance of the family meal, this article redirects attention away from issues of form and function towards issues of food choice. Policy implications and the importance for public health to recognise the way eating habits are defined by and reproduce social and cultural capital are discussed. © 2012 The Authors. Sociology of Health & Illness © 2012 Foundation for the Sociology of Health & Illness/JohnWiley & Sons Ltd.

Lawless C.J.,University of Edinburgh
British Journal of Criminology | Year: 2011

This paper addresses the effects of recent political and economic trends on the construction of forensic science in England and Wales. Using documentary sources and fieldwork, I show how neo-liberal initiatives have differentially reconstructed relationships between forensic scientists and the police. I argue that this stems from contested interpretations of scientific integration that have selectively appropriated elements of neo-liberalism. Neo-liberal reform of forensic science has, however, exposed actors to new risks, culminating in the UK Government's announcement to close the Forensic Science Service. Yet, rather than representing the end of 'marketization', debates concerning the organization of forensic science have entered a new phase. These hold significant implications for understanding the relationship between crime, science and advanced liberal governance. © 2011 The Author.

Brazzelli M.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2011

Faecal incontinence is a common and potentially distressing disorder of childhood. To assess the effects of behavioural and/or cognitive interventions for the management of faecal incontinence in children. We searched the Cochrane Incontinence Group Specialised Trials Register (searched 28 October 2011), which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and CINAHL, and handsearching of journals and conference proceedings, and the reference lists of relevant articles. We contacted authors in the field to identify any additional or unpublished studies. Randomised and quasi-randomised trials of behavioural and/or cognitive interventions with or without other treatments for the management of faecal incontinence in children. Reviewers selected studies from the literature, assessed study quality, and extracted data. Data were combined in a meta-analysis when appropriate. Twenty one randomised trials with a total of 1371 children met the inclusion criteria. Sample sizes were generally small. All studies but one investigated children with functional faecal incontinence. Interventions varied amongst trials and few outcomes were shared by trials addressing the same comparisons.Combined results of nine trials showed higher rather than lower rates of persisting symptoms of faecal incontinence up to 12 months when biofeedback was added to conventional treatment (OR 1.11 CI 95% 0.78 to 1.58). This result was consistent with that of two trials with longer follow-up (OR 1.31 CI 95% 0.80 to 2.15). In one trial the adjunct of anorectal manometry to conventional treatment did not result in higher success rates in chronically constipated children (OR 1.40 95% CI 0.72 to 2.73 at 24 months).In one small trial the adjunct of behaviour modification to laxative therapy was associated with a significant reduction in children's soiling episodes at both the three month (OR 0.14 CI 95% 0.04 to 0.51) and the 12 month assessment (OR 0.20 CI 95% 0.06 to 0.65). There is no evidence that biofeedback training adds any benefit to conventional treatment in the management of functional faecal incontinence in children. There was not enough evidence on which to assess the effects of biofeedback for the management of organic faecal incontinence. There is some evidence that behavioural interventions plus laxative therapy, rather than laxative therapy alone, improves continence in children with functional faecal incontinence associated with constipation.

Fitzpatrick D.R.,University of Edinburgh
Nature Genetics | Year: 2013

Two new loci for premature fusion of the cranial sutures in humans suggest a common endpoint in osteoblast regulation, linking upregulation of phosphorylated ERK1/2 and TWIST1 haploinsufficiency. © 2013 Nature America, Inc. All rights reserved.

Lombriser L.,University of Edinburgh
Annalen der Physik | Year: 2014

Chameleon fields may modify gravity on cluster scales while recovering general relativity locally. This article reviews signatures of chameleon modifications in the nonlinear cosmological structure, comparing different techniques to model them, summarising the current state of observational constraints, and concluding with an outlook on prospective constraints from future observations and applications of the analytic tools developed in the process to more general scalar-tensor theories. Particular focus is given to the Hu-Sawicki and designer models of f(R) gravity. © 2014 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Waser P.M.,Purdue University | Hadfield J.D.,University of Edinburgh
Molecular Ecology | Year: 2011

Estimating rates of movement among populations is never simple, and where young animals cannot all be captured at their birth sites, traditional field methods potentially underestimate dispersal rates. Genetic assignment tests appear to hold promise for detecting 'precapture' dispersal, and recent evidence suggests that even on the scale of dispersal between populations, genetic parentage analyses can also be informative. Herein, we examine the performance of both types of analysis with data from a 17-year study of dispersal in banner-tailed kangaroo rats Dipodomys spectabilis. We compare estimates of precapture dispersal from (i) the commonly used parentage analysis program cervus (ii) a pedigree-reconstruction program, MasterBayes, that combines genetic with spatial and other nongenetic information and (iii) genetic assignment procedures implemented by the program geneclass2, with (iv) rates of dispersal observed through recapture of a subset of animals initially marked shortly after weaning. geneclass2 estimates a larger proportion of precapture dispersers than MasterBayes, but both approaches as well as those based on field data alone, suggest that approximately 10% of adults in local populations are immigrants and that interpopulation dispersal is slightly female-biassed. All genetic procedures detect precapture dispersal between populations, but dispersers identified by MasterBayes are particularly compatible with what is independently known about body mass at dispersal, dispersal distance and distance between parents. Parentage analyses have considerable potential to infer the value of this otherwise elusive demographic parameter when most candidate parents can be genotyped and when nongenetic information, especially the distance separating candidate mothers and fathers, can be incorporated into the procedure. © 2011 Blackwell Publishing Ltd.

Hill W.G.,University of Edinburgh | Kirkpatrick M.,University of Texas at Austin
Annual Review of Ecology, Evolution, and Systematics | Year: 2010

We review the impact of developments from animal breeding on our understanding of evolution and on the methodology used in evolutionary biology. The theory developed for improvement of polygenic traits, in particular the breeders' equation and the effects of finite population size, has had a significant influence. The effectiveness of within population selection is exemplified by the continued rapid genetic change, often with concomitant effects on fitness, produced by breeders. Many of the models and methods for estimation of quantitative genetic parameters, notably the animal model, have been motivated by animal breeding problems. Results from selection programs and quantitative trait loci (QTL) experiments show quantitative traits are often highly polygenic and can be adequately modeled by the infinitesimal model. Copyright © 2010 by Annual Reviews. All rights reserved.

Furley P.,University of Edinburgh
Progress in Physical Geography | Year: 2010

Four major themes can be identified over the period 2008-2009: (1) the increasing use, sophistication and resolution of remote sensing techniques and the application of these methods to assessment of biomass, C-balance and biosphere-atmosphere interactions; (2) continued interest in dynamic change processes affecting individual species and plant communities, and the changing proportions of tree, shrub and herbaceous components; (3) the nature, impact and management of fire; and (4) increasing awareness of the importance of soils and soil moisture in shaping the nature and distribution of vegetation, particularly at local scales. © The Author(s) 2010.

Ennos R.A.,University of Edinburgh
Forestry | Year: 2015

Both natural and managed forests are currently suffering from increases in damage by pathogens. Here, an evolutionary ecology approach is adopted to analyse the factors that influence the levels of pathogen damage experienced by forest tree populations and consider the conditions under which stable co-existence of trees and pathogens occurs in natural populations. The demographic and genetic responses of tree-pathogen systems to anthropogenic perturbations are explored to identify where the greatest threats to resilience lie. Problems caused by native pathogens are likely to arise as a consequence both of rapid climate change and of forest management practices that lead to increases in species density, drastic reductions in genetic diversity and planting outside the native range. The most serious threats to forest trees are posed by introduction of exotic pathogens derived from related exotic tree species. Recovery following spread of exotic pathogens is likely to be both slow and uncertain and may not be possible without intensive programmes involving rapid selection and widespread dissemination of genotypes resistant to the exotic pathogen. © 2014 © Institute of Chartered Foresters, 2014. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Silvertown J.,University of Edinburgh
Trends in ecology & evolution | Year: 2015

The concept of ecosystem services (ES) neatly encapsulates the ways in which human society depends upon the existence and functioning of nature, but also draws power by chiming with dominant neoliberal ideology. Scientific paradigms such as this have an inherent tendency to stop adherents from recognizing alternative approaches. It is high time to examine whether the concept is being oversold with potentially damaging consequences. Many authors have questioned the monetization of ES, but the origin of the problem lies deeper in anthropocentrism. By illustration with alternatives, I attempt to show how the ES paradigm has constrained thought, particularly towards the monetization and financialization of nature, even when many ecologists and others oppose this trend. Copyright © 2015 Elsevier Ltd. All rights reserved.

Glasier A.,University of Edinburgh
Contraception | Year: 2010

Methods of contraception for use by men include condoms, withdrawal and vasectomy. Prevalence of use of a method and continuation rates are indirect measures of acceptability. Worldwide, none of these "male methods" accounts for more than 7% of contraceptive use although uptake varies considerably between countries. Acceptability can be assessed directly by asking about intended (hypothetical) use and assessing satisfaction during/after use. Since they have been around for a very long time, there are very few data of this nature on condoms (as contraceptives rather than for prevention of infection), withdrawal or vasectomy. There are direct data on the acceptability of hormonal methods for men but from relatively small clinical trials which undoubtedly do not represent the real world. Surveys undertaken among the male general public demonstrate that, whatever the setting, at least 25% of men - and in most countries substantially more - would consider using hormonal contraception. Although probably an overestimate of the number of potential users when such a method becomes available, it would appear that hormonal contraceptives for men may have an important place on the contraceptive menu. Despite commonly expressed views to the contrary, most women would trust their male partner to use a hormonal method. © 2010 Elsevier Inc. All rights reserved.

Davies J.,University of Edinburgh
Drug Discovery Today | Year: 2014

Pharmacology and regenerative medicine interact in two ways. One is the use of drugs to promote tissue regeneration. The other, less obvious but with great potential, is the use of techniques developed for regenerative medicine to engineer realistic human organoids for drug screening. This review focuses on testing for nephrotoxicity, often a problem with drugs and poorly predicted in animals. Current human-based screens mainly use proximal tubule cells growing in 2D monolayers. Realism might be improved by collagen-based culture systems that encourage proximal tubule cells to grow as tubules. More realistic would be a recently developed technique for engineering functioning 'mini-kidneys' from suspensions of stem cells, a technique that works in mouse but that could also be applied to humans. © 2013 Elsevier Ltd.

Background The benefit of CT coronary angiography (CTCA) in patients presenting with stable chest pain has not been systematically studied. We aimed to assess the effect of CTCA on the diagnosis, management, and outcome of patients referred to the cardiology clinic with suspected angina due to coronary heart disease. Methods In this prospective open-label, parallel-group, multicentre trial, we recruited patients aged 18-75 years referred for the assessment of suspected angina due to coronary heart disease from 12 cardiology chest pain clinics across Scotland. We randomly assigned (1:1) participants to standard care plus CTCA or standard care alone. Randomisation was done with a web-based service to ensure allocation concealment. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6 weeks. All analyses were intention to treat, and patients were analysed in the group they were allocated to, irrespective of compliance with scanning. This study is registered with ClinicalTrials.gov, number NCT01149590. Findings Between Nov 18, 2010, and Sept 24, 2014, we randomly assigned 4146 (42%) of 9849 patients who had been referred for assessment of suspected angina due to coronary heart disease. 47% of participants had a baseline clinic diagnosis of coronary heart disease and 36% had angina due to coronary heart disease. At 6 weeks, CTCA reclassified the diagnosis of coronary heart disease in 558 (27%) patients and the diagnosis of angina due to coronary heart disease in 481 (23%) patients (standard care 22 [1%] and 23 [1%]; p<0·0001). Although both the certainty (relative risk [RR] 2·56, 95% CI 2·33-2·79; p<0·0001) and frequency of coronary heart disease increased (1·09, 1·02-1·17; p=0·0172), the certainty increased (1·79, 1·62-1·96; p<0·0001) and frequency seemed to decrease (0·93, 0·85-1·02; p=0·1289) for the diagnosis of angina due to coronary heart disease. This changed planned investigations (15% vs 1%; p<0·0001) and treatments (23% vs 5%; p<0·0001) but did not affect 6-week symptom severity or subsequent admittances to hospital for chest pain. After 1·7 years, CTCA was associated with a 38% reduction in fatal and non-fatal myocardial infarction (26 vs 42, HR 0·62, 95% CI 0·38-1·01; p=0·0527), but this was not significant. Interpretation In patients with suspected angina due to coronary heart disease, CTCA clarifies the diagnosis, enables targeting of interventions, and might reduce the future risk of myocardial infarction. Funding The Chief Scientist Office of the Scottish Government Health and Social Care Directorates funded the trial with supplementary awards from Edinburgh and Lothian's Health Foundation Trust and the Heart Diseases Research Fund. © 2015 Elsevier Ltd.

Davey J.L.,Institute of Evolutionary Biology | Blaxter M.W.,University of Edinburgh
Briefings in Functional Genomics | Year: 2010

Next-generation sequencing technologies are making a substantial impact on many areas of biology, including the analysis of genetic diversity in populations. However, genome-scale population genetic studies have been accessible only to well-funded model systems. Restriction-site associated DNA sequencing, a method that samples at reduced complexity across target genomes, promises to deliver high resolution population genomic dataçthousands of sequenced markers across many individuals-for any organism at reasonable costs. It has found application in wild populations and non-traditional study species, and promises to become an important technology for ecological population genomics. © The Author 2011. Published by Oxford University Press. All rights reserved.

Bilbao S.,University of Edinburgh
IEEE Transactions on Audio, Speech and Language Processing | Year: 2012

Finite difference time-domain simulation methods in acoustics applications have seen increased interest recently. The simplest scheme exhibits various weaknesses, such as numerical dispersion and anisotropy. More general parameterized families of schemes are explored here, with a view towards reducing such numerical artefacts through optimization. Numerical results are presented. © 2006-2012 IEEE.

The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt-1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. These findings provide strong evidence for a protective role of HO-1 in pregnancy and identify HO as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, thus, they have the potential to ameliorate early onset preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies. © 2010 Elsevier B.V. All rights reserved.

Charlesworth B.,University of Edinburgh
Genetics | Year: 2012

The process of evolution at a given site in the genome can be influenced by the action of selection at other sites, especially when these are closely linked to it. Such selection reduces the effective population size experienced by the site in question (the Hill-Robertson effect), reducing the level of variability and the efficacy of selection. In particular, deleterious variants are continually being produced by mutation and then eliminated by selection at sites throughout the genome. The resulting reduction in variability at linked neutral or nearly neutral sites can be predicted from the theory of background selection, which assumes that deleterious mutations have such large effects that their behavior in the population is effectively deterministic. More weakly selected mutations can accumulate by Muller's ratchet after a shutdown of recombination, as in an evolving Y chromosome. Many functionally significant sites are probably so weakly selected that Hill-Robertson interference undermines the effective strength of selection upon them, when recombination is rare or absent. This leads to large departures from deterministic equilibrium and smaller effects on linked neutral sites than under background selection or Muller's ratchet. Evidence is discussed that is consistent with the action of these processes in shaping genome-wide patterns of variation and evolution. © 2012 by the Genetics Society of America.

Di Renzo M.,University Paris - Sud | Haas H.,University of Edinburgh
IEEE Transactions on Vehicular Technology | Year: 2012

In this paper, we study the performance of spatial modulation (SM) multiple-input-multiple-output (MIMO) wireless systems over generic fading channels. More precisely, a comprehensive analytical framework to compute the average bit error probability (ABEP) is introduced, which can be used for any MIMO setup, for arbitrary correlated fading channels, and for generic modulation schemes. It is shown that, when compared with state-of-the-art literature, our framework 1) has more general applicability over generalized fading channels, 2) is, in general, more accurate as it exploits an improved union-bound method, and, 3) more importantly, clearly highlights interesting fundamental trends about the performance of SM, which are difficult to capture with available frameworks. For example, by focusing on the canonical reference scenario with independent identically distributed Rayleigh fading, we introduce very simple formulas that yield insightful design information on the optimal modulation scheme to be used for the signal constellation diagram, as well as highlight the different roles played by the bit mapping on the signal and spatial constellation diagrams. Numerical results show that, for many MIMO setups, SM with phase-shift-keying (PSK) modulation outperforms SM with quadrature-amplitude modulation (QAM), which is a result never reported in the literature. In addition, by exploiting asymptotic analysis, closed-form formulas of the performance gain of SM over other single-antenna transmission technologies are provided. Numerical results show that SM can outperform many single-antenna systems and that, for any transmission rate, there is an optimal allocation of the information bits onto spatial and signal constellation diagrams. Furthermore, by focusing on the Nakagami-m fading scenario with generically correlated fading, we show that fading severity plays a very important role in determining the diversity gain of SM. In particular, the performance gain over single-antenna systems increases for fading channels less severe than Rayleigh fading, whereas it gets smaller for more severe fading channels. In addition, it is shown that the impact of fading correlation at the transmitter is reduced for less severe fading. Finally, analytical frameworks and claims are substantiated through extensive Monte Carlo simulations. © 2006 IEEE.

Sheikh A.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: This is an update of a Cochrane Review first published in The Cochrane Library in Issue 4, 2001 and previously updated in 2003 and 2007.It is estimated that in developed countries approximately 30% of the general population suffer from one or more allergic disorders, of which allergic rhinitis is particularly common. Perennial rhinitis is most often due to allergy to the house dust mite. In such patients house dust mite avoidance is logical, but there is considerable uncertainty regarding the efficacy and effectiveness of interventions designed to reduce dust mite exposure. OBJECTIVES: To assess the benefit (and harm) of measures designed to reduce house dust mite exposure in the management of house dust mite sensitive allergic rhinitis. SEARCH STRATEGY: Our search included the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials Register (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE and EMBASE. The date of the last search was 31 December 2009. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, in which house dust mite control measures have been evaluated in comparison with placebo or other dust mite avoidance measures, in patients with clinician-diagnosed allergic rhinitis and confirmed allergy to dust mite. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts, graded methodological quality using the Cochrane approach and extracted data. Meta-analysis was neither possible nor appropriate due to heterogeneity of the patient groups studied. MAIN RESULTS: Nine trials involving 501 participants satisfied the inclusion criteria. Only two studies investigating the effectiveness of mite impermeable bedding covers were of good quality; the remaining seven studies were small and of poor quality. Two trials investigated the efficacy of acaricides, another two trials investigated the role of high-efficiency particulate air (HEPA) filters. One trial, using a factorial design, investigated the efficacy of both acaricide and house dust mite impermeable bedding covers in isolation and combination; the remaining four trials investigated the efficacy of bedroom environmental control programmes involving use of house dust mite impermeable bedding covers. Seven of the nine trials reported that, when compared with control, the interventions studied resulted in significant reductions in house dust mite load. Of the interventions studied to date, acaricides appear to be the most promising type of intervention, although the findings from these studies need to be interpreted with care because of their methodological limitations. House dust mite impermeable bedding as an isolated intervention is unlikely to offer clinical benefit. No serious adverse effects were reported from any of the interventions. AUTHORS' CONCLUSIONS: Trials to date have on the whole been small and of poor methodological quality, making it difficult to offer any definitive recommendations on the role, if any, of house dust mite avoidance measures in the management of house dust mite sensitive perennial allergic rhinitis. The results of these studies suggest that use of acaricides and extensive bedroom-based environmental control programmes may be of some benefit in reducing rhinitis symptoms and, if considered appropriate, these should be the interventions of choice. Isolated use of house dust mite impermeable bedding is unlikely to prove effective.

Maher B.A.,Lancaster University | Thompson R.,University of Edinburgh
Journal of Quaternary Science | Year: 2012

Oxygen isotope variations in Chinese stalagmites have been widely interpreted as a record of the amount of East Asian summer monsoonal rainfall. This interpretation infers decreasing monsoonal rainfall from the mid-Holocene and large, dipolar rainfall oscillations within glaciations. However, the speleothem δ 18O variations conflict with independent palaeoclimate proxies (cave δ 13C, loess/palaeosol magnetic properties, δ 13C alkanes), which indicate no systematic decline in rainfall from the mid-Holocene, and no glacial rainfall maxima. Using mass balance calculations (which incorporate seasonality effects in both δ 18O concentration and amount of precipitation), we demonstrate that the cave δ 18O variations cannot be accounted for by summer rainfall changes, or rainfall seasonality or winter cooling, but instead reflect changes in moisture source. A possible driver of the δ 18O variations in Chinese stalagmites is precessional forcing of inter-hemispheric temperature gradients, and resultant shifts in the position and intensity of the subtropical pressure cells. Through such forcing, Indian monsoon-sourced δ 18O may have dominated at times of high boreal summer insolation, and local Pacific-sourced moisture at low insolation. Suppression of summer monsoonal rainfall during glacial stages may reflect diminished sea and land surface temperatures and the radiative impacts of increased regional dust fluxes. © 2012 John Wiley & Sons, Ltd.

Maizels R.M.,University of Edinburgh
Veterinary Parasitology | Year: 2013

Toxocara canis has extraordinary abilities to survive for many years in the tissues of diverse vertebrate species, as well as to develop to maturity in the intestinal tract of its definitive canid host. Human disease is caused by larval stages invading musculature, brain and the eye, and immune mechanisms appear to be ineffective at eliminating the infection. Survival of T. canis larvae can be attributed to two molecular strategies evolved by the parasite. Firstly, it releases quantities of 'excretory-secretory' products which include lectins, mucins and enzymes that interact with and modulate host immunity. For example, one lectin (CTL-1) is very similar to mammalian lectins, required for tissue inflammation, suggesting that T. canis may interfere with leucocyte extravasation into infected sites. The second strategy is the elaboration of a specialised mucin-rich surface coat; this is loosely attached to the parasite epicuticle in a fashion that permits rapid escape when host antibodies and cells adhere, resulting in an inflammatory reaction around a newly vacated focus. The mucins have been characterised as bearing multiple glycan side-chains, consisting of a blood-group-like trisaccharide with one or two O-methylation modifications. Both the lectins and these trisaccharides are targeted by host antibodies, with anti-lectin antibodies showing particular diagnostic promise. Antibodies to the mono-methylated trisaccharide appear to be T. canis-specific, as this epitope is not found in the closely related Toxocara cati, but all other antigenic determinants are very similar between the two species. This distinction may be important in designing new and more accurate diagnostic tests. Further tools to control toxocariasis could also arise from understanding the molecular cues and steps involved in larval development. In vitro-cultivated larvae express high levels of four mRNAs that are translationally silenced, as the proteins they encode are not detectable in cultured larvae. However, these appear to be produced once the parasite has entered the mammalian host, as they are recognised by specific antibodies in infected patients. Elucidating the function of these genes, or analysing if micro-RNA translational silencing suppresses production of the proteins, may point towards new drug targets for tissue-phase parasites in humans. © 2013 Elsevier B.V.

In the putatively ancestral population of Drosophila melanogaster, the ratio of silent DNA sequence diversity for X-linked loci to that for autosomal loci is approximately one, instead of the expected "null" value of 3/4. One possible explanation is that background selection (the hitchhiking effect of deleterious mutations) is more effective on the autosomes than on the X chromosome, because of the lack of crossing over in male Drosophila. The expected effects of background selection on neutral variability at sites in the middle of an X chromosome or an autosomal arm were calculated for different models of chromosome organization and methods of approximation, using current estimates of the deleterious mutation rate and distributions of the fitness effects of deleterious mutations. The robustness of the results to different distributions of fitness effects, dominance coefficients, mutation rates, mapping functions, and chromosome size was investigated. The predicted ratio of X-linked to autosomal variability is relatively insensitive to these variables, except for the mutation rate and map length. Provided that the deleterious mutation rate per genome is sufficiently large, it seems likely that background selection can account for the observed X to autosome ratio of variability in the ancestral population of D. melanogaster. The fact that this ratio is much less than one in D. pseudoobscura is also consistent with the model's predictions, since this species has a high rate of crossing over. The results suggest that background selection may play a major role in shaping patterns of molecular evolution and variation. © 2012 by the Genetics Society of America.

Orestis Palermos S.,University of Edinburgh
Cognitive Systems Research | Year: 2014

The 'causal-constitution' fallacy, the 'cognitive bloat' worry, and the persisting theoretical confusion about the fundamental difference between the hypotheses of embedded (HEMC) and extended (HEC) cognition are three interrelated worries, whose common point-and the problem they accentuate-is the lack of a principled criterion of constitution. Attempting to address the 'causal-constitution' fallacy, mathematically oriented philosophers of mind have previously suggested that the presence of non-linear relations between the inner and the outer contributions is sufficient for cognitive extension. The abstract idea of non-linearity, however, can be easily misunderstood and has, in the past, led to incorrect and counterintuitive conclusions about what may count as part of one's overall cognitive system. In order to prevent any further mistakes I revisit dynamical systems theory to study the nature of the continuous mutual interactions that give rise to the aforementioned non-linear relations. Moreover, focusing on these interactions will allow us to provide two distinct arguments in support of the ontological postulation of extended cognitive systems, as well as an objective criterion of constitution. Accordingly, I put forward a version of HEC that treats continuous mutual interactions (and the resultant non-linear relations) not just as sufficient but also as necessary for cognitive extension. Such a qualified version of HEC may exclude certain alleged cases of cognitive extension where the agent does not mutually interact with his artifacts (e.g., shopping lists and directory services), but it is immune both to the 'causal-constitution' fallacy and the 'cognitive bloat' worry, and it can be sharply distinguished from HEMC. © 2013 Elsevier B.V.

Hill W.G.,University of Edinburgh
Current Genomics | Year: 2012

The genetic analysis of quantitative or complex traits has been based mainly on statistical quantities such as genetic variances and heritability. These analyses continue to be developed, for example in studies of natural populations. Genomic methods are having an impact on progress and prospects. Actual relationships of individuals can be estimated enabling novel quantitative analyses. Increasing precision of linkage mapping is feasible with dense marker panels and designed stocks allowing multiple generations of recombination, and large SNP panels enable the use of genome wide association analysis utilising historical recombination. Whilst such analyses are identifying many loci for disease genes and traits such as height, typically each individually contributes a small amount of the variation. Only by fitting all SNPs without regard to significance can a high proportion be accounted for, so a classical polygenic model with near infinitesimally small effects remains a useful one. Theory indicates that a high proportion of variants will have low minor allele frequency, making detection difficult. Genomic selection, based on simultaneously fitting very dense markers and incorporating these with phenotypic data in breeding value prediction is revolutionising breeding programmes in agriculture and has a major potential role in human disease prediction. © 2012 Bentham Science Publishers.

Cramp L.J.,University of Edinburgh
Proceedings. Biological sciences / The Royal Society | Year: 2014

The appearance of farming, from its inception in the Near East around 12 000 years ago, finally reached the northwestern extremes of Europe by the fourth millennium BC or shortly thereafter. Various models have been invoked to explain the Neolithization of northern Europe; however, resolving these different scenarios has proved problematic due to poor faunal preservation and the lack of specificity achievable for commonly applied proxies. Here, we present new multi-proxy evidence, which qualitatively and quantitatively maps subsistence change in the northeast Atlantic archipelagos from the Late Mesolithic into the Neolithic and beyond. A model involving significant retention of hunter-gatherer-fisher influences was tested against one of the dominant adoptions of farming using a novel suite of lipid biomarkers, including dihydroxy fatty acids, ω-(o-alkylphenyl)alkanoic acids and stable carbon isotope signatures of individual fatty acids preserved in cooking vessels. These new findings, together with archaeozoological and human skeletal collagen bulk stable carbon isotope proxies, unequivocally confirm rejection of marine resources by early farmers coinciding with the adoption of intensive dairy farming. This pattern of Neolithization contrasts markedly to that occurring contemporaneously in the Baltic, suggesting that geographically distinct ecological and cultural influences dictated the evolution of subsistence practices at this critical phase of European prehistory.

Wavelength dispersive analysis of tephra grains and melt inclusions by EPMA has been carried out using a focused beam of 3 μm diameter without detected loss of sodium or potassium in standard glasses, including anhydrous basalts, a slightly hydrated rhyolite and a sodium-rich intermediate composition. The ability to make analyses without chemical modification is strongly dependent upon current density at the analysis site. Analysis with narrow beams requires extremely low beam currents that are normally associated with energy dispersive analysis. Experiments indicate that a value of 0.1 nA/μm 2 must not be exceeded, at least for moderately hydrated samples, if sodium loss is to be avoided. High resolution analysis without beam-induced analytical artefacts enables fully quantitative analysis of very distal and/or highly vesicular tephras and very small melt inclusions without the need to use post-analysis corrections. This development has enabled high quality analyses from crypto-tephra layers that were previously impossible to analyse, and has removed the potential for sampling bias within mixed tephra layers by making (in most cases) tephra grains accessible for analysis. The use of focused beams also increases the level of automation, and hence the cost-effectiveness of data collection. The current data suggest limits to the applicability of the beam conditions reported, and that they may lead to alkali loss in compositions most prone to beam-induced modification such as significantly hydrated and/or sodic tephras. © The Author(s) 2011.

Harte B.,University of Edinburgh | Richardson S.,University of Cape Town
Gondwana Research | Year: 2012

Three major suites of silicate inclusions in sublithospheric diamonds show evidence of formation at depths > 250 km, and for each suite there is evidence of their formation from subducted material. Two of these are the well known basic (majoritic garnet) and ultrabasic (MgSi-perovskite. +. ferropericlase) suites. The third, the recently recognised Ca-rich suite, is characterised by carbonate, Ca-Si-Ti minerals and some aluminous material. Carbon isotope ratios in the host diamonds and geochemical-petrological features of the inclusions themselves provide evidence for their derivation from subducted lithosphere materials. The diamonds hosting the basic and ultrabasic suites are suggested to form in fluids/melts resulting from the release of water caused by dehydration reactions affecting both the crustal and mantle portions of a subducting slab of ocean lithosphere. Conversely, the diamonds containing the Ca-rich suite are linked with the formation of carbonatitic melts. In the Juina kimberlite province of Brazil, all three suites have been found in close proximity. A model is presented whereby the formation of the suites occurs progressively during the subduction and stagnation of a single lithospheric slab, with all three suites being transported to the lithosphere by a plume with which the carbonatitic melts of the Ca-rich suite are associated. Nd-Sr isotopic data are presented for the Juina majoritic-garnet inclusions, which supports their formation from oceanic crust of Mesozoic age. In conjunction with published age data for a Ca-Si-Ti inclusion, the Juina (Brazil) sublithospheric inclusions document a series of events involving diamond formation during and following the emplacement of a subducted slab between ca 190 and 90. Ma beneath west Gondwanaland. This slab and related subducted slabs dating from the Palaeozoic at the Gondwanan margin may be the source of the widespread DUPAL geochemical anomaly in the South Atlantic and Indian Oceans. The kimberlites bringing the diamonds to the Earth's surface may have arisen from a superplume, developed from a graveyard of former Gondwanan stagnant slabs, at the Core-Mantle-Boundary. © 2011.

The objective of this article is to use the geology and tectonics of a critical part of the Tethyan orogen, represented by Greece and Albania, to shed light on the tectonic development of Tethys on a regional to global scale. A review of existing Tethyan reconstructions reveals little consensus concerning key aspects, such as the timing and direction of subduction, arc magmatism, ophiolite genesis, and continental collision. The regional to local-scale geology of individual regions, therefore, has to be considered in detail to test existing models and to develop a viable tectonic reconstruction. For Carboniferous time, much evidence suggests that the Korabi-Pelagonian crustal unit as exposed in Albania and Greece formed above a northward-dipping subduction zone along the Eurasian continental margin, with Palaeotethys to the south. However, there is also evidence of southward subduction beneath Gondwana, especially from southern Greece and central-southern Turkey. Palaeotethys is inferred to have closed in Europe as far to the east as the longitude of Libya, although remaining open beyond this region. Uncertainty still exists regarding the Pangaea A-type reconstruction that would restore all the present units in the area within the Eastern Mediterranean region versus the Pangaea B-type reconstruction that would require right-lateral displacement of exotic terranes by up to 3500km eastwards. In either reconstruction, fragments of the Variscan collisional orogen are likely to have been displaced variable distances eastwards in the Balkan region prior to ∼Late Permian-Early Triassic time. From the Late Permian, the Greece-Albania crustal units were located in their present relative position within Tethys as a whole. From the mid-Permian onwards, the northern margin of Gondwana was affected by crustal extension. A Mesozoic ocean (i.e. the Pindos-Mirdita Ocean) then rifted during Early-Middle Triassic time, culminating in final continental break-up and sea-floor spreading during the Late Triassic (Carnian-Norian). Subduction-influenced volcanics of mainly Early-Middle Triassic age probably reflect the extraction of magma from sub-continental lithosphere that was enriched in subduction-related fluids and volatiles during an earlier Variscan(?) subduction event. The existence of Late Triassic mid-ocean ridge-type igneous rocks, known locally in Albania and Greece, points to rifting of a Red Sea-type oceanic basin rather than a back-arc basin related to contemporaneous subduction. After initial, inferred slow spreading at a Late Triassic, rifted ocean ridge and spreading during the Early Jurassic, the ocean basin underwent regional convergence. Subduction was initiated at, or near, a spreading axis perhaps adjacent to an oceanic fracture zone. The Jurassic supra-subduction zone-type ophiolites of both Greece and Albania largely relate to melting of rising asthenosphere in the presence of aqueous volatiles derived from subducting oceanic lithosphere. High-magnesian boninite-type magmas that are present both in the Albanian and Greece ophiolites and in some underlying melanges reflect remelting of previously depleted oceanic upper mantle. Localized MOR-type ophiolites of Late-Middle Jurassic age, mainly exposed in northeast Albania, were created at a rifted spreading axis. The amphibolite-facies metamorphic sole of the ophiolites was mainly derived from the oceanic crust (including within-plate-type seamounts), whereas the underlying lower-grade, greenschist-facies sole was mainly sourced from the rifted continental margin. The melange, dismembered thrust sheets, and polymict debris flows (olistostromes) beneath the ophiolites formed by accretion and gravity reworking of continental margin units. The in situ radiolarian chert cover of the ophiolites in northern Albania is overlain by polymict debris flows (olistostromes). Pelagic carbonate deposition followed during Tithonian-Berriasian time, and then a regional carbonate platform was restored during the Cretaceous. Exhumation of deeply buried parts of the overridden continental margin probably took place during the Early Cretaceous. Structural evidence, mainly from northern Greece (Vourinos, Pindos, and Othris areas), indicates that the ophiolites, the metamorphic sole, the accretionary melange, and the underlying continental margin units were all deformed by top-to-the-northeast thrusting during late Middle-early Late Jurassic time. However, such kinematic evidence is not obviously replicated in Albania, characterized by reports of ∼southwest-directed (or variable) emplacement. The remaining Pindos-Mirdita oceanic crust subducted northeastwards during Late Cretaceous-Eocene time, whereas oceanic crust continued to form in the south Aegean region at least locally during Late Cretaceous time. During early Cenozoic time, the Pindos-Mirdita Ocean closed progressively southwards, triggering mainly southward progradation of turbidites derived from the overriding Korabi-Pelagonian microcontinent. Smaller volumes of sediment were also derived from the Apulia (Adria) continent. The Mesohellenic Trough of Greece and its counterpart in Albania evolved from an Eocene fore-arc-type basin above subducting oceanic lithosphere to a thrust-top basin as continental crust continued to underthrust during the Oligocene after final closure of the Pindos-Mirdita Ocean. Miocene and Plio-Quaternary successor flexural fore-deeps developed in response to continuing regional plate convergence. The preferred tectonic alternatives are assembled into a new overall tectonic model, which in turn needs to be tested and developed in the light of future studies. © 2012 Copyright Taylor and Francis Group, LLC.

Fallowfield J.A.,University of Edinburgh
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2011

Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. © 2011 the American Physiological Society.

Ginn F.,University of Edinburgh
Transactions of the Institute of British Geographers | Year: 2014

In response to the pressing need to re-constitute the ways we live with non-humans, more-than-human geography's distinctive contribution has been to describe an ethics based not on 'certain subjects' but on the relational entanglement of life: to show that 'we' are connected and thus invited to care. This paper aims to suggest, however, that this relational diagnostic obscures as much as it reveals and that detachment, as much as relation, provides an everyday ethic that can accommodate more-than-human difference. I do this by analysing how life is stuck together and pulled apart in the British domestic garden, drawing on life history interviews and 'show me your garden' walking tours with experienced gardeners. The article is aligned with a widening bestiary of companion species in geography, and considers the appearances and disappearances of a domestic monster: the slug. Therefore in contrast to existing literature the paper explores gardening's darker aspects. First, I describe how slugs and gardeners are 'sticky': joined together by shared histories, curiosity and disgust. The paper then shifts to examine how gardeners practice detachment: distancing themselves from the act of killing slugs but yet avowing the violence of their actions; acknowledging the limits of their capacities to bend space to their will and imagination; recognising the vulnerability of slugs, and being transformed by that recognition. The analysis shows first, that the emphasis on gathering together and relationality obscures what lies outside relations, and second how detachment emerges not as the negation, but as an enabling constituent of more-than-human ethics. In conclusion the paper argues for looser mappings of relationality and ethics that attend more fully to the distance between species. © 2014 Royal Geographical Society (with the Institute of British Geographers).

Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R. We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain. We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.

Ulipristal acetate (UPA) was licensed as an emergency contraceptive (EC) in Europe in 2009. By the end of May 2013, over 1.4 million courses had been used. The rationale for using UPA for EC in favor of the much more commonly used levonorgestrel (LNG) is based on data on efficacy, safety and side effects.Availability: Use of UPA will remain limited until it is available without a doctor's prescription.Efficacy: In two large clinical trials among women presenting for EC up to 120 hours after unprotected sex, UPA was as effective as LNG at preventing pregnancy. When the two trials were combined in a meta analysis UPA was superior, almost halving the risk of pregnancy compared with LNG. Biomedical studies have shown that UPA inhibits or delays ovulation more effectively than LNG at a stage of the cycle when the risk of pregnancy is highest.Safety and side effects: UPA and LNG have similar side effect profiles and to date no serious adverse events have been attributed to use of UPA for EC. Data on pregnancies conceived in association with UPA use are reassuring. There is no evidence for teratogenesis or for any increased risk of ectopic pregnancy or miscarriage. © 2014 Informa UK Ltd. All rights reserved.

Bilbao S.,University of Edinburgh
Journal of the Acoustical Society of America | Year: 2012

The snare drum is a complex system, relying on the interaction of multiple components: the drumheads, or membranes, a set of snares, the surrounding acoustic field and an internal cavity. Because these components are multidimensional, and due to a strong distributed non-linearity (the snare interaction), many techniques used frequently in physical modeling synthesis applications, such as digital waveguides and modal methods are difficult to apply. In this article, finite difference time domain techniques are applied to a full 3D system, and various features of interest, such as the coupling between membranes, and the interaction between the membranes and the snares, are examined in detail. Also discussed are various numerical features, such as spurious splitting of degenerate modes and bandwidth limitation, and estimates of computational complexity are provided. Sound examples are presented. © 2012 Acoustical Society of America.

Cates M.E.,University of Edinburgh
Reports on Progress in Physics | Year: 2012

Microbiology is the science of microbes, particularly bacteria. Many bacteria are motile: they are capable of self-propulsion. Among these, a significant class execute so-called run-and-tumble motion: they follow a fairly straight path for a certain distance, then abruptly change direction before repeating the process. This dynamics has something in common with Brownian motion (it is diffusive at large scales), and also something in contrast. Specifically, motility parameters such as the run speed and tumble rate depend on the local environment and hence can vary in space. When they do so, even if a steady state is reached, this is not generally invariant under time reversal: the principle of detailed balance, which restores the microscopic time-reversal symmetry of systems in thermal equilibrium, is mesoscopically absent in motile bacteria. This lack of detailed balance (allowed by the flux of chemical energy that drives motility) creates pitfalls for the unwary modeller. Here I review some statisticalmechanical models for bacterial motility, presenting them as a paradigm for exploring diffusion without detailed balance. I also discuss the extent to which statistical physics is useful in understanding real or potential microbiological experiments. © 2012 IOP Publishing Ltd.

After an initial burst of enthusiasm in the 1990s, community-based forest management (CBFM) is increasingly being viewed with a critical eye. Evidence suggests that many programs have failed to promote their stated objectives of sustainability, efficiency, equity, democratic participation and poverty reduction. A large volume of academic literature now exists on CBFM, examining both the success and failure of such initiatives in a wide variety of countries. Through analysis of key themes, concepts and issues in CBFM, this article provides a review of CBFM initiatives in tropical developing countries for policymakers, practitioners and planners wishing to gain an understanding of this wide-ranging, interdisciplinary academic literature. The article identifies key institutions and incentives that appear to significantly affect the success or failure of CBFM initiatives. In particular, it reports that consideration of institutional and socioeconomic factors along with personal characteristics of key stakeholders such as beliefs, attitudes, financial resources and skills are important determinants of CBFM outcomes. However, local incentive structures also appear to be important. There is increasing recognition in the literature of the need to consider the conditions under which local politicians entrusted with carrying out CBFM initiatives will deem it worthwhile to invest their scarce time and resources on environmental governance. © Her Majesty the Queen in Rights of United Kingdom 2010.

Nieuwland M.S.,University of Edinburgh
Journal of Cognitive Neuroscience | Year: 2015

How does knowledge of real-world events shape our understanding of incoming language? Do temporal terms like “before” and “after” impact the online recruitment of real-world event knowledge? These questions were addressed in two ERP experiments, wherein participants read sentences that started with “before” or “after” and contained a critical word that rendered each sentence true or false (e.g., “Before/After the global economic crisis, securing a mortgage was easy/harder”). The critical words were matched on predictability, rated truth value, and semantic relatedness to the words in the sentence. Regardless of whether participants explicitly verified the sentences or not, false-aftersentences elicited larger N400s than true-after-sentences, consistent with the well-established finding that semantic retrieval of concepts is facilitated when they are consistent with real-world knowledge. However, although the truth judgments did not differ between before- and after-sentences, no such sentence N400 truth value effect occurred in before-sentences, whereas falsebefore- sentences elicited an enhanced subsequent positive ERPs. The temporal term “before” itself elicited more negative ERPs at central electrode channels than “after.” These patterns of results show that, irrespective of ultimate sentence truth value judgments, semantic retrieval of concepts is momentarily facilitated when they are consistent with the known event outcome compared to when they are not. However, this inappropriate facilitation incurs later processing costs as reflected in the subsequent positive ERP deflections. The results suggest that automatic activation of event knowledge can impede the incremental semantic processes required to establish sentence truth value. © 2015 Massachusetts Institute of Technology.

A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ∼73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 × 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 × 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 × 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA). Copyright © 2012 Elsevier Inc. All rights reserved.

Ingram G.C.,University of Edinburgh
Protoplasma | Year: 2010

The formation of viable angiosperm seeds involves the co-ordinated growth and development of three genetically distinct organisms, the maternally derived seed coat and the zygotic embryo and endosperm. The physical relationships of these tissues are initially established during the specification and differentiation of the female gametophyte within the tissues of the developing ovule. The molecular programmes implicated in both ovule and seed development involve elements of globally important pathways (such as auxin signalling), as well as ovule- and seed- specific pathways. Recurrent themes, such as the precisely controlled death of specific cell types and the regulation of cell-cell communication and nutrition by the selective establishment of symplastic and apoplastic barriers, appear to play key roles in both pre- and post-fertilization seed development. Much of post-fertilization seed growth occurs during a key developmental window shortly after fertilization and involves the dramatic expansion of the young endosperm, constrained by surrounding maternal tissues. The complex tissue-specific regulation of carbohydrate metabolism in specific seed compartments has been shown to provide a driving force for this early seed expansion. The embryo, which is arguably the most important component of the seed, appears to be only minimally involved in early seed development. Given the evolutionary and agronomic importance of angiosperm seeds, the complex combination of communication pathways which co-ordinate their growth and development remains remarkably poorly understood. © 2010 Springer-Verlag.

Lohse K.,University of Edinburgh | Frantz L.A.F.,Wageningen University
Genetics | Year: 2014

Although there has been much interest in estimating histories of divergence and admixture from genomic data, it has proved difficult to distinguish recent admixture from long-term structure in the ancestral population. Thus, recent genome-wide analyses based on summary statistics have sparked controversy about the possibility of interbreeding between Neandertals and modern humans in Eurasia. Here we derive the probability of full mutational configurations in nonrecombining sequence blocks under both admixture and ancestral structure scenarios. Dividing the genome into short blocks gives an efficient way to compute maximumlikelihood estimates of parameters. We apply this likelihood scheme to triplets of human and Neandertal genomes and compare the relative support for a model of admixture from Neandertals into Eurasian populations after their expansion out of Africa against a history of persistent structure in their common ancestral population in Africa. Our analysis allows us to conclusively reject a model of ancestral structure in Africa and instead reveals strong support for Neandertal admixture in Eurasia at a higher rate (3.427.3%) than suggested previously. Using analysis and simulations we show that our inference is more powerful than previous summary statistics and robust to realistic levels of recombination. © 2014 by the Genetics Society of America.

Saunders D.S.,University of Edinburgh
Journal of Insect Physiology | Year: 2010

This review examines several controversial aspects of photoperiodism in insects and mites including the role of the circadian system in night length measurement, the nature of apparent hourglass-like responses, and whether or not the circadian component in photoperiodism is the same as that in overt behavioural rhythms. These aspects of the phenomenon are discussed in terms of the entrainment of circadian oscillations by cycles of light and temperature. There is considerable variety of photoperiodic response within the insects (and other arthropods) to show, inter alia, circannual rhythms, internal and external coincidence night length timers, and in some species, non-circadian hourglass-like devices. Many apparent hourglass-like responses, however, could be circadian 'clocks' of the external coincidence type involving oscillations that dampen below threshold in extended periods of darkness. The review also concludes that there is little evidence in favour of the " Hourglass clock-oscillator counter" model proposed for the mite Tetranychus urticae by Vaz Nunes and Veerman (1982a). The responses of this species to complex light and temperature cycles may also be interpreted in terms of a damped oscillator version of external coincidence. © 2010 Elsevier Ltd.

Giannopoulos A.,University of Edinburgh
IEEE Transactions on Antennas and Propagation | Year: 2012

An unsplit implementation of higher order perfectly matched layers (PMLs) using a recursive integration approach is presented. The formulation, which is based on the complex coordinate stretching of space, is developed for a general complex frequency-shifted stretching function but is applicable to PMLs employing the standard stretching function or a mixture of either types. The approach results in the development of two general formulae that could be used to easily generate PML correction equations for any PML order. Numerical results from finite-difference time-domain models are presented to illustrate the validity of the approach. © 2006 IEEE.

MacDonald R.A.R.,University of Edinburgh
International Journal of Qualitative Studies on Health and Well-being | Year: 2013

The relationship between arts participation and health is currently very topical. Motivated by a desire to investigate innovative, non-invasive, and economically viable interventions that embrace contemporary definitions of health, practitioners and researchers across the world have been developing and researching arts inventions. One of the key drivers in this vigorous research milieu is the growth of qualitative research within health care contexts and researchers interested in exploring the potential benefits of musical participation have fully embraced the advances that have taken place in health-related qualitative research. The following article presents a number of different types of qualitative research projects focused on exploring the process and outcomes of music interventions. It also presents a new conceptual model for music, health and well-being. This new model develops on a previous version of MacDonald, Kreutz, and Mitchell (2012b) by incorporating new elements and contextualization and providing detailed experimental examples to support the various components. © 2013 R. MacDonald.

Smoktunowicz A.,University of Edinburgh
Selecta Mathematica, New Series | Year: 2014

In 1964, Golod and Shafarevich found that, provided that the number of relations of each degree satisfies some bounds, there exist infinitely dimensional algebras satisfying the relations. These algebras are called Golod–Shafarevich algebras. This paper provides bounds for the growth function on images of Golod–Shafarevich algebras based upon the number of defining relations. This extends results from Smoktunowicz and Bartholdi (Q J Math. doi:10.1093/qmath/hat005 2013) and Smoktunowicz (J Algebra 381:116–130, 2013). Lower bounds of growth for constructed algebras are also obtained, permitting the construction of algebras with various growth functions of various entropies. In particular, the paper answers a question by Drensky (A private communication, 2013) by constructing algebras with subexponential growth satisfying given relations, under mild assumption on the number of generating relations of each degree. Examples of nil algebras with neither polynomial nor exponential growth over uncountable fields are also constructed, answering a question by Zelmanov (2013). Recently, several open questions concerning the commutativity of algebras satisfying a prescribed number of defining relations have arisen from the study of noncommutative singularities. Additionally, this paper solves one such question, posed by Donovan and Wemyss (Noncommutative deformations and flops, ArXiv:1309.0698v2 [math.AG]). © 2014, Springer Basel.

Knowles S.C.L.,University of Edinburgh
International Journal for Parasitology | Year: 2011

The question of how helminths may alter the course of concurrent malaria infection has attracted much interest in recent years. In particular, it has been suggested that by creating an anti-inflammatory immune environment, helminth co-infection may dampen both protective and immunopathological responses to malaria parasites, thus altering malaria infection dynamics and disease severity. Both synergistic and antagonistic interactions are reported in the literature, and the causes of variation among studies are not well understood. Here, meta-analysis of 42 mouse co-infection experiments was used to address how helminths influence malaria parasite replication and host mortality, and explore the factors explaining variation in findings. Most notably, this analysis revealed contrasting effects of helminth co-infection in lethal and resolving malaria models. Whilst co-infection exacerbated mortality and increased peak parasitaemia in ordinarily resolving malaria infections (Plasmodium chabaudi and Plasmodium yoelii), effects among lethal malaria infections (Plasmodium berghei) tended to be in the opposite direction with no change in parasitaemia. In the subset of experiments on cerebral malaria models (P. berghei ANKA strain in a susceptible host), helminth co-infection significantly delayed death. These findings are consistent with the hypothesis that depending on the existing balance of pro- and anti-inflammatory responses mounted against malaria parasites in a given host, immune responses elicited by helminth co-infection may either promote or inhibit malarial disease. However, despite such broad patterns, a prominent feature of this dataset was great heterogeneity in effects across studies. A key future challenge therefore lies in explaining the biological causes of this variation, including a more thorough exploration of non-immunological mechanisms of helminth-malaria interaction. © 2011 Australian Society for Parasitology Inc.

Withers C.W.J.,University of Edinburgh
Transactions of the Institute of British Geographers | Year: 2013

The paper explores the promotion of method in nineteenth-century British geography. Attention is paid to the emphasis accorded scientific instruments in a period when scientific subjects were, in practice and in personnel, 'disciplining' themselves. The role ascribed to scientific instruments and method is examined with reference to the work in the Royal Geographical Society of Julian R. Jackson and his What to observe, or the traveller's remembrancer (1841), and William Hamilton's essay on geographical methods in John Herschel's Manual of scientific enquiry (1849). These works are further explored with reference to two related texts, the Society's Hints to travellers (Raper and Fitzroy 1854) and Francis Galton's The art of travel (1855). The paper for the first time brings together evidence for the place of scientific instruments within geography's methodological pronouncements with scholarship in the history of technology and the history of science. In doing so, the paper highlights the importance of critical histories of geography's methods, instruments and associated practices. The conclusion addresses the implications of such research for providing yet richer histories of geography that might address not just the subject's cognitive content and institutional context but matters of epistemological procedure, moral conduct and authorial regimen in relation to precision instrumentation. © 2012 The Author. Transactions of the Institute of British Geographers © 2012 Royal Geographical Society (with the Institute of British Geographers).

A key question in the literature on payments for ecosystem services (PES) is how payments incentivize conservation action and, in particular, how they interact with other motivations, including motivations for environmental stewardship. Related to this question are concerns about the temporal sustainability of PES: what happens when payments cease and whether a 'no pay, no care' environmental ethic is fostered. I present empirical research from a case study in western Uganda, where forest-adjacent communities are paid in exchange for planting trees on private lands, for carbon sequestration. The study demonstrates the range of values people have for trees in the landscape and the range of motivations for participating in PES schemes. However, the analysis shows that payments are clearly the main motivation for involvement, except in one area where people are more motivated by aesthetic and existence values for trees. Given the widespread importance of money in motivating involvement, I investigate the profitability of participation over time. This profitability analysis, in combination with qualitative data on perceptions of, and plans for, the future, contributes to understanding the temporal sustainability of PES. I draw on various strands of evidence to argue that the way participants prioritize payments may constitute a threat to the long-term maintenance of PES activities, particularly in situations such as in this case study, in which there is a mismatch between payments and contract length. © 2012 Fauna & Flora Internationa.

Dutia M.B.,University of Edinburgh
Current Opinion in Otolaryngology and Head and Neck Surgery | Year: 2010

Purpose of Review This article reviews recent studies that have provided experimental evidence for mechanisms of neural and synaptic plasticity in the brain during vestibular compensation, the behavioural recovery that takes place following peripheral vestibular lesions. Recent Findings: First, experimental evidence from animal studies indicates that an unbalanced vestibular commissural system is a fundamental cause of the syndrome of oculomotor and postural deficits after unilateral labyrinthectomy. Second, recent studies suggest the involvement of both GABAergic and glycinergic commissural neurons. In addition gliosis and reactive neurogenesis in the ipsilesional vestibular nuclei appear to be involved in compensation. Third, evidence from cerebellar-deficient mutant mice demonstrates an important role for cerebellum-dependent motor learning in the longer term. Factors such as stress steroids and neuromodulators such as histamine influence these plasticity mechanisms and may thus contribute to the development of compensation in patients. Summary: Vestibular compensation involves multiple, parallel plastic processes at various sites in the brain. Experimental evidence suggests that adaptive changes in the sensitivity of ipsilesional vestibular neurons to the inhibitory neurotransmitters GABA and glycine, changes in the electrophysiological excitability of vestibular neurons, changes in the inhibitory control of the brainstem vestibular networks by the cerebellum, gliosis and neurogenesis in the ipsilesional vestibular nuclei, and activity-dependent reorganization of the synaptic connectivity of the vestibular pathways are mechanisms involved in compensation. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Clostridium difficile infection is now a major concern throughout the developed world and its occurrence is a consequence of broad-spectrum antibiotic therapy primarily in the elderly in-patient population and high spore loads in hospitals in these regions. With the emergence of a hypervirulent, endemic strain, more severe disease is being recognized and is occurring in previously considered unusual patient groups. Vancomycin and metronidazole are the current mainstays for therapy of severe and nonsevere disease, respectively. Relapse is a major concern, with treatment options for these cases often difficult. Any new drug must be better than vancomycin for severe disease with fewer relapses. Fidaxomicin, a macrocyclic RNA polymerase inhibitor, has a narrow spectrum of activity, which is almost C. difficile specific. This drug appears to have a higher clinical cure rate than vancomycin, and fewer patients relapse following initial treatment. From the results of a recent Phase III trial, fidaxomicin appears to be an extremely promising drug for treating C. difficile infection and preventing relapses. © 2010 Future Medicine Ltd.

There is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias. We conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both. We identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3-5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size. RhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials.

Ironside J.W.,University of Edinburgh
Haemophilia | Year: 2010

Variant Creutzfeldt-Jakob disease (CJD) is an emerging form of human prion disease caused by oral exposure to the bovine spongiform encephalopathy agent. Most cases have occurred in the UK, but smaller numbers of cases have been identified in 10 other countries worldwide. All confirmed cases belong to a single genetic subgroup defined by methionine homozygosity at codon 129 in the prion protein gene. Variant CJD has a widespread distribution of infectivity in the body, involving lymphoid tissues during at least the latter part of the incubation period. This is unlike other forms of human prion disease, and raised concerns that the transmissible agent might also be present in blood. To date, four probable cases of variant CJD infection have been identified following transfusion of packed red blood cells from asymptomatic donors who subsequently died from variant CJD. Recently, one case of likely transmission of variant CJD infection by UK factor VIII (FVIII) concentrates has been reported in an elderly haemophilic patient in the UK, who had been treated with FVIII produced from pooled plasma to which a donor who subsequently died from variant CJD had contributed. The recipient showed no signs or symptoms of variant CJD during life, but evidence of variant CJD infection was detected in his spleen following a postmortem examination. Continued surveillance is required to investigate the prevalence of secondary variant CJD infection in other patients with bleeding disorders who have been treated with UK-sourced pooled plasma products. © 2010 The Author. Journal compilation © 2010 Blackwell Publishing Ltd.

Hill W.G.,University of Edinburgh
G3 (Bethesda, Md.) | Year: 2013

Determination of degree of relationship traditionally has been undertaken using genotypic data on individual loci, typically assumed to be independent. With dense marker data as now available, it is possible to identify the regions of the genome shared identical by descent (ibd). This information can be used to determine pedigree relationship (R), e.g., cousins vs. second cousins, and also to distinguish pedigrees that have the same Wright's relationship (R) such as half-sibs and uncle-nephew. We use simulation to investigate the accuracy with which pedigree relationship can be inferred from genome sharing for uniparental relatives (a common ancestor on only one side of their pedigree), specifically the number, position (whether at chromosome ends), and length of shared regions ibd on each chromosome. Moments of the distribution of the likelihood ratio (including its expectation, the Kullback-Leibler distance) for alternative relationships are estimated for model human genomes, with the ratio of the mean to the SD of the likelihood ratio providing a useful reference point. Two relationships differing in R can be readily distinguished provided at least one has high R, e.g., approximately 98.5% correct assignment of cousins and half-cousins, but only approximately 75% for second cousins once removed and third cousins. Two relationships with the same R can be distinguished only if R is high, e.g., half-sibs and uncle-nephew, with probability of correct assignment being approximately 5/6.

Woolhouse M.,University of Edinburgh
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Formal, quantitative approaches are now widely used to make predictions about the likelihood of an infectious disease outbreak, how the disease will spread, and how to control it. Several wellestablished methodologies are available, including risk factor analysis, risk modelling and dynamic modelling. Even so, predictive modelling is very much the 'art of the possible', which tends to drive research effort towards some areas and away from others which may be at least as important. Building on the undoubted success of quantitative modelling of the epidemiology and control of human and animal diseases such as AIDS, influenza, foot-and-mouth disease and BSE, attention needs to be paid to developing a more holistic framework that captures the role of the underlying drivers of disease risks, from demography and behaviour to land use and climate change. At the same time, there is still considerable room for improvement in how quantitative analyses and their outputs are communicated to policy makers and other stakeholders. A starting point would be generally accepted guidelines for 'good practice' for the development and the use of predictive models. © 2011 The Royal Society.

Collins S.,University of Edinburgh
Evolutionary Biology | Year: 2011

Experimental microbial evolution has focused on the particular ecological scenario where a population is placed suddenly in an environment where its fitness is low, and then adapts while the environment remains stable. In line with this, most microbial evolution studies use fitness measures that report how evolved genotypes fare when competed directly against their own distant ancestor while other studies compare life history traits (such as growth rates) of ancestral and evolved genotypes. This standard way of measuring and reporting changes in fitness has resulted in a consistent body of literature that explains adaptation when populations evolve in this "standard ecological scenario." Here, I suggest that for experimental evolution to investigate adaptation in other ecological scenarios, such as fluctuating or persistently changing environments, measures of fitness must be expanded such that they not only continue to be comparable between experiments, but also account for evolution and demographic effects in all environments that an evolving lineage experiences. I examine two non-standard measures of fitness-fitness flux and the total number of reproductive events-as potential ways to quantify adaptation by integrating historical information about selection over many environments. This approach could allow us to make quantitative and biologically-meaningful comparisons of adaptation across diverse ecological scenarios. I use the case study of understanding how phytoplankton communities may respond to global change, where environmental variables change continuously, to explore concrete ways of using non-standard fitness measures that consider both demographic effects and selection in changing, rather than in changed, environments. © 2010 Springer Science+Business Media, LLC.

Patenaude G.,University of Edinburgh
Global Environmental Change | Year: 2011

The influence of business schools on business practitioners is considerable. An important proportion of corporate leaders hold a degree in business administration or an MBA, if not both. In the context of climate change, this influence matters: greenhouse gas (GHG) emissions from a selection of global 500 companies approximate that of the USA and the EU15 combined. Not only do corporations have a significant climate footprint, but the impact of climate change on the business landscape is already noticeable. Yet, meeting the managerial challenges that climate change brings requires knowledge only moderately addressed in business education and scholarship today. Climate change tends to be discussed in electives - hence reaching only a fraction of students - and tends to be treated alongside a myriad of other corporate social responsibility issues. Moreover, from 1992 to 2008, only seven articles with titles containing climate change or global warming were published in the top-30 peer-reviewed management journals (this paper, see also Goodall, 2008). In this paper, by mapping the diffusion of climate change within press media and academic peer-reviewed publications, I argue that understanding the existing lag in business scholarship engagement requires a fundamental understanding of processes that either hinder or lead to the diffusion of new ideas. To do so, I present a simple yet novel approach for the quantification of climate change or global warming (CCorGW) coverage relative to population size. My results on the diffusion of the climate change idea over time show: (a) an overall increase in proportional coverage in all databases (b) tipping points around the late 1980s and circa 2005 and (c) delays in adoption between press categories. I explicate the occurrence of these tipping points as well as the existence of delays by theoretically unifying my analyses with results from previous studies under the umbrella of the diffusion of innovation paradigm. I suggest that the following key factors have contributed in slowing the diffusion within business scholarship: (a) corporate values, beliefs and operational modes (b) social structures and incentives prevailing within academia and finally (b) academia's valued research communication channels. I conclude by elaborating key recommendations to facilitate the diffusion of this idea to business scholars and other influential audiences. © 2010 Elsevier Ltd.

Simmonds P.,University of Edinburgh
BMC Research Notes | Year: 2012

Background: There is an increasing need to develop bioinformatic tools to organise and analyse the rapidly growing amount of nucleotide and amino acid sequence data in organisms ranging from viruses to eukaryotes. Finding. A simple sequence editor (SSE) was developed to create an integrated environment where sequences can be aligned, annotated, classified and directly analysed by a number of built-in bioinformatic programs. SSE incorporates a sequence editor for the creation of sequence alignments, a process assisted by integrated CLUSTAL/MUSCLE alignment programs and automated removal of indels. Sequences can be fully annotated and classified into groups and annotated of sequences and sequence groups and access to analytical programs that analyse diversity, recombination and RNA secondary structure. Methods for analysing sequence diversity include measures of divergence and evolutionary distances, identity plots to detect regions of nucleotide or amino acid homology, reconstruction of sequence changes, mono-, di- and higher order nucleotide compositional biases and codon usage. Association Index calculations, GroupScans, Bootscanning and TreeOrder scans perform phylogenetic analyses that reconcile group membership with tree branching orders and provide powerful methods for examining segregation of alleles and detection of recombination events. Phylogeny changes across alignments and scoring of branching order differences between trees using the Robinson-Fould algorithm allow effective visualisation of the sites of recombination events. RNA secondary and tertiary structures play important roles in gene expression and RNA virus replication. For the latter, persistence of infection is additionally associated with pervasive RNA secondary structure throughout viral genomic RNA that modulates interactions with innate cell defences. SSE provides several programs to scan alignments for RNA secondary structure through folding energy thermodynamic calculations and phylogenetic methods (detection of co-variant changes, and structure conservation between divergent sequences). These analyses complement methods based on detection of sequence constraints, such as suppression of synonymous site variability. For each program, results can be plotted in real time during analysis through an integrated graphics package, providing publication quality graphs. Results can be also directed to tabulated datafiles for import into spreadsheet or database programs for further analysis. Conclusions: SSE combines sequence editor functions with analytical tools in a comprehensive and user-friendly package that assists considerably in bioinformatic and evolution research. © 2012 Simmonds; licensee BioMed Central Ltd.

Background: The results of the CLOTS 3 trial showed that intermittent pneumatic compression (IPC) reduced the risk of deep vein thrombosis and improved survival in immobile patients with stroke. IPC is now being widely used in stroke units. Here we describe the disability, living circumstances, quality of life, and hospital costs of patients in CLOTS 3. Methods: In CLOTS 3, a parallel group trial in 94 UK hospitals, immobile patients with stroke from days 0 to 3 of admission were assigned with a computer-generated allocation sequence in a 1:1 ratio to IPC or no IPC through a central randomisation system. We followed up patients at about 6 months with postal or telephone questionnaire to assess the secondary endpoints: disability (Oxford Handicap Scale [OHS]), living circumstances, health-related quality of life (EQ5D-3L), and hospital costs (based on use of IPC and length of hospital stay). Patients and carers who completed the postal questionnaires were not masked to treatment allocation, but telephone follow-up in non-responders was masked. All analyses were by intention to treat. This trial is registered, number ISRCTN93529999. Findings: Between Dec 8, 2008, and Sept 6, 2012, we enrolled 2876 patients, with 1438 in each group. Despite the previously reported reduction in the risk of proximal deep vein thrombosis at 30 days (primary endpoint), there were no significant differences in disability (OHS 0-2 vs 3-6, adjusted odds ratio [OR] 0·98, 95% CI 0·80 to 1·19, p=0·83; adjusted ordinal analysis common OR 0·97, 95% CI 0·86 to 1·11), living circumstances (institutional care vs not; adjusted OR 1·11, 95% CI 0·89 to 1·37; p=0·358), or health-related quality of life (median utility value 0·26, IQR -0·07 to 0·66 with IPC, and 0·27, -0·06 to 0·64, with no IPC; p=0·952). The estimated cost of IPC was £64·10 per patient (SD 28·3). The direct costs of preventing a deep vein thrombosis and death were £1282 (95% CI 785 to 3077) and £2756 (1346 to not estimable), respectively, with IPC. Hospital costs increased by £451 with IPC compared with no IPC because of a longer stay in hospital (mean 44·5 days [SD 37·6] vs 42·8 days [37·2]; mean difference 1·8 days, 95% CI -1·0 to 4·5). By 6 months, despite an increase in survival (IPC 152·5 days [SD 60·6] vs no IPC 148·1 days [64·3]; mean difference 4·5 days, 95% CI -0·2 to 9·1), there was a non-significant increase in quality-adjusted survival associated with IPC (IPC 27·6 days [SD 40·6] vs no IPC 26·7 days [39·6]; mean difference 0·9 days, 95% CI -2·1 to 3·9). Interpretation: IPC is inexpensive, prevents deep vein thrombosis, improves survival but not functional outcomes, and does not lead to a significant gain in quality-adjusted survival. When deciding whether to treat patients with IPC, clinicians need to take into account all these potential effects. Funding: National Institute of Health Research Health Technology Assessment Programme, Chief Scientist Office of Scottish Government, and Covidien. © 2014 Dennis et al. Open Access article distributed under the terms of CC BY.

Van Limbergen J.,Dalhousie University | Radford-Smith G.,Queensland Institute of Medical Research | Satsangi J.,University of Edinburgh
Nature Reviews Gastroenterology and Hepatology | Year: 2014

IBD is a spectrum of chronic disorders that constitute an important health problem worldwide. The hunt for genetic determinants of disease onset and course has culminated in the Immunochip project, which has identified >160 loci containing IBD susceptibility genes. In this Review, we highlight how genetic association studies have informed our understanding of the pathogenesis of IBD by focusing research efforts on key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis. Several of these novel genetic markers and cellular pathways are promising candidates for patient stratification and therapeutic targeting. © 2014 Macmillan Publishers Limited.

This paper presents findings on expert perceptions of uncertainty in carbon capture and storage (CCS) technology and policy in the UK, through survey data and semi-structured interviews with 19 individual participants. Experts were interviewed in industry, research, and non-governmental organisations (NGOs) in the summer of 2009 and were asked to comment on a range of technical processes as well as policy concerns. The survey revealed that perceptions of the technology conform to a 'certainty trough' with users expressing the lowest level of uncertainty, and outsiders expressing the highest level of uncertainty. The interviews revealed that experts express certitude in the prospects for deploying large-scale CCS technology in the UK, all the while questioning several underlying technical and policy premises that are necessary to ensure this goal. © 2011 Elsevier Ltd.

Miller W.R.,University of Edinburgh
Journal of Steroid Biochemistry and Molecular Biology | Year: 2010

Neoadjuvant treatment provides an exceptional setting in which to monitor clinical, pathological, proliferative and molecular responses to aromatase inhibitors. Sequential measurements of the primary tumour provide an accurate assessment of clinical changes and the relatively easy access to the tumour within the breast means that biopsies are available for histological and molecular measurements before and during treatment. Large randomised trials (P024 and IMPACT) together with informative nonrandomised studies have demonstrated clinical responses to third generation aromatase inhibitors in 40-70% of ER-positive tumours, rates generally significantly higher than observed with tamoxifen. Pathological responses in terms of reduced cellularity/increased fibrosis are also seen in 65-75% of cases. Whilst these are more often seen in clinically responding tumours, the correlation between clinical and pathological response is not absolute. A marked feature of treatment with third generation inhibitors is a reduction in cellular proliferation. Using Ki67 as a marker, this may be observed as early as 10-14 days into treatment. Reduction in proliferation with treatment may be seen in both clinically responding and non-responding tumours, although incidence and degree of effect are higher in responding cases. Aromatase inhibitor treatment frequently fails to reduce proliferation in tumours over-expressing HER-2. In terms of molecular events, aromatase inhibitor treatment is associated with changes in expression of genes classically associated with oestrogen regulation (KIAA0101, ZWINT, IRS1 and TFF1) and cell cycle progression, most notably mitotic phase proteins (CDC2, CCNB1 and CKS2). Changes occur both in clinically responding and non-responding tumours. Although expression of no individual gene correlates absolutely with response status, expression signatures can be produced which distinguish between responding and non-responding tumours. In terms of gene ontology, terms relating to macro-molecular biosynthesis, translation and structural components of ribosomes are significantly enriched. Finally, molecular signatures can be used to illustrate the relative homogeneity of responding tumours and the disparate nature of non-responding tumours suggesting multiple and diverse pathways associated with resistance. © 2009 Elsevier Ltd. All rights reserved.

Cabrera C.P.,University of Edinburgh
G3 (Bethesda, Md.) | Year: 2012

Genome-wide association studies (GWAS) aim to detect single nucleotide polymorphisms (SNP) associated with trait variation. However, due to the large number of tests, standard analysis techniques impose highly stringent significance thresholds, leaving potentially associated SNPs undetected, and much of the trait genetic variation unexplained. Pathway- and network-based methodologies applied to GWAS aim to detect associations missed by standard single-marker approaches. The complex and non-random architecture of the genome makes it a challenge to derive an appropriate testing framework for such methodologies. We developed a rapid and simple permutation approach that uses GWAS SNP association results to establish the significance of pathway associations while accounting for the linkage disequilibrium structure of SNPs and the clustering of functionally related elements in the genome. All SNPs used in the GWAS are placed in a "circular genome" according to their location. Then the complete set of SNP association P values are permuted by rotation with respect to the genomic locations of the SNPs. Once these "simulated" P values are assigned, the joint gene P values are calculated using Fisher's combination test, and the association of pathways is tested using the hypergeometric test. The circular genomic permutation approach was applied to a human genome-wide association dataset. The data consists of 719 individuals from the ORCADES study genotyped for ~300,000 SNPs and measured for 51 traits ranging from physical to biochemical measurements. KEGG pathways (n = 225) were used as the sets of pathways to be tested. Our results demonstrate that the circular genomic permutations provide robust association P values. The non-permuted hypergeometric analysis generates ~1400 pathway-trait combination results with an association P value more significant than P ≤ 0.05, whereas applying circular genomic permutation reduces the number of significant results to a more credible 40% of that value. The circular permutation software ("genomicper") is available as an R package at http://cran.r-project.org/.

Pickersgill M.,University of Edinburgh
New Genetics and Society | Year: 2011

In recent years, attempts have increasingly been made to connect neuroscience and law. Scientists and lawyers are imagining and actively fostering the realization of futures in which neuroscience will play a prominent role in the activity of courts. In this article I take these debates as my empirical object. I trace the emergence of neurolegal discourse, explore its focus on free will and lie detection, and show how expectations about the potential role neuroscience might play in the law are being embedded in new research programs and funding streams. In so doing, I analyze the role of particular "sociotechnical imaginaries" in stimulating, directing and restricting neurolegal discourse and highlight the ways in which new visions of law, science and scientists are produced in the process. Sociotechnical imaginaries are shown to be salient in structuring anticipatory discourse, and represent a key target for social scientific intervention in such debates. © 2011 Taylor & Francis.

Robertson L.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2012

Peripheral arterial disease (PAD) is frequently treated by balloon angioplasty. Restenosis/reocclusion of the dilated segments occurs often, depending on length of occlusion, lower leg outflow, stage of disease and presence of cardiovascular risk factors. To prevent reocclusion, patients are treated with antithrombotic agents. This is an update of a review first published in 2005. To determine whether any antithrombotic drug is more effective in preventing restenosis or reocclusion after peripheral endovascular treatment, compared to another antithrombotic drug, no treatment, placebo or other vasoactive drugs. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched 14 February 2012) and CENTRAL (2012, Issue 1). We selected randomised controlled trials (RCTs). Participants were patients with symptomatic PAD treated by endovascular revascularisation of the pelvic or femoropopliteal arteries. Interventions were anticoagulant, antiplatelet or other vasoactive drug therapy compared with no treatment, placebo or any other vasoactive drug. Clinical endpoints were reocclusion, restenosis, amputation, death, myocardial infarction, stroke, major bleeding and other side effects, such as minor bleeding, puncture site bleeding, gastrointestinal side effects and haematoma. We independently extracted and assessed details of the number of randomised patients, treatment, study design, patient characteristics and risk of bias. Analysis was based on intention-to-treat data. To examine the effects of outcomes such as reocclusion, restenosis, amputation and major bleeding, we computed odds ratios (OR) with 95% confidence intervals (CI) using a fixed-effect model. Twenty-two trials with a total of 3529 patients are included (14 in the original review and a further eight in this update). For the majority of comparisons, only one trial was available so results were rarely combined in meta-analyses. Individual trials were generally small and risk of bias was often unclear due to limitations in reporting. Three trials reported on drug versus placebo/control; results were consistently available for a maximum follow-up of only six months.

Rimer J.,University of Edinburgh
Cochrane database of systematic reviews (Online) | Year: 2012

Depression is a common and important cause of morbidity and mortality worldwide. Depression is commonly treated with antidepressants and/or psychotherapy, but some people may prefer alternative approaches such as exercise. There are a number of theoretical reasons why exercise may improve depression. This is an update of an earlier review first published in 2009. To determine the effectiveness of exercise in the treatment of depression. Our secondary outcomes included drop-outs from exercise and control groups, costs, quality of life and adverse events. We searched the Cochrane Depression, Anxiety and Neurosis (CCDAN) Review Group's Specialised Register (CCDANCTR), CENTRAL, MEDLINE, EMBASE, Sports Discus and PsycINFO for eligible studies (to February 2010). We also searched www.controlled-trials.com in November 2010. The CCDAN Group searched its Specialised Register in June 2011 and potentially eligible trials were listed as 'awaiting assessment'. Randomised controlled trials in which exercise was compared to standard treatment, no treatment or a placebo treatment in adults (aged 18 and over) with depression, as defined by trial authors. We excluded trials of postnatal depression. For this update, two review authors extracted data on outcomes at the end of the trial. We used these data to calculate effect sizes for each trial using Hedges' g method and a standardised mean difference (SMD) for the overall pooled effect, using a random-effects model. Where trials used a number of different tools to assess depression, we included the main outcome measure only in the meta-analysis. We systematically extracted data on adverse effects and two authors performed the 'Risk of bias' assessments. Thirty-two trials (1858 participants) fulfilled our inclusion criteria, of which 30 provided data for meta-analyses. Randomisation was adequately concealed in 11 studies, 12 used intention-to-treat analyses and nine used blinded outcome assessors. For the 28 trials (1101 participants) comparing exercise with no treatment or a control intervention, at post-treatment analysis the pooled SMD was -0.67 (95% confidence interval (CI) -0.90 to -0.43), indicating a moderate clinical effect. However, when we included only the four trials (326 participants) with adequate allocation concealment, intention-to-treat analysis and blinded outcome assessment, the pooled SMD was -0.31 (95% CI -0.63 to 0.01) indicating a small effect in favour of exercise. There was no difference in drop-outs between exercise and control groups. Pooled data from the seven trials (373 participants) that provided long-term follow-up data also found a small effect in favour of exercise (SMD -0.39, 95% CI -0.69 to -0.09). Of the six trials comparing exercise with cognitive behavioural therapy (152 participants), the effect of exercise was not significantly different from that of cognitive therapy. There were insufficient data to determine risks, costs and quality of life.Five potentially eligible studies identified by the search of the CCDAN Specialised Register in 2011 are listed as 'awaiting classification' and will be included in the next update of this review. Exercise seems to improve depressive symptoms in people with a diagnosis of depression when compared with no treatment or control intervention, however since analyses of methodologically robust trials show a much smaller effect in favour of exercise, some caution is required in interpreting these results.

Hadfield J.D.,University of Edinburgh
Journal of Statistical Software | Year: 2010

Generalized linear mixed models provide a flexible framework for modeling a range of data, although with non-Gaussian response variables the likelihood cannot be obtained in closed form. Markov chain Monte Carlo methods solve this problem by sampling from a series of simpler conditional distributions that can be evaluated. The R package MCMCglmm implements such an algorithm for a range of model fitting problems. More than one response variable can be analyzed simultaneously, and these variables are allowed to follow Gaussian, Poisson, multi(bi)nominal, exponential, zero-inflated and censored distributions. A range of variance structures are permitted for the random effects, including interactions with categorical or continuous variables (i.e., random regression), and more complicated variance structures that arise through shared ancestry, either through a pedigree or through a phylogeny. Missing values are permitted in the response variable(s) and data can be known up to some level of measurement error as in meta-analysis. All simulation is done in C/C++ using the CSparse library for sparse linear systems.

Stevens P.,University of Edinburgh
Software and Systems Modeling | Year: 2010

We consider the OMG's queries, views and transformations standard as applied to the specification of bidirectional transformations between models. We discuss what is meant by bidirectional transformations, and the model-driven development scenarios in which they are needed. We analyse the fundamental requirements on tools which support such transformations, and discuss some semantic issues which arise. In particular, we show that any transformation language sufficient to the needs of model-driven development would have to be able to express non-bijective transformations. We argue that a considerable amount of basic research is needed before suitable tools will be fully realisable, and suggest directions for this future research. © 2008 Springer-Verlag.

Wardrop N.A.,University of Edinburgh
PLoS neglected tropical diseases | Year: 2010

The persistent spread of Rhodesian human African trypanosomiasis (HAT) in Uganda in recent years has increased concerns of a potential overlap with the Gambian form of the disease. Recent research has aimed to increase the evidence base for targeting control measures by focusing on the environmental and climatic factors that control the spatial distribution of the disease. One recent study used simple logistic regression methods to explore the relationship between prevalence of Rhodesian HAT and several social, environmental and climatic variables in two of the most recently affected districts of Uganda, and suggested the disease had spread into the study area due to the movement of infected, untreated livestock. Here we extend this study to account for spatial autocorrelation, incorporate uncertainty in input data and model parameters and undertake predictive mapping for risk of high HAT prevalence in future. Using a spatial analysis in which a generalised linear geostatistical model is used in a Bayesian framework to account explicitly for spatial autocorrelation and incorporate uncertainty in input data and model parameters we are able to demonstrate a more rigorous analytical approach, potentially resulting in more accurate parameter and significance estimates and increased predictive accuracy, thereby allowing an assessment of the validity of the livestock movement hypothesis given more robust parameter estimation and appropriate assessment of covariate effects. Analysis strongly supports the theory that Rhodesian HAT was imported to the study area via the movement of untreated, infected livestock from endemic areas. The confounding effect of health care accessibility on the spatial distribution of Rhodesian HAT and the linkages between the disease's distribution and minimum land surface temperature have also been confirmed via the application of these methods. Predictive mapping indicates an increased risk of high HAT prevalence in the future in areas surrounding livestock markets, demonstrating the importance of livestock trading for continuing disease spread. Adherence to government policy to treat livestock at the point of sale is essential to prevent the spread of sleeping sickness in Uganda.

Bilbao S.,University of Edinburgh
IEEE Transactions on Audio, Speech and Language Processing | Year: 2013

Due to recent increases in computing power, room acoustics simulation in 3D using time stepping schemes is becoming a viable alternative to standard methods based on ray tracing and the image source method. Finite Difference Time Domain (FDTD) methods, operating over regular grids, are perhaps the best known among such methods, which simulate the acoustic field in its entirety over the problem domain. In a realistic room acoustics setting, working over a regular grid is attractive from a computational standpoint, but is complicated by geometrical considerations, particularly when the geometry does not conform neatly to the grid, and those of boundary conditions which emulate the properties of real wall materials. Both such features may be dealt with through an appeal to methods operating over unstructured grids, such as finite volume methods, which reduce to FDTD when employed over regular grids. Through numerical energy analysis, such methods lead to direct stability conditions for complex problems, including convenient geometrical conditions at irregular boundaries. Simulation results are presented. © 2006-2012 IEEE.

Sharp P.M.,University of Edinburgh | Hahn B.H.,University of Pennsylvania
Cold Spring Harbor Perspectives in Medicine | Year: 2011

Acquired immunodeficiency syndrome (AIDS) of humans is caused by two lentiviruses, human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2). Here, we describe the origins and evolution of these viruses, and the circumstances that led to the AIDS pandemic. Both HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M-the principal cause of the AIDS pandemic. We discuss how host restriction factors have shaped the emergence of new SIV zoonoses by imposing adaptive hurdles to cross-species transmission and/or secondary spread. We also show that AIDS has likely afflicted chimpanzees long before the emergence of HIV. Tracing the genetic changes that occurred as SIVs crossed from monkeys to apes and from apes to humans provides a new framework to examine the requirements of successful host switches and to gauge future zoonotic risk. © 2011 Cold Spring Harbor Laboratory Press; all rights reserved.

Nelson S.M.,University of Glasgow | Telfer E.E.,University of Edinburgh | Anderson R.A.,Queens Medical Research Institute
Human Reproduction Update | Year: 2013

BACKGROUND: Advanced maternal age is associated with reduced fertility and adverse pregnancy outcomes. This review details recent developments in our understanding of the biology and mechanisms underlying reproductive ageing in women and the implications for fertility and pregnancy. METHODS: Sociological online libraries (IBSS, SocINDEX), PubMed and Google Scholar were searched for relevant demographic, epidemiological, clinical and biological studies, using key words and hierarchical MeSH terms. From this, we identified and focused on key topics where it was judged that there had been clinically relevant advances in the understanding of ovarian and uterine ageing with implications for improved diagnostics and novel interventions. RESULTS: Mapping of the ovarian reserve, follicular dynamics and associated biomarkers, across the reproductive lifespan has recently been performed. This now allows an assessment of the effects of environmental, lifestyle and prenatal exposures on follicular dynamics and the identification of their impact during periods of germ cell vulnerability and may also facilitate early identification of individuals with shorter reproductive lifespans. If women choose to time their family based on their ovarian reserve this would redefine the meaning of family planning. Despite recent reports of the potential existence of stem cells which may be used to restore the primordial follicle and thereby the oocyte pool, therapeutic interventions in female reproductive ageing at present remain limited. Maternal ageing has detrimental effects on decidual and placental development, which may be related to repeated exposure to sex steroids and underlie the association of ageing with adverse perinatal outcomes. CONCLUSIONS: Ageing has incontrovertible detrimental effects on the ovary and the uterus. Our enhanced understanding of ovarian ageing will facilitate early identification of individuals at greatest risk, and novel therapeutic interventions. Changes in both ovary and uterus are in addition to age-related co-morbidities, which together have synergistic effects on reducing the probability of a successful pregnancy outcome. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Research on district heating has focused on technical-economic appraisal of its contribution to energy and carbon saving in urban centres. There is however lack of analysis of political and social processes which govern its actual take up. This paper examines these processes through a case study of Aberdeen, Scotland. Interviews and documentary analysis are used to examine the 2002 development of Aberdeen Heat and Power (AHP), an independent energy services company (ESCo). Technical-economic feasibility was a necessary component of appraisal, but not sufficient to govern decision-making. In the UK centralised energy market, DH investment is unattractive to commercial investors, and local authorities lack capacity and expertise in energy provision. In Aberdeen, the politics of fuel poverty converged with climate politics, creating an a-typical willingness to innovate through improvisation. The welfare priority resulted in creation of a non-profit locally-owned ESCo, using cost- rather than market-based heat tariffs. AHP has developed three combined heat and power energy centres and heat networks, supplying 34. MWh/pa of heat. Carbon savings are estimated to be 45% in comparison with electric heating, and heating costs are reduced by a similar amount. The conclusion outlines potential policy improvements. © 2014 Elsevier Ltd.