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Oxford, United Kingdom

The University of Oxford is a collegiate research university located in Oxford, England. While having no known date of foundation, there is evidence of teaching as far back as 1096, making it the oldest university in the English-speaking world, and the world's second-oldest surviving university. It grew rapidly from 1167 when Henry II banned English students from attending the University of Paris. After disputes between students and Oxford townsfolk in 1209, some academics fled northeast to Cambridge, where they established what became the University of Cambridge. The two "ancient universities" are frequently jointly referred to as "Oxbridge".The University is made up from a variety of institutions, including 38 constituent colleges and a full range of academic departments which are organised into four Divisions. All the colleges are self-governing institutions as part of the University, each controlling its own membership and with its own internal structure and activities. Being a city university, it does not have a main campus; instead, all the buildings and facilities are scattered throughout the metropolitan centre.Most undergraduate teaching at Oxford is organised around weekly tutorials at the self-governing colleges and halls, supported by classes, lectures and laboratory work provided by university faculties and departments. Oxford is the home of several notable scholarships, including the Clarendon Scholarship which was launched in 2001 and the Rhodes Scholarship which has brought graduate students to read at the university for more than a century. Oxford operates the largest university press in the world and the largest academic library system in the United Kingdom.Oxford has educated many notable alumni, including 27 Nobel laureates , 26 British Prime Ministers and many foreign heads of state. Wikipedia.


Thavanesan N.,University of Oxford
British Journal of Nutrition | Year: 2011

The increase in the prevalence of obesity in recent years has prompted research into alternative methods of modulating body weight and body fat. The last decade has reflected this with a surge in studies investigating the potential of green tea as a natural agent of weight loss, with a view to confirming and elucidating the mechanisms underlying its effect on the body. Currently, it is widely believed that the polyphenolic components present in green tea have an anti-obesogenic effect on fat homeostasis, by increasing thermogenesis or reducing fat absorption among other ways. The data published to date, however, are inconsistent, with numerous putative modes of action suggested therein. While several unimodal mechanisms have been postulated, a more plausible explanation of the observed results might involve a multimodal approach. Such a mechanism is suggested here, involving simultaneous inhibition of the enzymes catechol-O-methyltransferase, acetyl-CoA carboxylase, fatty acid synthase and impeding absorption of fat via the gut. An evaluation of the available evidence supports a role of green tea in weight loss; however the extent of the effects obtained is still subject to debate, and requires more objective quantification in future research. © 2011 The Author.


Mcdowell L.,University of Oxford
Transactions of the Institute of British Geographers | Year: 2011

In popular representations, including journalism, film and drama, a tendency to attribute blame for the recent financial crisis to the greed and venality of individual bankers has been noticeable. In this paper, I explore some of these representations, focusing on the ways in which blame is attributed to the irrational behaviour of actors operating in a heteronormative culture in which masculinity and risk-taking were, until the crash, highly rewarded. This is a marked shift from earlier claims that the growing reliance on apparently rational mathematical methods of calculating risk would abolish the cycles of boom and bust that characterise financial markets. I argue that the analysis of story-telling, financial journalism and dramatic representations complements other ways of explaining financial crises, including structural analyses. In an attempt to mirror these representations, I present my arguments as a drama in five acts, before concluding with an assessment of the significance of different narrative representations. © 2011 The Author. Transactions of the Institute of British Geographers © 2011 Royal Geographical Society (with the Institute of British Geographers).


Fricker M.D.,University of Oxford
Antioxidants and Redox Signaling | Year: 2016

Significance: A wealth of fluorescent reporters and imaging systems are now available to characterize dynamic physiological processes in living cells with high spatiotemporal resolution. The most reliable probes for quantitative measurements show shifts in their excitation or emission spectrum, rather than just a change in intensity, as spectral shifts are independent of optical path length, illumination intensity, probe concentration, and photobleaching, and they can be easily determined by ratiometric measurements at two wavelengths. Recent Advances: A number of ratiometric fluorescent reporters, such as reduction-oxidation-sensitive green fluorescent protein (roGFP), have been developed that respond to the glutathione redox potential and allow redox imaging in vivo. roGFP and its derivatives can be expressed in the cytoplasm or targeted to different organelles, giving fine control of measurements from sub-cellular compartments. Furthermore, roGFP can be imaged with probes for other physiological parameters, such as reactive oxygen species or mitochondrial membrane potential, to give multi-channel, multi-dimensional 4D (x,y,z,t) images. Critical Issues: Live cell imaging approaches are needed to capture transient or highly spatially localized physiological behavior from intact, living specimens, which are often not accessible by other biochemical or genetic means. Future Directions: The next challenge is to be able to extract useful data rapidly from such large (GByte) images with due care given to the assumptions used during image processing. This article describes a suite of software programs, available for download, that provide intuitive user interfaces to conduct multi-channel ratio imaging, or alternative analysis methods such as pixel-population statistics or image segmentation and object-based ratio analysis. Antioxid. Redox Signal. 24, 752-762. © Copyright 2016, Mary Ann Liebert, Inc. 2016.


Hanke T.,University of Oxford
Expert Opinion on Biological Therapy | Year: 2014

Introduction: Effective vaccines are the best solution for stopping the spread of HIV/AIDS and other infectious diseases. Their development and in-depth understanding of pathogen-host interactions rely on technological advances. Areas covered: Rational vaccine development can be effectively approached by conceptual separation of, on one hand, design of immunogens from improving their presentation to the immune system and, on the other, induction of antibodies from induction of killer CD8+ T cells. The biggest roadblock for many vaccines is the pathogens' variability. This is best tackled by focusing both antibodies and T cells on the functionally most conserved regions of proteins common to many variants, including escape mutants. For vectored vaccines, these 'universal' subunit immunogens are most efficiently delivered using heterologous prime-boost regimens, which can be further optimised by adjuvantation and route of delivery. Expert opinion: Development of vaccines against human diseases has many features in common. Acceleration of vaccine discovery depends on basic research and new technologies. Novel strategies should be safely, but rapidly tested in humans. While out-of-the-box thinking is important, vaccine success largely depends on incremental advances best achieved through small, systematic, iterative clinical studies. Failures are inevitable, but the end rewards are huge. The future will be exciting. © 2014 Informa UK, Ltd.


Garnett T.,University of Oxford
Proceedings of the Nutrition Society | Year: 2013

The global food system makes a significant contribution to climate changing greenhouse gas emissions with all stages in the supply chain, from agricultural production through processing, distribution, retailing, home food preparation and waste, playing a part. It also gives rise to other major environmental impacts, including biodiversity loss and water extraction and pollution. Policy makers are increasingly aware of the need to address these concerns, but at the same time they are faced with a growing burden of food security and nutrition-related problems, and tasked with ensuring that there is enough food to meet the needs of a growing global population. In short, more people need to be fed better, with less environmental impact. How might this be achieved? Broadly, three main 'takes' or perspectives, on the issues and their interactions, appear to be emerging. Depending on one's view point, the problem can be conceptualised as a production challenge, in which case there is a need to change how food is produced by improving the unit efficiency of food production; a consumption challenge, which requires changes to the dietary drivers that determine food production; or a socio-economic challenge, which requires changes in how the food system is governed. This paper considers these perspectives in turn, their implications for nutrition and climate change, and their strengths and weaknesses. Finally, an argument is made for a reorientation of policy thinking which uses the insights provided by all three perspectives, rather than, as is the situation today, privileging one over the other. Copyright © 2013 The Author.


Wyatt T.D.,University of Oxford
Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology | Year: 2010

Pheromones have been found in species in almost every part of the animal kingdom, including mammals. Pheromones (a molecule or defined combination of molecules) are species-wide signals which elicit innate responses (though responses can be conditional on development as well as context, experience, and internal state). In contrast, signature mixtures, in invertebrates and vertebrates, are variable subsets of molecules of an animal's chemical profile which are learnt by other animals, allowing them to distinguish individuals or colonies. All signature mixtures, and almost all pheromones, whatever the size of molecules, are detected by olfaction (as defined by receptor families and glomerular processing), in mammals by the main olfactory system or vomeronasal system or both. There is convergence on a glomerular organization of olfaction. The processing of all signature mixtures, and most pheromones, is combinatorial across a number of glomeruli, even for some sex pheromones which appear to have 'labeled lines'. Narrowly specific pheromone receptors are found, but are not a prerequisite for a molecule to be a pheromone. A small minority of pheromones act directly on target tissues (allohormone pheromones) or are detected by non-glomerular chemoreceptors, such as taste. The proposed definitions for pheromone and signature mixture are based on the heuristic value of separating these kinds of chemical information. In contrast to a species-wide pheromone, there is no single signature mixture to find, as signature mixtures are a 'receiver-side' phenomenon and it is the differences in signature mixtures which allow animals to distinguish each other. © 2010 Springer-Verlag.


Flodgren G.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Healthcare-associated infections (HAIs) are a major threat to patient safety, and are associated with mortality rates varying from 5% to 35%. Important risk factors associated with HAIs are the use of invasive medical devices (e.g. central lines, urinary catheters and mechanical ventilators), and poor staff adherence to infection prevention practices during insertion and care for the devices when in place. There are electronic databases for primary studies up to June 2012: the Cochrane Effective Paractice and Organisation of Care (EPOC) Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), (DARE) for related reviews. We included randomised controlled trials (RCTs), non-randomised controlled trials (NRCTs), controlled before-after (CBA) studies and interrupted time series (ITS) studies included 13 studies: one cluster randomised controlled trial (CRCT) and 12 ITS studies, involving 40 hospitals, 51 intensive care units (ICUs), 27 wards, and more than 3504 patients and 1406 healthcare professionals. central line-associated blood stream infections (CLABSIs); another six studies targeted adherence to guidelines to prevent ventilator-associated pneumonia (VAP), and one study focused on decrease of 7.36 (-10.82 to 3.14) cases per 1000 ventilator days (five studies and 15 sites). The one included cluster randomised controlled trial (CRCT) observed, improved urinary catheter practices five weeks after the intervention (absolute difference 12.2 percentage points), however, the statistical significance of this is unknown given a unit of analysis error. It is worth noting that N = 6 interventions that did result in significantly decreased infection rates involved more than one care personnel showed the largest step change (-22.9 cases per 1000 ventilator days (standard error (SE) 4.0), and also the largest slope change (-6.45 cases per 1000 ventilator days (SE 1.42, P = 0.002)) among the included studies. We attempted to combine the results for studies targeting the same indwelling medical device (central line catheters or mechanical ventilators) and reporting the same outcomes (CLABSI and VAP rate) in two separate meta-analyses, but due to very high statistical heterogeneity among included studies (I(2) up to 97%), we did not retain these analyses. Six of the included studies reported post-intervention adherence scores ranging from 14% to 98%. The effect on rates of median effect for the change in level (interquartile range (IQR)) for the six CLABSI studies being observed at three months follow-up was a decrease of 0.6 (-2.74 to 0.28) cases per 1000 central line days (six studies and 36 sites). This change was not sustained over longer follow-up times. The low to very low quality of the evidence of studies aspect of care that is supported by evidence e.g. dentists/dental auxiliaries performing oral care for VAP prevention.


Using Metro Manila as a case study, this paper investigates whether and how its current urban form and pattern of transformation can be explained by the theories of gentrification developed within the cities of the Global North. Two core features of gentrification are examined: the production of exclusive spaces and the related displacement of the poor or low-income households. The uneven development across the metropolis is discussed in terms of the longstanding tension between the weak city-state and the dominance of the landed elites. Falling through the gap are the urban poor, who arrange their housing within informal settlements and are exposed to multiple vulnerabilities, including the risk of displacement. Drawing on an empirical study of the displacement impacts of a public transportation project, this paper provides useful insights into how gentrification-induced displacement may unfold if land-based development takes place in a densely populated metropolis such as Metro Manila. © 2014, © Urban Studies Journal Limited 2014.


Cowen P.J.,University of Oxford
Psychological Medicine | Year: 2010

Salivary cortisol sampling has confirmed the presence of increased cortisol secretion in depression and has also revealed that some aspects of hypothalamo-pituitary-adrenal (HPA) axis disturbance have trait-like characteristics that may predict the risk of future illness. Persistent hypersecretion of cortisol in individuals vulnerable to depression also has implications for the medical co-morbidities associated with mood disorder. Pharmacological treatments targeted at the HPA axis represent a novel approach to the management of depression and its complications; however, a better understanding of the molecular basis of HPA axis dysfunction in depressed patients will be needed before this promise can be fulfilled. © Copyright Cambridge University Press 2009.


Agarwal S.,University of Oxford
PLoS computational biology | Year: 2010

The idea of "date" and "party" hubs has been influential in the study of protein-protein interaction networks. Date hubs display low co-expression with their partners, whilst party hubs have high co-expression. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. Here, we show that the reported importance of date hubs to network connectivity can in fact be attributed to a tiny subset of them. Crucially, these few, extremely central, hubs do not display particularly low expression correlation, undermining the idea of a link between this quantity and hub function. The date/party distinction was originally motivated by an approximately bimodal distribution of hub co-expression; we show that this feature is not always robust to methodological changes. Additionally, topological properties of hubs do not in general correlate with co-expression. However, we find significant correlations between interaction centrality and the functional similarity of the interacting proteins. We suggest that thinking in terms of a date/party dichotomy for hubs in protein interaction networks is not meaningful, and it might be more useful to conceive of roles for protein-protein interactions rather than for individual proteins.


Luqmani R.,University of Oxford
Nature Reviews Rheumatology | Year: 2013

A fundamental change in management of antineutrophil cytoplasmic antibody-associated vasculitis in the past 10 years is the early focussed use of aggressive immunosuppression, using regimens comprised of widely available medications. Using a clinical framework to quantify morbidity, we can induce remission in most patients within 3-6 months using glucocorticoids plus methotrexate, cyclophosphamide or rituximab, with additional plasmapheresis when indicated. Difficulty in maintaining remission probably relates to the difference between true pathophysiological remission and the absence of clinical, serological or radiological evidence of disease activity. For surviving patients, the cumulative problems of relapse, burden of disease, or its treatment are coupled with pre-existing diseases or new conditions arising since diagnosis. Initial early control should reduce subsequent damage, but what effect it will have on relapse is not clear. In the absence of a cure, future trials should focus on reducing toxicity and comorbidity as well as controlling disease. © 2013 Macmillan Publishers Limited. All rights reserved.


Rothwell P.M.,University of Oxford
Current Hypertension Reports | Year: 2011

Exactly how hypertension causes end organ damage and vascular events is poorly understood. Yet the concept that underlying "usual" blood pressure (BP) accounts for all BP-related risk of vascular events and for the benefits of BP-lowering drugs has come to underpin clinical guidelines on the diagnosis and treatment of hypertension. This article reviews evidence that variability in BP also predicts risk of stroke and other vascular events independently of mean BP and evidence that drug-class effects on variability in BP explain differences in the effectiveness of BP-lowering drugs in preventing stroke. © 2011 Springer Science+Business Media, LLC.


Freeman M.,University of Oxford
Annual review of cell and developmental biology | Year: 2014

The rhomboid proteases were first discovered as regulators of Drosophila EGF receptor signaling; soon after, it was recognized that they represented the founder members of a widespread family of intramembrane serine proteases conserved in all kingdoms. More recently still, the family was promoted to a superfamily, encompassing a wide variety of distantly related proteins. One of the surprises has been that many members of the rhomboid-like superfamily are not active proteases. Given the size of this clan, and its relatively recent discovery, there is still much to learn. Nevertheless, we already understand much about how rhomboid proteases perform their surprising function of cleaving transmembrane domains. We also already know that members of the rhomboid-like superfamily participate in biological functions as diverse as growth factor signaling, mitochondrial dynamics, inflammation, parasite invasion, and the machinery of protein quality control. Their potential medical significance is now becoming apparent in several areas.


Grochola L.F.,University of Oxford
Cold Spring Harbor perspectives in biology | Year: 2010

The p53 tumor suppressor pathway is central both in reducing cancer frequency in vertebrates and in mediating the response of commonly used cancer therapies. This article aims to summarize and discuss a large body of evidence suggesting that the p53 pathway harbors functional inherited single-nucleotide polymorphisms (SNPs) that affect p53 signaling in cells, resulting in differences in cancer risk and clinical outcome in humans. The insights gained through these studies into how the functional p53 pathway SNPs could help in the tailoring of cancer therapies to the individual are discussed. Moreover, recent work is discussed that suggests that many more functional p53 pathway SNPs are yet to be fully characterized and that a thorough analysis of the functional human genetics of this important tumor suppressor pathway is required.


Massey T.,University of Oxford
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Use of topical NSAIDs to treat acute musculoskeletal conditions is widely accepted in some parts of the world, but not in others. Their main attraction is their potential to provide pain relief without associated systemic adverse events. OBJECTIVES: To review the evidence from randomised, double-blind, controlled trials on the efficacy and safety of topically applied NSAIDs in acute pain. SEARCH STRATEGY: We searched MEDLINE, EMBASE, The Cochrane Library, and our own in-house database to December 2009. We sought unpublished studies by asking personal contacts and searching on-line clinical trial registers and manufacturers web sites. SELECTION CRITERIA: We included randomised, double-blind, active or placebo (inert carrier)-controlled trials in which treatments were administered to adult patients with acute pain resulting from strains, sprains or sports or overuse-type injuries (twisted ankle, for instance). There had to be at least 10 participants in each treatment arm, with application of treatment at least once daily. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and validity, and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. MAIN RESULTS: Forty-seven studies were included; most compared topical NSAIDs in the form of a gel, spray, or cream with a similar placebo, with 3455 participants in the overall analysis of efficacy. For all topical NSAIDs combined, compared with placebo, the number needed to treat to benefit (NNT) for clinical success, equivalent to 50% pain relief, was 4.5 (3.9 to 5.3) for treatment periods of 6 to 14 days. Topical diclofenac, ibuprofen, ketoprofen, and piroxicam were of similar efficacy, but indomethacin and benzydamine were not significantly better than placebo. Local skin reactions were generally mild and transient, and did not differ from placebo. There were very few systemic adverse events or withdrawals due to adverse events. There were insufficient data to reliably compare individual topical NSAIDs with each other or the same oral NSAID. AUTHORS' CONCLUSIONS: Topical NSAIDs can provide good levels of pain relief, without the systemic adverse events associated with oral NSAIDs, when used to treat acute musculoskeletal conditions.


Malhi Y.,University of Oxford
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The rainforests are the great green heart of Africa, and present a unique combination of ecological, climatic and human interactions. In this synthesis paper, we review the past and present state processes of change in African rainforests, and explore the challenges and opportunities for maintaining a viable future for these biomes. We draw in particular on the insights and new analyses emerging from the Theme Issue on 'African rainforests: past, present and future' of Philosophical Transactions of the Royal Society B. A combination of features characterize the African rainforest biome, including a history of climate variation; forest expansion and retreat; a long history of human interaction with the biome; a relatively low plant species diversity but large tree biomass; a historically exceptionally high animal biomass that is now being severely hunted down; the dominance of selective logging; small-scale farming and bushmeat hunting as the major forms of direct human pressure; and, in Central Africa, the particular context of mineral- and oil-driven economies that have resulted in unusually low rates of deforestation and agricultural activity. We conclude by discussing how this combination of factors influences the prospects for African forests in the twenty-first century.


Lu X.,University of Oxford
Cold Spring Harbor perspectives in biology | Year: 2010

The tumor suppressor p53 is a master sensor of stress that controls many biological functions, including implantation, cell-fate decisions, metabolism, and aging. In response to a defined stress signal such as gamma radiation, the response of p53 is heterogeneous in vivo. Like a complex barcode, the ability of p53 to function as a central hub that integrates defined stress signals into decisive cellular responses, in a time- and cell-type dependent manner, is facilitated by the extraordinary complexity of its regulation. Key components of this barcode are the autoregulation loops, which positively or negatively regulate p53's activities. Thus, this article focuses on reviewing our current understanding of how autoregulation loops formed between p53 and how its transcriptional targets regulate the activities of p53 at a variety of levels, through mdm2-dependent and -independent pathways. Knowing that a large number of autoregulation loops exist that influence p53's activity, our future challenge is to elucidate which of these play a central role in regulating p53, under which conditions, in response to what stress, and at which particular stage of our lives. Such knowledge may ultimately lead to the development of more effective anticancer therapeutics.


Lloyd-Hughes J.,University of Oxford
Applied Physics Letters | Year: 2012

A theoretical framework is presented that calculates the conductivity of polar semiconductors at terahertz frequencies without resorting to phenomenological fit parameters, using an expression derived from the Boltzmann transport equation. The time-dependent photoconductivity of InAs and the temperature dependent conductivity of n-doped GaAs are found experimentally by terahertz time-domain spectroscopy. The observed deviation from the Drude-Lorentz conductivity in these model systems is accounted for by this approach, which calculates the energy-dependent electron scattering time. © 2012 American Institute of Physics.


The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms.Molecular Psychiatry advance online publication, 16 September 2014; doi:10.1038/mp.2014.91. © 2014 Macmillan Publishers Limited


Randolph S.E.,University of Oxford
Animal health research reviews / Conference of Research Workers in Animal Diseases | Year: 2013

Before attributing cause and consequence to climate change, the precise patterns of change must be known. Ground records across much of Europe show a 1-2 °C rise in temperatures in 1989 with no significant rise since then. The timing and spatial uniformity of this pattern, relative to changes in the distribution and incidence of many vector-borne diseases, are sufficient to falsify most simple claims that climate change is the principal cause of disease emergence. Furthermore, age-specific increases in incidence indicate causes other than, or in addition to, climate change. Unfortunately, many public health professionals repeat the received wisdom that climate change is worsening the burden of indirectly transmitted infections; this 'expert opinion' soon becomes consensus dogma divorced from quantitative evidence. The pressing need is to gather appropriate data to test the simple concept that the composition and relative importance of disparate multifactorial factors, commonly integrated within a causal nexus, will inevitably vary with the geographical, cultural, socio-economical, wildlife, etc. context. The greatest impact of warming occurs at the geographical limits of current distributions, where low temperatures limit the hazard of infected vectors. Within core endemic regions, changing exposure of humans to this hazard, through changing socio-economic factors is evidently more important amongst both the poor and the wealthy.


Harper S.,University of Oxford
Science | Year: 2014

The challenge of global population aging has been brought into sharper focus by the financial crisis of 2008. In particular, growing national debt has drawn government attention to two apparently conflicting priorities: the need to sustain public spending on pensions and health care versus the need to reduce budget deficits. A number of countries are consequently reconsidering their pension and health care provisions, which account for up to 40% of all government spending in advanced economies. Yet population aging is a global phenomenon that will continue to affect all regions of the world. By 2050 there will be the same number of old as young in the world, with 2 billion people aged 60 or over and another 2 billion under age 15, each group accounting for 21% of the world's population. Copyright © 2014 by the American Association for the Advancement of Science; all rights reserved.


Knight J.C.,University of Oxford
Genome Medicine | Year: 2014

The diversity of regulatory genetic variants and their mechanisms of action reflect the complexity and context-specificity of gene regulation. Regulatory variants are important in human disease and defining such variants and establishing mechanism is crucial to the interpretation of disease-association studies. This review describes approaches for identifying and functionally characterizing regulatory variants, illustrated using examples from common diseases. Insights from recent advances in resolving the functional epigenomic regulatory landscape in which variants act are highlighted, showing how this has enabled functional annotation of variants and the generation of hypotheses about mechanism of action. The utility of quantitative trait mapping at the transcript, protein and metabolite level to define association of specific genes with particular variants and further inform disease associations are reviewed. Establishing mechanism of action is an essential step in resolving functional regulatory variants, and this review describes how this is being facilitated by new methods for analyzing allele-specific expression, mapping chromatin interactions and advances in genome editing. Finally, integrative approaches are discussed together with examples highlighting how defining the mechanism of action of regulatory variants and identifying specific modulated genes can maximize the translational utility of genome-wide association studies to understand the pathogenesis of diseases and discover new drug targets or opportunities to repurpose existing drugs to treat them. © 2014 Knight; licensee BioMed Central Ltd.


Adesso G.,University of Nottingham | Datta A.,University of Oxford
Physical Review Letters | Year: 2010

Quantum discord, a measure of genuinely quantum correlations, is generalized to continuous variable systems. For all two-mode Gaussian states, we calculate analytically the quantum discord and a related measure of classical correlations, solving an optimization over all Gaussian measurements. Almost all two-mode Gaussian states are shown to have quantum correlations, while for separable states, the discord is smaller than unity. For a given amount of entanglement, it admits tight upper and lower bounds. Via a duality between entanglement and classical correlations, we derive a closed formula for the Gaussian entanglement of formation of a family of three-mode Gaussian states. © 2010 The American Physical Society.


Herring N.,University of Oxford
Experimental Physiology | Year: 2015

Acute myocardial infarction and congestive cardiac failure are characterized by high levels of cardiac sympathetic drive. In these conditions, sympathetic neurotransmitters such as neuropeptide Y (NPY) can be released in addition to noradrenaline, and plasma levels correlate with infarct size and mortality. Even in the presence of β-blockers, NPY is able to bind to its own receptors located on cholinergic ganglia and ventricular myocytes. In this symposium report, I review the evidence that NPY can inhibit acetylcholine release during vagus nerve stimulation and limit the subsequent bradycardia. I also present preliminary, as yet unpublished data, demonstrating that NPY may be pro-arrhythmic by directly influencing ventricular electrophysiology. Targeting NPY receptors pharmacologically may therefore be a useful therapeutic strategy both to reduce heart rate and to prevent arrhythmias in the setting of myocardial infarction and chronic heart failure. Such medications would be expected to act synergistically with β-blockers, angiotensin-converting enzyme inhibitors and implantable cardiac devices, such as defibrillators and vagus nerve stimulators. © 2014 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.


We now take for granted that despite the disproportionate contribution of females to initial growth of their progeny, there is little or no asymmetry in the contribution of males and females to the eventual character of their shared offspring. In fact, this key insight was only established towards the end of the eighteenth century by Joseph Koelreuter's pioneering plant breeding experiments. If males and females supply equal amounts of hereditary material, then the latter must double each time an embryo is conceived. How then does the amount of this mysterious stuff not multiply exponentially from generation to generation? A compensatory mechanism for diluting the hereditary material must exist, one that ensures that if each parent contributes one half, each grandparent contributes a quarter, and each great grandparent merely an eighth. An important piece of the puzzle of how hereditary material is diluted at each generation has been elucidated over the past ten years. © 2015 The Author. BioEssays published by WILEY Periodicals, Inc.


Thakker R.V.,University of Oxford
Molecular and Cellular Endocrinology | Year: 2014

Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3-9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation. © 2013 Elsevier Ireland Ltd.


McVean G.,University of Oxford
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Recombination between homologous, but non-allelic, stretches of DNA such as gene families, segmental duplications and repeat elements is an important source of mutation. In humans, recent studies have identified short DNA motifs that both determine the location of 40 per cent of meiotic cross-over hotspots and are significantly enriched at the breakpoints of recurrent nonallelic homologous recombination (NAHR) syndromes. Unexpectedly, the most highly penetrant form of the motif occurs on the background of an inactive repeat element family (THE1 elements) and the motif also has strong recombinogenic activity on currently active element families including Alu and LINE2 elements. Analysis of genetic variation among members of these repeat families indicates an important role for NAHR in their evolution. Given the potential for double-strand breaks within repeat DNA to cause pathological rearrangement, the association between repeats and hotspots is surprising. Here we consider possible explanations for why selection acting against NAHR has not eliminated hotspots from repeat DNA including mechanistic constraints, possible benefits to repeat DNA from recruiting hotspots and rapid evolution of the recombination machinery. I suggest that rapid evolution of hotspot motifs may, surprisingly, tend to favour sequences present in repeat DNA and outline the data required to differentiate between hypotheses. © 2010 The Royal Society.


Tyson J.J.,Virginia State University | Novak B.,University of Oxford
Annual Review of Physical Chemistry | Year: 2010

The signal-response characteristics of a living cell are determined by complex networks of interacting genes, proteins, and metabolites. Understanding how cells respond to specific challenges, how these responses are contravened in diseased cells, and how to intervene pharmacologically in the decision-making processes of cells requires an accurate theory of the information-processing capabilities of macromolecular regulatory networks. Adopting an engineer's approach to control systems, we ask whether realistic cellular control networks can be decomposed into simple regulatory motifs that carry out specific functions in a cell. We show that such functional motifs exist and review the experimental evidence that they control cellular responses as expected. Copyright © 2010 by Annual Reviews. All rights reserved.


Saunders K.E.,University of Oxford
Bipolar disorders | Year: 2013

Suicidal behaviour is common in people suffering with bipolar disorder, and suicide is a leading cause of death in this group. Our aim in this review is to provide an overview of key assessment and management strategies, highlight research findings relevant to suicide prevention, and identify important areas for future research. We reviewed the published literature regarding the risk factors for and management of suicida\l behaviour in individuals with bipolar disorder using the Pubmed and PsychINFO databases. Where available, we focused our search on systematic reviews. Suicide is usually associated with a depressive phase, although mixed affective states also convey increased risk. All individuals with bipolar disorder should have an up-to-date crisis management plan which outlines the action to be taken should suicidal behaviour emerge. Timely clinical assessment is essential in ensuring that those at high risk are identified. This should include mental state examination, consideration of risk factors, and evaluation of issues such as access to means, preparatory acts before suicide, and also protective factors. While pharmacological approaches are the mainstay of management, less specific measures, such as the removal of access to means, are also important in ensuring safety in the acute situation. Intensifying the clinical support of both patients and relatives, and the sharing of risk information with other health agencies are essential in management. Specific psychological treatments are likely to be helpful in preventing crises, although the evidence base is limited. The aetiology of suicidal behaviour in bipolar disorder is multifactorial and requires proactive crisis planning and management. A range of issues need to be addressed in the assessment of at-risk patients. Determining the efficacy of interventions specific to reducing suicidality in bipolar disorder should be a research priority. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


May R.M.,University of Oxford
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Beginning with an outline of uncertainties about the number of species on Earth today, this paper addresses likely causes and consequences of the manifest acceleration in extinction rates over the past few centuries. The ultimate causes are habitat destruction, alien introductions, overexploitation and climate change. Increases in human numbers and per capita impacts underlie all of these. Against a background review of these factors, I conclude with a discussion of the policy implications for equitably proportionate actions-and of the difficulties in achieving them. © 2010 The Royal Society.


Seddon N.,University of Oxford
Proceedings. Biological sciences / The Royal Society | Year: 2013

Sexual selection is proposed to be an important driver of diversification in animal systems, yet previous tests of this hypothesis have produced mixed results and the mechanisms involved remain unclear. Here, we use a novel phylogenetic approach to assess the influence of sexual selection on patterns of evolutionary change during 84 recent speciation events across 23 passerine bird families. We show that elevated levels of sexual selection are associated with more rapid phenotypic divergence between related lineages, and that this effect is restricted to male plumage traits proposed to function in mate choice and species recognition. Conversely, we found no evidence that sexual selection promoted divergence in female plumage traits, or in male traits related to foraging and locomotion. These results provide strong evidence that female choice and male-male competition are dominant mechanisms driving divergence during speciation in birds, potentially linking sexual selection to the accelerated evolution of pre-mating reproductive isolation.


Gardner A.,University of Oxford
Journal of Theoretical Biology | Year: 2010

Population viscosity has been proposed as an important mechanism for the evolution of cooperation. The idea is that if individuals do not disperse far during the course of their lives, they will tend to interact with their genealogical relatives, which may give kin-selected benefits for cooperation. However, in the simplest model of population structure, the evolution of cooperation is unaffected by the rate of dispersal, owing to dispersal also mediating competition between social partners. This surprising result has generated much research interest in recent years. Here I show that dispersal does matter if there is a sex difference in dispersal rate, even when the expression of cooperation is not conditional upon the actor's dispersal status or sex. In particular, I show that cooperation among juveniles is relatively favoured when there is a small sex bias in adult dispersal in favour of the sex with the greatest variance in reproductive success, and is relatively disfavoured when this sex bias is large or in the opposite direction. This is because dispersal by individuals of each sex can have different consequences for the genetic structure of the population. © 2009 Elsevier Ltd. All rights reserved.


Bishop D.V.M.,University of Oxford
PLoS ONE | Year: 2010

Aim: There are substantial differences in the amount of research concerned with different disorders. This paper considers why. Methods: Bibliographic searches were conducted to identify publications (1985-2009) concerned with 35 neurodevelopmental disorders: Developmental dyslexia, Developmental dyscalculia, Developmental coordination disorder, Speech sound disorder, Specific language impairment, Attention deficit hyperactivity disorder, Autistic spectrum disorder, Tourette syndrome, Intellectual disability, Angelman syndrome, Cerebral palsy, Cornelia de Lange syndrome, Cri du chat syndrome, Down syndrome, Duchenne muscular dystrophy, Fetal alcohol syndrome, Fragile X syndrome, Galactosaemia, Klinefelter syndrome, Lesch-Nyhan syndrome, Lowe syndrome, Marfan syndrome, Neurofibromatosis type 1, Noonan syndrome, Phenylketonuria, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Trisomy 18, Tuberous sclerosis, Turner syndrome, Velocardiofacial syndrome, Williams syndrome, XXX and XYY. A publication index reflecting N publications relative to prevalence was derived. Results: The publication index was higher for rare than common conditions. However, this was partly explained by the tendency for rare disorders to be more severe. Interpretation: Although research activity is predictable from severity and prevalence, there are exceptions. Low rates of research, and relatively low levels of NIH funding, characterise conditions that are the domain of a single discipline with limited research resources. Growth in research is not explained by severity, and was exceptionally steep for autism and ADHD. © 2010 Dorothy V. M. Bishop.


Kolling N.,University of Oxford
Science (New York, N.Y.) | Year: 2012

Behavioral economic studies involving limited numbers of choices have provided key insights into neural decision-making mechanisms. By contrast, animals' foraging choices arise in the context of sequences of encounters with prey or food. On each encounter, the animal chooses whether to engage or, if the environment is sufficiently rich, to search elsewhere. The cost of foraging is also critical. We demonstrate that humans can alternate between two modes of choice, comparative decision-making and foraging, depending on distinct neural mechanisms in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) using distinct reference frames; in ACC, choice variables are represented in invariant reference to foraging or searching for alternatives. Whereas vmPFC encodes values of specific well-defined options, ACC encodes the average value of the foraging environment and cost of foraging.


Bishop D.V.M.,University of Oxford
Behavior Genetics | Year: 2010

Traditionally, autistic spectrum disorder (ASD) and specific language impairment (SLI) are regarded as distinct conditions with separate etiologies. Yet these disorders co-occur at above chance levels, suggesting shared etiology. Simulations, however, show that additive pleiotropic genes cannot account for observed rates of language impairment in relatives, which are higher for probands with SLI than for those with ASD + language impairment. An alternative account is in terms of 'phenomimicry', i.e., language impairment in comorbid cases may be a consequence of ASD risk factors, and different from that seen in SLI. However, this cannot explain why molecular genetic studies have found a common risk genotype for ASD and SLI. This paper explores whether nonadditive genetic influences could account for both family and molecular findings. A modified simulation involving G × G interactions obtained levels of comorbidity and rates of impairment in relatives more consistent with observed values. The simulations further suggest that the shape of distributions of phenotypic trait scores for different genotypes may provide evidence of whether a gene is involved in epistasis. © 2010 The Author(s).


Wyatt T.D.,University of Oxford
Proceedings. Biological sciences / The Royal Society | Year: 2015

As humans are mammals, it is possible, perhaps even probable, that we have pheromones. However, there is no robust bioassay-led evidence for the widely published claims that four steroid molecules are human pheromones: androstenone, androstenol, androstadienone and estratetraenol. In the absence of sound reasons to test the molecules, positive results in studies need to be treated with scepticism as these are highly likely to be false positives. Common problems include small sample sizes, an overestimate of effect size (as no effect can be expected), positive publication bias and lack of replication. Instead, if we are to find human pheromones, we need to treat ourselves as if we were a newly discovered mammal, and use the rigorous methods already proven successful in pheromone research on other species. Establishing a pheromone relies on demonstration of an odour-mediated behavioural or physiological response, identification and synthesis of the bioactive molecule(s), followed by bioassay confirmation of activity. Likely sources include our sebaceous glands. Comparison of secretions from adult and pre-pubertal humans may highlight potential molecules involved in sexual behaviour. One of the most promising human pheromone leads is a nipple secretion from the areola glands produced by all lactating mothers, which stimulates suckling by any baby not just their own. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


Pettit B.,University of Oxford
Proceedings. Biological sciences / The Royal Society | Year: 2013

For animals that travel in groups, the directional choices of conspecifics are potentially a rich source of information for spatial learning. In this study, we investigate how the opportunity to follow a locally experienced demonstrator affects route learning by pigeons over repeated homing flights. This test of social influences on navigation takes advantage of the individually distinctive routes that pigeons establish when trained alone. We found that pigeons learn routes just as effectively while flying with a partner as control pigeons do while flying alone. However, rather than learning the exact route of the demonstrator, the paired routes shifted over repeated flights, which suggests that the birds with less local experience also took an active role in the navigational task. The efficiency of the original routes was a key factor in how far they shifted, with less efficient routes undergoing the greatest changes. In this context, inefficient routes are unlikely to be maintained through repeated rounds of social transmission, and instead more efficient routes are achieved because of the interaction between social learning and information pooling.


Stevens C.J.,University of Oxford
Computers, Materials and Continua | Year: 2013

Metamaterials offer new propagation modes for electromagnetic signals which have been explored as media for data exchange. They also offer a good prospect for efficient power transfer. This paper considers the limits on transferable power and their consequences in relation to magneto inductive waves in 1 and 2 dimensional magnetic metamaterial structures. The upper limit is found to be directly related to the voltage tolerance of capacitances used in the meta-material's construction. Higher resonant frequencies offer better efficiency and higher maximum powers. For a proposed device operating in the Qi band (100-200k Hz) power transfer limits of 140 W are derived. The effects of finite length guides on performance and limitations imposed by standing waves and improper termination are explored.Copyright © 2013 Tech Science Press.


Noble D.,University of Oxford
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2010

Biophysics at the systems level, as distinct from molecular biophysics, acquired its most famous paradigm in the work of Hodgkin and Huxley, who integrated their equations for the nerve impulse in 1952. Their approach has since been extended to other organs of the body, notably including the heart. The modern field of computational biology has expanded rapidly during the first decade of the twenty-first century and, through its contribution to what is now called systems biology, it is set to revise many of the fundamental principles of biology, including the relations between genotypes and phenotypes. Evolutionary theory, in particular, will require re-assessment. To succeed in this, computational and systems biology will need to develop the theoretical framework required to deal with multilevel interactions. While computational power is necessary, and is forthcoming, it is not sufficient. We will also require mathematical insight, perhaps of a nature we have not yet identified. This article is therefore also a challenge to mathematicians to develop such insights. © 2010 The Royal Society.


Cowey A.,University of Oxford
Current Biology | Year: 2010

Some patients can discriminate unseen visual stimuli within a field defect caused by damage to the primary visual cortex. The pathways for this 'blindsight' have never been established, but recent studies implicate hitherto overlooked cells in the thalamic LGN. © 2010 Elsevier Ltd. All rights reserved.


Snaith H.J.,University of Oxford | Ducati C.,University of Cambridge
Nano Letters | Year: 2010

Improving the solar light harvesting and photon-to-electron conversion efficiency for hybrid, organic?inorganic photovoltaics are critical challenges. Titania based solid-state hybrid solar cells are moderately efficient at converting visible photons to electrons, but major electrical losses still remain. A material based paradigm shift is required to dramatically enhance the performance of these devices. Here, we present an investigation into solid-state dye-sensitized solar cells (SDSCs) incorporating a molecular hole-transporter and mesoporous tin oxide electrodes, in place of titania usually employed. We investigate the influence of treating the surface of the SnO2 with different oxides and find that MgO "passivated" SnO2 electrodes demonstrate an unprecedented absorbed photon-to-electron conversion efficiency of near unity across a broad spectral range. A dual surface treatment of TiO2 followed by MgO enables tuning of the solar cell photovoltage, fill factor, and efficiency with visible light absorbing cells delivering 3% solar-to-electrical full sun power conversion efficiency. © 2010 American Chemical Society.


Harmer C.J.,University of Oxford
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant drugs. However, neither the way in which serotonin may alleviate depressed mood  nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed  is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients.


Shepard L.D.,University of Oxford
Epidemiology and Psychiatric Sciences | Year: 2013

Aims. The purpose of this systematic review is to identify and appraise the present state of prevalence research on the mental health of polygynous women, or plural wives, and to summarize its implications for future research and social work practice. Methods. PsycInfo (1967 to November 2011) and Medline (1985 to November 2011) databases, systematic bibliography hand-searches, personal communication with a leading expert, and gray literature searching were applied in a systematic literature search of the prevalence of mental-health issues in polygynous women compared to monogamous women. Twenty-two studies meeting eligibility criteria were identified. Study characteristics, methods and findings were systematically extracted and appraised for quality. Results. The identified studies are of mixed methodological quality, but generally suggest a more significant prevalence of mental-health issues in polygynous women compared to monogamous women. Individual studies report a higher prevalence of somatization, depression, anxiety, hostility, psychoticism and psychiatric disorder in polygynous wives as well as reduced life and marital satisfaction, problematic family functioning and low self-esteem. Conclusions. The current state of the research reveals with moderate confidence, a more significant prevalence of mental-health issues in polygynous women as compared to monogamous women. Implications for practice and research are indicated. Copyright © Cambridge University Press 2012.


Johnson P.J.,University of Oxford
PloS one | Year: 2010

We explore variation in the prices paid by recreational hunters of trophy animals in Africa and its possible causes, including perceived rarity. Previous work has raised the possibility that extinction can result if demand rises fast enough as a species becomes rarer. We attempt to disentangle this from other inter-correlated influences affecting price. Species with larger body sizes and larger trophies were more valuable. Value increased less steeply as a function of size for bovids than for felids and the effect was consistent across countries. Power laws, ubiquitous in physical and social systems, described the trends. The exponent was approximately 0.4 for bovids, compared with approximately 1.0 for felids. Rarity (as indexed by IUCN score) influenced the value of bovid trophies - price was higher for species in categories denoting higher global threat. There was substantial variation in price among and within families not explained by either size or rarity. This may be attributable to a 'charisma' effect, which seems likely to be a general attribute of human perceptions of wildlife. Species where prices were higher than predicted by size or rarity are ranked high in published accounts of desirability by hunters. We conclude that the valuation of these species is explicable to a large extent by body size and perceived rarity, and that differences in valuation between taxonomic groups are related to less easily quantified 'charisma' effects. These findings are relevant for conservationists considering the threat status of species exploited in open access markets, and where license quotas are adjusted in response to changes in perceived rarity.


Stead L.F.,University of Oxford
Cochrane database of systematic reviews (Online) | Year: 2012

Both behavioural support (including brief advice and counselling) and pharmacotherapies (including nicotine replacement therapy (NRT), varenicline and bupropion) are effective in helping people to stop smoking. Combining both treatment approaches is recommended where possible, but the size of the treatment effect with different combinations and in different settings and populations is unclear. To assess the effect of combining behavioural support and medication to aid smoking cessation, compared to a minimal intervention or usual care, and to identify whether there are different effects depending on characteristics of the treatment setting, intervention, population treated, or take-up of treatment. We searched the Cochrane Tobacco Addiction Group Specialised Register in July 2012 for records with any mention of pharmacotherapy, including any type of NRT, bupropion, nortriptyline or varenicline. Randomized or quasi-randomized controlled trials evaluating combinations of pharmacotherapy and behavioural support for smoking cessation, compared to a control receiving usual care or brief advice or less intensive behavioural support. We excluded trials recruiting only pregnant women, trials recruiting only adolescents, and trials with less than six months follow-up. Search results were prescreened by one author and inclusion or exclusion of potentially relevant trials was agreed by both authors. Data was extracted by one author and checked by the other.The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. Forty-one studies with a total of more than 20,000 participants met the inclusion criteria. A large proportion of studies recruited people in healthcare settings or with specific health needs. Most studies provided NRT. Behavioural support was typically provided by specialists in cessation counselling, who offered between four and eight contact sessions. The planned maximum duration of contact was typically more than 30 minutes but less than 300 minutes. Overall, studies were at low or unclear risk of bias, and findings were not sensitive to the exclusion of any of the three studies rated at high risk of bias in one domain. One large study (the Lung Health Study) contributed heterogeneity due to a substantially larger treatment effect than seen in other studies (RR 3.88, 95% CI 3.35 to 4.50). Since this study used a particularly intensive intervention which included extended availability of nicotine gum, multiple group sessions and long term maintenance and recycling contacts, the results may not be comparable with the interventions used in other studies, and hence it was not pooled in other analyses. Based on the remaining 40 studies (15,021 participants) there was good evidence for a benefit of combination pharmacotherapy and behavioural treatment compared to usual care or brief advice or less intensive behavioural support (RR 1.82, 95% CI 1.66 to 2.00) with moderate statistical heterogeneity (I2 = 40%). The pooled estimate for 31 trials that recruited participants in healthcare settings (RR 2.06, 95% CI 1.81 to 2.34) was higher than for eight trials with community-based recruitment (RR 1.53, 95% CI 1.33 to 1.76). Pooled estimates were lower in a subgroup of trials where the behavioural intervention was provided by specialist counsellors versus trials where counselling was linked to usual care (specialist: RR 1.73, 95% CI 1.55 to 1.93, 28 trials; usual provider: RR 2.41, 95% CI 1.91 to 3.02, 8 trials) but this was largely attributable to the small effect size in two trials using specialist counsellors where the take-up of the planned intervention was low, and one usual provider trial with alarge effect. There was little indirect evidence that the relative effect of an intervention differed according to whether participants in a trial were required to be motivated to make a quit attempt or not. There was only weak evidence that studies offering more sessions had larger effects and there was not clear evidence that increasing the duration of contact increased the effect, but there was more evidence of a dose-response relationship when analyses were limited to trials where the take-up of treatment was high. Interventions that combine pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. Further trials would be unlikely to change this conclusion. We did not find strong evidence from indirect comparisons that offering more intensive behavioural support was associated with larger treatment effects but this could be because intensive interventions are less likely to be delivered in full.


Rinaldi S.,University of Oxford
Journal of the Peripheral Nervous System | Year: 2013

Understanding of Guillain-Barré syndrome (GBS) has progressed substantially since the seminal 1916 report by Guillain et al. Although Guillain, Barré, and Strohl summarised the syndrome based on observations of two French infantrymen, 2012 saw the beginning of an ambitious collaborative study designed to collect detailed data from at least 1,000 patients worldwide (IGOS, www.gbsstudies.org/about-igos). Progress has been made in many areas even since GBS was last reviewed in this journal in 2009. GBS subsequently received prominent attention in light of concerns regarding H1N1 influenza vaccinations, and several large-scale surveillance studies resulted. Despite these developments, and promising pre-clinical studies, disease-modifying therapies for GBS have not substantially altered since intravenous immunoglobulin was introduced over 20 years ago. In other areas, management has improved. Antibiotic prophylaxis in ventilated patients reduces respiratory tract infection, thromboprophylaxis has reduced the risk of venous thromboembolism, and there is increasing awareness of the benefit of high-intensity rehabilitation. This article highlights some of the interesting and thought-provoking developments of the last 3 years, and is based on a plenary lecture given at the 2012 Peripheral Nerve Society (PNS) meeting. © 2013 Peripheral Nerve Society.


Tunbridge E.M.,University of Oxford
International Review of Neurobiology | Year: 2010

The catechol- O-methyltransferase (COMT) gene is of significant interest to neuroscience, due to its role in modulating dopamine function. COMT is dynamically regulated; its expression is altered during normal brain development and in response to environmental stimuli. In many cases the underlying molecular basis for these effects is unknown; however, in some cases (e.g., estrogenic regulation in the case of sex differences) regulatory mechanisms have been identified. COMT contains several functional polymorphisms and haplotypes, including the well-studied Val158Met polymorphism. Here I review the regulation of COMT and the functional polymorphisms within its sequence with respect to brain function. © 2010 Elsevier Inc.


Willis M.C.,University of Oxford
Angewandte Chemie - International Edition | Year: 2010

Controlling carbonyl groups: Identification of the correct ligand/counterion combination was essential to allow the efficient and selective rhodium-catalyzed conversion of a series of ketobenzaldehydes into the corresponding phthalides using the title reaction (see scheme; cod=cycloocta-l,5-diene). © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Bilyard T.,University of Oxford
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The rotary motor F(1)-ATPase from the thermophilic Bacillus PS3 (TF(1)) is one of the best-studied of all molecular machines. F(1)-ATPase is the part of the enzyme F(1)F(O)-ATP synthase that is responsible for generating most of the ATP in living cells. Single-molecule experiments have provided a detailed understanding of how ATP hydrolysis and synthesis are coupled to internal rotation within the motor. In this work, we present evidence that mesophilic F(1)-ATPase from Escherichia coli (EF(1)) is governed by the same mechanism as TF(1) under laboratory conditions. Using optical microscopy to measure rotation of a variety of marker particles attached to the γ-subunit of single surface-bound EF(1) molecules, we characterized the ATP-binding, catalytic and inhibited states of EF(1). We also show that the ATP-binding and catalytic states are separated by 35±3°. At room temperature, chemical processes occur faster in EF(1) than in TF(1), and we present a methodology to compensate for artefacts that occur when the enzymatic rates are comparable to the experimental temporal resolution. Furthermore, we show that the molecule-to-molecule variation observed at high ATP concentration in our single-molecule assays can be accounted for by variation in the orientation of the rotating markers.


Leake M.C.,University of Oxford
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The esteemed physicist Erwin Schrödinger, whose name is associated with the most notorious equation of quantum mechanics, also wrote a brief essay entitled 'What is Life?', asking: 'How can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?' The 60+ years following this seminal work have seen enormous developments in our understanding of biology on the molecular scale, with physics playing a key role in solving many central problems through the development and application of new physical science techniques, biophysical analysis and rigorous intellectual insight. The early days of single-molecule biophysics research was centred around molecular motors and biopolymers, largely divorced from a real physiological context. The new generation of single-molecule bioscience investigations has much greater scope, involving robust methods for understanding molecular-level details of the most fundamental biological processes in far more realistic, and technically challenging, physiological contexts, emerging into a new field of 'single-molecule cellular biophysics'. Here, I outline how this new field has evolved, discuss the key active areas of current research and speculate on where this may all lead in the near future.


Debreczeni J.E.,Astrazeneca | Emsley P.,University of Oxford
Acta Crystallographica Section D: Biological Crystallography | Year: 2012

Coot is a molecular-graphics application primarily aimed to assist in model building and validation of biological macromolecules. Recently, tools have been added to work with small molecules. The newly incorporated tools for the manipulation and validation of ligands include interaction with PRODRG, subgraph isomorphism-based tools, representation of ligand chemistry, ligand fitting and analysis, and are described here. © International Union of Crystallography 2012.


Gromak N.,University of Oxford
Biochemical Society Transactions | Year: 2012

Most human genes transcribed by RNA Pol II (polymerase II) contain short exons separated by long tracts of non-coding intronic sequences. In addition to their role in generating proteomic diversity through the process of alternative splicing, intronic sequences host many ncRNAs (non-coding RNAs), involved in various gene regulation processes. miRNAs (microRNAs) are short ncRNAs that mediate either mRNA transcript translational repression and/or degradation. Between 50 and 80% of miRNAs are encoded within introns of host mRNA genes. This observation suggests that there is co-regulation between the miRNA biogenesis and pre-mRNA splicing processes. The present review summarizes current advances in this field and discusses possible roles for intronic co-transcriptional cleavage events in the regulation of human gene expression. ©The Authors Journal compilation ©2012 Biochemical Society.


Newby J.M.,University of Oxford
Physical Biology | Year: 2012

The stochastic mutual repressor model is analysed using perturbation methods. This simple model of a gene circuit consists of two genes and three promotor states. Either of the two protein products can dimerize, forming a repressor molecule that binds to the promotor of the other gene. When the repressor is bound to a promotor, the corresponding gene is not transcribed and no protein is produced. Either one of the promotors can be repressed at any given time or both can be unrepressed, leaving three possible promotor states. This model is analysed in its bistable regime in which the deterministic limit exhibits two stable fixed points and an unstable saddle, and the case of small noise is considered. On small timescales, the stochastic process fluctuates near one of the stable fixed points, and on large timescales, a metastable transition can occur, where fluctuations drive the system past the unstable saddle to the other stable fixed point. To explore how different intrinsic noise sources affect these transitions, fluctuations in protein production and degradation are eliminated, leaving fluctuations in the promotor state as the only source of noise in the system. The process without protein noise is then compared to the process with weak protein noise using perturbation methods and Monte Carlo simulations. It is found that some significant differences in the random process emerge when the intrinsic noise source is removed. © 2012 IOP Publishing Ltd.


Jones P.B.,University of Oxford
Monthly Notices of the Royal Astronomical Society | Year: 2012

Little attention has so far been paid to the division of the observed population between pulsars of the two spin directions that are possible. Almost all pulsars with positive corotational charge density at the polar caps are expected to satisfy space-charge-limited flow boundary conditions. Charge separation by blackbody photoelectric transitions in moving ions limits the acceleration potential, analogously with the more usually considered pair creation. However, the limitation is more severe so that proton and ion energies can be relativistic but not ultrarelativistic, and these allow the growth of Langmuir-mode-induced turbulence that couples directly with the radiation field, as shown by Asseo, Pelletier & Sol. The consequences of this, and of the several possible physical states of the polar cap, are described, qualitatively, as possible explanations for the complex phenomena of nulls, subpulse drift and mode switching observed in subsets of pulsars. © 2012 The Author Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Ponting C.P.,University of Oxford
Cell | Year: 2012

Not all bases in the human genome are equally prone to chance mutations. Michaelson et al. show that individuals can acquire clusters of de novo DNA changes and propose that the likelihood of single base pair change differs across three orders of magnitude. © 2012 Elsevier Inc.


Martelli D.,Kings College London | Sparks J.,University of Oxford
Nuclear Physics B | Year: 2013

We present the gravity dual to a class of three-dimensional N=2 supersymmetric gauge theories on a biaxially squashed three-sphere, with a non-trivial background gauge field. This is described by a 1/2 BPS Euclidean solution of four-dimensional N=2 gauged supergravity, consisting of a Taub-NUT-AdS metric with a non-trivial instanton for the graviphoton field. The holographic free energy of this solution agrees precisely with the large N limit of the free energy obtained from the localized partition function of a class of Chern-Simons quiver gauge theories. We also discuss a different supersymmetric solution, whose boundary is a biaxially squashed Lens space S3/Z2 with a topologically non-trivial background gauge field. This metric is of Eguchi-Hanson-AdS type, although it is not Einstein, and has a single unit of gauge field flux through the S 2 cycle. © 2012 Elsevier B.V.


Rider O.J.,University of Oxford
Circulation. Cardiovascular imaging | Year: 2015

BACKGROUND: As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy.METHODS AND RESULTS: Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001).CONCLUSIONS: A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling. © 2014 American Heart Association, Inc.


Sternberg T.,University of Oxford
Applied Geography | Year: 2012

In 2011 winter drought in eastern China's wheat-growing region had significant implications beyond the country's borders. Potential crop failure due to drought led China to buy wheat on the international market and contributed to a doubling of global wheat prices; the resultant price spikes had a serious economic impact in Egypt, the world's largest wheat importer, where bread prices tripled. Quantifying the 2011 drought in China's wheat region with the Standard Precipitation Index identified extreme drought across the region that peaked in January 2011. Findings document the spatial extent and severity of the drought as the most serious on record and explain China's efforts to minimize the 2011 drought's domestic impact. The country's mitigation efforts had repercussions in Egypt where high food prices were a contributory factor to civil unrest. Tracking the drought - wheat price rise - protest trajectory suggests the potential direct and indirect links between natural hazards, food security and political stability at local and global scales. © 2012 Elsevier Ltd.


Fawcett T.,University of Oxford
Building Research and Information | Year: 2014

Low carbon housing retrofit is often understood as a one-off, whole-house activity. However, an alternative model of low carbon retrofit is presented whereby improvements happen step by step over several years. This staged approach is described and contrasted with the one-off approach, and empirical evidence on both models is presented. Three key questions are considered: whether an over-time low carbon retrofit could be attractive for owner-occupiers; whether it could deliver sufficient carbon and energy savings; and what policy support would be needed. The benefits of over-time low carbon retrofit are explored through householder survey and qualitative data, as well as the time scales that apply to housing, renovation and homeowners. Technical issues around energy savings are explored, and the risks of lock out investigated. Policy support measures specifically for over-time low carbon retrofit are suggested, with reference to existing policy approaches in the United Kingdom and European Union. Over-time low carbon retrofit could be attractive to (some) householders - at least 60% carbon savings could be achieved - and policy could be designed to recognize and support this form of low carbon retrofit. This approach provides an additional route to the uptake of energy-efficiency and renewable-energy measures. © 2013 Taylor & Francis.


Ratcliffe P.J.,University of Oxford
Journal of Physiology | Year: 2013

Studies of regulation of the haematopoietic growth factor erythropoietin led to the unexpected discovery of a widespread system of direct oxygen sensing that regulates gene expression in animals. The oxygen-sensitive signal is generated by a series of non-haem Fe(II)- and 2-oxoglutarate-dependent dioxygenases that catalyse the post-translational hydroxylation of specific residues in the transcription factor hypoxia-inducible factor (HIF). These hydroxylations promote both oxygen-dependent degradation and oxygen-dependent inactivation of HIF, but are suppressed in hypoxia, leading to the accumulation of HIF and assembly of an active transcriptional complex in hypoxic cells. Hypoxia-inducible factor activates an extensive transcriptional cascade that interfaces with other cell signalling pathways, microRNA networks and RNA-protein translational control systems. The relationship of these cellular signalling pathways to the integrated physiology of oxygen homeostasis and the implication of dysregulating these massive physiological pathways in diseases such as cancer are discussed. © 2013 The Author. The Journal of Physiology © 2013 The Physiological Society.


Ellis A.,Kings College London | Bennett D.L.H.,University of Oxford
British Journal of Anaesthesia | Year: 2013

Inflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach. © 2013 © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


A systematic review of purine analogs revealed heterogeneity between trials in treatment effects on response and progression free survival, but not survival, perhaps partly due to variations in analytical methods. In addition, combination treatments required evaluation. Therefore, individual patient data were sought for all randomized trials in untreated chronic lymphocytic leukemia which involved a purine analog, but which did not include antibody therapies. Sixteen trials were found, addressing seven comparisons. Eight trials, with 2,753 patients, showed that single agent purine analog improved progression free survival (odds ratio=0.71; 95% confidence interval=0.63- 0.79). Heterogeneity remained substantial. Three trials, with 1,403 patients, showed that progression free survival was further improved by the addition of cyclophosphamide (odds ratio=0.54; 0.47-0.62). Fewer data were available on the addition of other drugs to purine analog, and none showed clear benefit. Two trials, with 544 patients, suggested cladribine improved progression free survival compared to fludarabine (odds ratio=0.77; 0.63-0.95). No differences were seen in overall survival for any comparisons. In conclusion, purine analogs, particularly combined with cyclophosphamide, significantly improve progression free survival but not survival. Some groups, such as the elderly, may not see the same benefits and maximizing doses may be important for all treatments, including chlorambucil. Longer follow up, consistent definitions and detailed reporting of trials should be encouraged. © 2012 Ferrata Storti Foundation.


Sherrington D.,University of Oxford | Sherrington D.,Santa Fe Institute
Physical Review Letters | Year: 2013

In an attempt to understand the origin of relaxor ferroelectricity, it is shown that interesting behavior of the onset of nonergodicity and of precursor nanodomains, found in first-principles simulations of the relaxor alloy Ba(Zr1-xTix)O3, can easily be understood within a simple mapping to a soft pseudospin glass. © 2013 American Physical Society.


Odling-Smee J.,University of Oxford
The Quarterly review of biology | Year: 2013

Niche construction theory (NCT) explicitly recognizes environmental modication by organisms ("niche construction") and their legacy overtime ("ecological inheritance") to be evolutionary processes in their own right. Here we illustrate how niche construction theory provides usedl conceptual tools and theoretical insights for integrating ecosystem ecology and evolutionary theory. We begin by briefly describing NCT, and illustrating how it deifers from conventional evolutionary approaches. We then distinguish between two aspects ofniche construction--environment alteration and subsequent evolution in response to constructed environments--equating the first of these with "ecosystem engineering." We describe some of the ecological and evolutionary impacts on ecosystems of niche construction, ecosystem engineering and ecological inheritance, and illustrate how these processes trigger ecological and evolutionary feedbacks and leave detectable ecological signatures that are open to investigation. FIinally, we provide a practical guide to how NCT could be deployed by ecologists and evolutionary biologists to aeplore ecoeoolutionay dynamics. We suggest that, by highlighting the ecological and evolutionay ramifications of changes that organisms bring about in ecosystems, NCT helps link ecosystem ecology to evolutionary biology, potentially leading to a deeper understanding of how ecosystems change over time.


Maroney O.J.E.,University of Oxford
Physical Review Letters | Year: 2013

We examine the relationship between quantum contextuality (in both the standard Kochen-Specker sense and in the generalized sense proposed by Spekkens) and models of quantum theory in which the quantum state is maximally epistemic. We find that preparation noncontextual models must be maximally epistemic, and these in turn must be Kochen-Specker noncontextual. This implies that the Kochen-Specker theorem is sufficient to establish both the impossibility of maximally epistemic models and the impossibility of preparation noncontextual models. The implication from preparation noncontextual to maximally epistemic then also yields a proof of Bell's theorem from an Einstein-Podolsky-Rosen-like argument. © 2013 American Physical Society.


Bell A.R.,University of Oxford
Astroparticle Physics | Year: 2013

This review describes the basic theory of cosmic ray acceleration by shocks including the plasma instabilities confining cosmic rays near the shock, the effect of the magnetic field orientation, the maximum cosmic ray energy and the shape of the cosmic ray spectrum. Attention is directed mainly towards Galactic cosmic rays accelerated by supernova remnants. © 2012 Elsevier B.V. All rights reserved.


Madhok V.,University of New Mexico | Datta A.,University of Oxford
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

We present an operational interpretation of quantum discord based on the quantum state merging protocol. Quantum discord is the markup in the cost of quantum communication in the process of quantum state merging, if one discards relevant prior information. Our interpretation has an intuitive explanation based on the strong subadditivity of von Neumann entropy. We use our result to provide operational interpretations of other quantities like the local purity and quantum deficit. Finally, we discuss in brief some instances where our interpretation is valid in the single-copy scenario. © 2011 American Physical Society.


Amphawan A.,University of Oxford
Optics Express | Year: 2011

With rapidly growing bandwidth demands in Local Area Networks, it is imperative to support next generation speeds beyond 40Gbit/s. Various holographic optimization techniques using spatial light modulators have recently been explored for adaptive channel impulse response improvement of MMF links. Most of these experiments are algorithmic-oriented. In this paper, a set of lenses and a spatial light modulator, acting as a binary amplitude filter, played the pivotal role in generating the input modal electric field into a graded-index MMF, rather than algorithms. By using a priori theoretical information to generate the incident modal electric field at the MMF, the bandwidth was increased by up to 3.4 times. © 2011 Optical Society of America.


Faizal M.,University of Oxford
Nuclear Physics B | Year: 2013

In this paper we will discuss non-anticommutative deformations of the harmonic superspace. We will analyse the non-anticommutative deformation of the superspace that break the supersymmetry from N=3 supersymmetry to N=2 supersymmetry. We will then study the ABJ theory in this non-anticommutative superspace. This deformed ABJ theory will be shown to posses N=5 supersymmetry. © 2012 Elsevier B.V.


Irani S.R.,University of Oxford
Discovery medicine | Year: 2011

The field of autoimmune encephalopathies has expanded rapidly in the last few years. It is now well-established that a substantial proportion of encephalitides are associated with autoantibodies directed against the extracellular domains of cell-surface proteins which are critical in the regulation of neuronal excitability. These include LGI1, CASPR2, contactin-2 (VGKC-complex antibodies), and the NMDA, AMPA, and GABA(B) receptors. The clinical importance of these conditions lies in their frequent immunotherapy-response and, less commonly, their association with distinctive tumors. Studies which have examined cohorts of patients defined by these serum antibodies have identified a number of clinical features that have helped understand the core phenotypes of these conditions. In addition, sensitive antibody assays have allowed the expansion of the phenotypes to include a minority of patients with isolated epilepsies or psychoses. There is also evidence that autoimmune encephalitis may progress to adult-onset hippocampal sclerosis. Clinical, and accumulating scientific, data strongly suggest direct pathogenicity of these autoantibodies. The generation of the autoantibody, in some patients, can be explained by the presence of tumors which express their antigenic target. Serum antibody levels are higher than their levels in CSF in the vast majority of cases. However, the majority of patients do not harbor a tumor and the etiology of the disease in these patients is less clear. Below, we suggest models for the etiology and pathogenic mechanisms of these autoantibodies by incorporating concepts such as serum generation of the autoantibodies, the blood-brain barrier, intrathecal antibody production, and prodromal infections.


Signaling through the T cell receptor (TCR) initiates adaptive immunity and its perturbation may results in autoimmunity. The plasma membrane scaffolding protein LAT acts as a central organizer of the TCR signaling machinery to activate many functional pathways. LAT-deficient mice develop an autoimmune syndrome but the mechanism of this pathology is unknown. In this work we have compared global dynamics of TCR signaling by MS-based quantitative phosphoproteomics in LAT-sufficient and LAT-defective Jurkat T cells. Surprisingly, we found that many TCR-induced phosphorylation events persist in the absence of LAT, despite ERK and PLCγ1 phosphorylation being repressed. Most importantly, the absence of LAT resulted in augmented and persistent tyrosine phosphorylation of CD3ζ and ZAP70. This indicates that LAT signaling hub is also implicated in negative feedback signals to modulate upstream phosphorylation events. Phosphorylation kinetics data resulting from this investigation is documented in a database (phosphoTCR) accessible online. The MS data have been deposited to the ProteomeXchange with identifier PXD000341.


Jepson P.,University of Oxford
Ecography | Year: 2016

In the context of aging European conservation institutions rewilding has emerged as a popular and scientific expression of new directions in ecology and conservation management associated with the restoration of ecosystem function through reassembly of trophic levels involving the reintroduction of large mammals. It introduces a radical new natural archetype that evokes a positive environmentalism. The Oostvaardersplassen experiment in the Netherlands demonstrates the agency of rewilding for nature development and engaging diverse publics in debates on what is natural and the future of conservation policy. If conservation is to retain its cultural and policy visibility and influence in a 21st century multi-cultural Europe, our conservation institutions and the natures we value must adapt. In this forum I frame rewilding as an asset for institutional adaptation that is being constrained by substantive institutional and societal resistance. I argue the need for strategic investment in a European network of experimental rewilding sites. These would bring rewilding into densely populated areas, develop the science and practice of ecosystem restoration, and promote public debate on nature conservation futures. The 'Fitness check' of European nature conservation legislation mandated in 2014 is a case of high politics. In this situation, compromise and negotiation is inevitable and the environmental lobby needs something to advocate as well as defend. A rewilding agenda could fulfil this need. © 2016 Nordic Society Oikos.


Morgan B.J.,University of Oxford
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

Density-functional-theory calculations have been used to examine stabilization of the low density BCT polymorph by epitaxial strain. The relative energies of B4 and BCT polymorphs were calculated for ZnO, ZnS, and CdS, as a function of epitaxial strain, for a B4[0001]||BCT[010]/ B4[12̄10]||BCT[001] correspondence. The phase stability is mapped in {u,v} parameter space and the challenge of identifying a suitable epitaxial support to direct growth of the BCT phase is discussed. For ZnS, ZnSe, ZnTe, CdS, and CdSe, the optimized " BCT " geometry is orthorhombically distorted, in contrast to the tetragonal lattices of ZnO, CdO, and InN. This orthorhombic distortion is associated with a rotation of the four-membered rings in the BCT structure, and is enhanced in ZnO, ZnS, and CdS under epitaxial strain. © 2010 The American Physical Society.


Sweetlove L.J.,University of Oxford | Obata T.,Max Planck Institute of Molecular Plant Physiology | Fernie A.R.,Max Planck Institute of Molecular Plant Physiology
Trends in Plant Science | Year: 2014

Flux is one of the most informative measures of metabolic behavior. Its estimation requires integration of experimental and modeling approaches and, thus, is at the heart of metabolic systems biology. In this review, we argue that flux analysis and modeling of a range of plant systems points to the importance of the supply of metabolic inputs and demand for metabolic end-products as key drivers of metabolic behavior. This has implications for metabolic engineering, and the use of in silico models will be important to help design more effective engineering strategies. We also consider the importance of cell type-specific metabolism and the challenges of characterizing metabolism at this resolution. A combination of new measurement technologies and modeling approaches is bringing us closer to integrating metabolic behavior with whole-plant physiology and growth. © 2013 Elsevier Ltd.


The International Network of Obstetric Survey Systems (INOSS) is a multi-country collaboration formed to facilitate studies of uncommon and severe complications of pregnancy and childbirth. Collaborations such as INOSS offer many benefits in the study of rare complications. The use of uniform case definitions, common datasets, specifically collected detailed data and prospectively agreed comparative and combined analyses all add to the validity of studies and their utility to guide policy and clinical practice and hence improve the quality of care. Such multi-national collaborations allow for the conduct of robust studies less subject to many of the biases attributed to typical observational studies. For very rare conditions such collaborations may provide the only route to providing high quality evidence to guide practice. Clinicians and researchers conducting studies into rare and severe complications should consider working through a network such as INOSS to maximize the value of their research. © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.


Sharpe M.,University of Oxford
British Journal of Psychiatry | Year: 2014

Psychological medicine (liaison psychiatry) aims to integrate psychiatry into other areas of medicine. It is currently enjoying considerable expansion. The degree to which it can take advantage of this opportunity will be important not only for its own future, but also for the survival of psychiatry as a medical discipline.


Khan N.F.,University of Oxford
The British journal of general practice : the journal of the Royal College of General Practitioners | Year: 2010

BACKGROUND: The UK-based General Practice Research Database (GPRD) is a valuable source of longitudinal primary care records and is increasingly used for epidemiological research. AIM: To conduct a systematic review of the literature on accuracy and completeness of diagnostic coding in the GPRD. DESIGN OF STUDY: Systematic review. METHOD: Six electronic databases were searched using search terms relating to the GPRD, in association with terms synonymous with validity, accuracy, concordance, and recording. A positive predictive value was calculated for each diagnosis that considered a comparison with a gold standard. Studies were also considered that compared the GPRD with other databases and national statistics. RESULTS: A total of 49 papers are included in this review. Forty papers conducted validation of a clinical diagnosis in the GPRD. When assessed against a gold standard (validation using GP questionnaire, primary care medical records, or hospital correspondence), most of the diagnoses were accurately recorded in the patient electronic record. Acute conditions were not as well recorded, with positive predictive values lower than 50%. Twelve papers compared prevalence or consultation rates in the GPRD against other primary care databases or national statistics. Generally, there was good agreement between disease prevalence and consultation rates between the GPRD and other datasets; however, rates of diabetes and musculoskeletal conditions were underestimated in the GPRD. CONCLUSION: Most of the diagnoses coded in the GPRD are well recorded. Researchers using the GPRD may want to consider how well the disease of interest is recorded before planning research, and consider how to optimise the identification of clinical events.


Mayou R.,University of Oxford
British Journal of Psychiatry | Year: 2014

DSM-5 is a modest improvement on DSM-IV, notably in abandoning the distinction between medically explained and unexplained symptoms, but problems remain. The chapter text is incoherent, contradicts the classification and will be clinically unhelpful. ICD-11 should attempt a more logical and consistent revision.


Deacon R.,University of Oxford
Journal of visualized experiments : JoVE | Year: 2012

Deterioration in the ability to perform "Activities of daily living" (ADL) is an early sign of Alzheimer's disease (AD). Preclinical behavioural screening of possible treatments for AD currently largely focuses on cognitive testing, which frequently demands expensive equipment and lots of experimenter time. However, human episodic memory (the most severely affected aspect of memory in AD) is different to rodent memory, which seems to be largely non-episodic. Therefore the present ways of screening for new AD treatments for AD in rodents are intrinsically unlikely to succeed. A new approach to preclinical screening would be to characterise the ADL of mice. Fortuitously, several such assays have recently been developed at Oxford, and here the three most sensitive and well-characterised are presented. Burrowing was first developed in Oxford. It evolved from a need to develop a mouse hoarding paradigm. Most published rodent hoarding paradigms required a distant food source to be linked to the home cage by a connecting passage. This would involve modifying the home cage as well as making a mouse-proof connecting passage and food source. So it was considered whether it would be possible to put the food source inside the cage. It was found that if a container was placed on the floor it was emptied by the next morning., The food pellets were, however, simply deposited in a heap at the container entrance, rather than placed in a discrete place away from the container, as might be expected if the mice were truly hoarding them. Close inspection showed that the mice were performing digging ("burrowing") movements, not carrying the pellets in their mouths to a selected place as they would if truly hoarding them. Food pellets are not an essential substrate for burrowing; mice will empty tubes filled with sand, gravel, even soiled bedding from their own cage. Moreover, they will empty a full tube even if an empty one is placed next to it. Several nesting protocols exist in the literature. The present Oxford one simplifies the procedure and has a well-defined scoring system for nest quality. A hoarding paradigm was later developed in which the mice, rather than hoarding back to the real home cage, were adapted to living in the "home base" of a hoarding apparatus. This home base was connected to a tube made of wire mesh, the distal end of which contained the food source. This arrangement proved to yield good hoarding behaviour, as long as the mice were adapted to living in the "home base" during the day and only allowed to enter the hoarding tube at night. Copyright © 2012 Creative Commons Attribution License


Kovrizhin D.L.,University of Oxford
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

We developed a density matrix renormalization group technique to study quantum Hall fractions of fast rotating bosons. In this paper, we present a discussion of the method together with the results which we obtain in three distinct cases of the narrow-channel, cylinder, and spherical geometries. In the narrow-channel case, which is relevant to anisotropic confining traps in the limit of extremely fast rotation, we find a series of zero-temperature phase transitions in the strongly interacting regime as a function of the interaction strength between bosons. We compute energies and density profiles for different filling fractions on a cylinder and compare the convergence rates of the method in the cylinder and a sphere geometries. © 2010 The American Physical Society.


Wood M.J.A.,University of Oxford
Science Translational Medicine | Year: 2010

Antisense oligonucleotide (AO)-mediated exon skipping is a promising new therapy for Duchenne muscular dystrophy (DMD), recently demonstrating proof of principle for restoring the absent dystrophin protein in DMD patients. However, the range of AO chemistries available for exon skipping is limited; effective systemic dystrophin protein restoration has yet to be demonstrated and will be required for disease modification in patients; and the current approach is mutation-specific, necessitating the development of multiple AO drugs to treat all DMD patients. This is therefore a highly complex drug development challenge.


Essler F.H.L.,University of Oxford
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

We consider excitations with the quantum numbers of a hole in the one-dimensional Hubbard model below half-filling. We calculate the finite-size corrections to the energy. The results are then used to determine threshold singularities in the single-particle Green's function for commensurate fillings. We present the analogous results for the Yang-Gaudin model (electron gas with δ -function interactions). © 2010 The American Physical Society.


Benson R.B.J.,University of Oxford | Druckenmiller P.S.,University of Alaska Fairbanks
Biological Reviews | Year: 2014

Marine and terrestrial animals show a mosaic of lineage extinctions and diversifications during the Jurassic-Cretaceous transition. However, despite its potential importance in shaping animal evolution, few palaeontological studies have focussed on this interval and the possible climate and biotic drivers of its faunal turnover. In consequence evolutionary patterns in most groups are poorly understood. We use a new, large morphological dataset to examine patterns of lineage diversity and disparity (variety of form) in the marine tetrapod clade Plesiosauria, and compare these patterns with those of other organisms. Although seven plesiosaurian lineages have been hypothesised as crossing the Jurassic-Cretaceous boundary, our most parsimonious topology suggests the number was only three. The robust recovery of a novel group including most Cretaceous plesiosauroids (Xenopsaria, new clade) is instrumental in this result. Substantial plesiosaurian turnover occurred during the Jurassic-Cretaceous boundary interval, including the loss of substantial pliosaurid, and cryptoclidid diversity and disparity, followed by the radiation of Xenopsaria during the Early Cretaceous. Possible physical drivers of this turnover include climatic fluctuations that influenced oceanic productivity and diversity: Late Jurassic climates were characterised by widespread global monsoonal conditions and increased nutrient flux into the opening Atlantic-Tethys, resulting in eutrophication and a highly productive, but taxonomically depauperate, plankton. Latest Jurassic and Early Cretaceous climates were more arid, resulting in oligotrophic ocean conditions and high taxonomic diversity of radiolarians, calcareous nannoplankton and possibly ammonoids. However, the observation of discordant extinction patterns in other marine tetrapod groups such as ichthyosaurs and marine crocodylomorphs suggests that clade-specific factors may have been more important than overarching extrinsic drivers of faunal turnover during the Jurassic-Cretaceous boundary interval. © 2013 Cambridge Philosophical Society.


Little S.,University of Oxford
Annals of neurology | Year: 2013

Brain-computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof-of-principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS. We tested BCI-controlled adaptive DBS (aDBS) of the subthalamic nucleus in 8 PD patients. Feedback was provided by processing of the local field potentials recorded directly from the stimulation electrodes. The results were compared to no stimulation, conventional continuous stimulation (cDBS), and random intermittent stimulation. Both unblinded and blinded clinical assessments of motor effect were performed using the Unified Parkinson's Disease Rating Scale. Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p = 0.03) and 27% (p = 0.005) better than cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time compared to cDBS, and a corresponding reduction in energy requirements (p < 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation. BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD. Copyright © 2013 American Neurological Association.


Friedman M.,University of Oxford
Proceedings of the Royal Society B: Biological Sciences | Year: 2012

Giant suspension feeders such as mysticete whales, basking and whale sharks, and the extinct (indicated by '†') †pachycormiform teleosts are conspicuous members of modern and fossil marine vertebrate faunas. Whether convergent anatomical features common to these clades arose along similar evolutionary pathways has remained unclear because of a lack of information surrounding the origins of all groups of large-bodied suspension feeders apart from baleen whales. New investigation reveals that the enigmatic ray-finned fish †Ohmdenia, from the Lower Jurassic (Toarcian, 183.0-175.6 Ma) Posidonia Shale Lagerstä tte, represents the immediate sister group of edentulous †pachycormiforms, the longest lived radiation of large vertebrate suspension feeders. †Ohmdenia bisects the long morphological branch leading to suspension-feeding †pachycormiforms, providing information on the sequence of anatomical transformations preceding this major ecological shift that can be compared to changes associated with the origin of modern mysticetes. Similarities include initial modifications to jaw geometry associated with the reduction of dentition, followed by the loss of teeth. The evolution of largest body sizes within both radiations occurs only after the apparent onset of microphagy. Comparing the fit of contrasting evolutionary models to functionally relevant morphological measurements for whales and †pachycormiform fishes reveals strong support for a common adaptive peak shared by suspension-feeding members of both clades. © 2011 The Royal Society.


Foster K.R.,University of Oxford | Bell T.,Imperial College London
Current Biology | Year: 2012

Microbial cells secrete numerous enzymes, scavenging molecules, and signals that can promote the growth and survival of other cells around them [1-4]. This observation is consistent with the evolution of cooperation within species [5], and there is now an increasing emphasis on the importance of cooperation between different microbial species [4, 6]. We lack, however, a systematic test of the importance of mutually positive interactions between different species, which is vital for assessing the commonness and importance of cooperative evolution in natural communities. Here, we study the extent of mutually positive interaction among bacterial strains isolated from a common aquatic environment. Using data collected from two independent experiments evaluating community productivity across diversity gradients, we show that (1) in pairwise species combinations, the great majority of interactions are net negative and (2) there is no evidence that strong higher-order positive effects arise when more than two species are mixed together. Our data do not exclude the possibility of positive effects in one direction where one species gains at the expense of another, i.e., predator-prey-like interactions. However, these do not constitute cooperation and our analysis suggests that the typical result of adaptation to other microbial species will be competitive, rather than cooperative, phenotypes. © 2012 Elsevier Ltd. All rights reserved.


Davies R.,University of Oxford
Nuclear Physics B | Year: 2011

Multiply-connected Calabi-Yau threefolds are of particular interest for both string theorists and mathematicians. Recently it was pointed out that one of the generic degenerations of these spaces (occurring at codimension one in moduli space) is an isolated singularity which is a finite cyclic quotient of the conifold; these were called hyperconifolds. It was also shown that if the order of the quotient group is even, such singular varieties have projective crepant resolutions, which are therefore smooth Calabi-Yau manifolds. The resulting topological transitions were called hyperconifold transitions, and change the fundamental group as well as the Hodge numbers. Here Batyrev's construction of Calabi-Yau hypersurfaces in toric fourfolds is used to demonstrate that certain compact examples containing the remaining hyperconifolds - the Z3 and Z5 cases - also have Calabi-Yau resolutions. The mirrors of the resulting transitions are studied and it is found, surprisingly, that they are ordinary conifold transitions. These are the first examples of conifold transitions with mirrors which are more exotic extremal transitions. The new hyperconifold transitions are also used to construct a small number of new Calabi-Yau manifolds, with small Hodge numbers and fundamental group Z3 or Z5. Finally, it is demonstrated that a hyperconifold is a physically sensible background in Type IIB string theory. In analogy to the conifold case, non-perturbative dynamics smooth the physical moduli space, such that hyperconifold transitions correspond to non-singular processes in the full theory. © 2011 Elsevier B.V.


Moore R.A.,University of Oxford
Cochrane database of systematic reviews (Online) | Year: 2011

Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data. To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone. We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event. The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken.There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions.NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids.Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (≥ 8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg.Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours. There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.


Abramsky S.,University of Oxford | Brandenburger A.,New York University
New Journal of Physics | Year: 2011

We use the mathematical language of sheaf theory to give a unified treatment of non-locality and contextuality, in a setting that generalizes the familiar probability tables used in non-locality theory to arbitrary measurement covers; this includes Kochen-Specker configurations and more. We show that contextuality, and non-locality as a special case, correspond exactly to obstructions to the existence of global sections. We describe a linear algebraic approach to computing these obstructions, which allows a systematic treatment of arguments for non-locality and contextuality. We distinguish a proper hierarchy of strengths of no-go theorems, and show that three leading examples-due to Bell, Hardy and Greenberger, Horne and Zeilinger, respectively-occupy successively higher levels of this hierarchy. A general correspondence is shown between the existence of local hidden-variable realizations using negative probabilities, and no-signalling; this is based on a result showing that the linear subspaces generated by the non-contextual and no-signalling models, over an arbitrary measurement cover, coincide. Maximal non-locality is generalized to maximal contextuality, and characterized in purely qualitative terms, as the non-existence of global sections in the support. A general setting is developed for the Kochen-Specker-type results, as generic, modelindependent proofs of maximal contextuality, and a new combinatorial condition is given, which generalizes the 'parity proofs' commonly found in the literature. We also show how our abstract setting can be represented in quantum mechanics. This leads to a strengthening of the usual no-signalling theorem, which shows that quantum mechanics obeys no-signalling for arbitrary families of commuting observables, not just those represented on different factors of a tensor product. © IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.


Riley P.R.,University of Oxford
Current Topics in Developmental Biology | Year: 2012

The epicardium is a mesothelial cell layer which contributes to the coronary vessels and myocardium and acts as an important source of trophic signals to maintain continued growth and differentiation of the developing heart. The precise lineage potential of the embryonic epicardium has come under recent scrutiny with notable questions around its capacity to give rise to derivative vascular endothelial cells and cardiomyocytes. The importance of the epicardium is not restricted to heart formation. Recent studies in the adult heart have highlighted a paracrine role in modulating injury and have begun to realize its potential as a source of progenitor cells (EPDCs) which may be reactivated toward facilitating neovascularization and myocardial repair after ischemic injury. Thus, the adult epicardium has an embryological origin and emerges as a prime exemplar of the paradigm of activated resident stem cell therapy in regenerative medicine, whereupon a major goal is to restore embryonic plasticity to otherwise dormant adult progenitors and facilitate organ repair. In this review, we will explore current thinking on the origins of the epicardium, its role as a signaling center, lineage heterogeneity, and controversy around epicardial potential within the developing heart. We will extrapolate to the adult injury setting, drawing on key studies in zebrafish and mouse which establish the basis for the adult epicardium as a target for cardiovascular regeneration. Finally, we will consider translation of this potential to the human lineage alongside the prospects for discovery of target cell-based therapeutics. © 2012 Elsevier Inc.


Jones P.B.,University of Oxford
Monthly Notices of the Royal Astronomical Society | Year: 2012

Photoelectric absorption of blackbody photons is an important process which limits the acceleration of ions under the space-charge-limited flow boundary condition at the polar caps of pulsars with positive corotational charge density. Photoelectric cross-sections in high magnetic fields have been found for the geometrical conditions of the problem, and ion transition rates calculated as functions of the surface temperatures on both the polar cap and the general neutron-star surface. The general surface temperature is the more important and, unless it is below 10 5K, limits the acceleration electric field in the open magnetosphere to values far below those needed either for electron-positron pair creation or slot-gap X-ray sources. But such ion beams are unstable against growth of a quasi-longitudinal Langmuir mode at rates that can be observationally significant as a source of coherent radio emission. © 2011 The Author Monthly Notices of the Royal Astronomical Society © 2011 RAS.


Caux J.-S.,University of Amsterdam | Essler F.H.L.,University of Oxford
Physical Review Letters | Year: 2013

We consider quantum quenches in integrable models. We argue that the behavior of local observables at late times after the quench is given by their expectation values with respect to a single representative Hamiltonian eigenstate. This can be viewed as a generalization of the eigenstate thermalization hypothesis to quantum integrable models. We present a method for constructing this representative state by means of a generalized thermodynamic Bethe ansatz (GTBA). Going further, we introduce a framework for calculating the time dependence of local observables as they evolve towards their stationary values. As an explicit example we consider quantum quenches in the transverse-field Ising chain and show that previously derived results are recovered efficiently within our framework. © 2013 American Physical Society.


Bressloff P.C.,University of Utah | Newby J.M.,University of Oxford
Reviews of Modern Physics | Year: 2013

The interior of a living cell is a crowded, heterogenuous, fluctuating environment. Hence, a major challenge in modeling intracellular transport is to analyze stochastic processes within complex environments. Broadly speaking, there are two basic mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an overdamped Brownian particle. On the other hand, active transport requires chemical energy, usually in the form of adenosine triphosphate hydrolysis, and can be direction specific, allowing biomolecules to be transported long distances; this is particularly important in neurons due to their complex geometry. In this review a wide range of analytical methods and models of intracellular transport is presented. In the case of diffusive transport, narrow escape problems, diffusion to a small target, confined and single-file diffusion, homogenization theory, and fractional diffusion are considered. In the case of active transport, Brownian ratchets, random walk models, exclusion processes, random intermittent search processes, quasi-steady-state reduction methods, and mean-field approximations are considered. Applications include receptor trafficking, axonal transport, membrane diffusion, nuclear transport, protein-DNA interactions, virus trafficking, and the self-organization of subcellular structures. © 2013 American Physical Society.


Norbury C.J.,University of Oxford
Nature Reviews Molecular Cell Biology | Year: 2013

The addition of poly(A) tails to eukaryotic nuclear mRNAs promotes their stability, export to the cytoplasm and translation. Subsequently, the balance between exonucleolytic deadenylation and selective re-establishment of translation-competent poly(A) tails by cytoplasmic poly(A) polymerases is essential for the appropriate regulation of gene expression from oocytes to neurons. In recent years, surprising roles for cytoplasmic poly(A) polymerase-related enzymes that add uridylyl, rather than adenylyl, residues to RNA 3′ ends have also emerged. These terminal uridylyl transferases promote the turnover of certain mRNAs but also modify microRNAs, their precursors and other small RNAs to modulate their stability or biological functions. © 2013 Macmillan Publishers Limited. All rights reserved.


Hsu H.J.,National Kaohsiung Normal University | Bishop D.V.M.,University of Oxford
Developmental Science | Year: 2014

This study tested the procedural deficit hypothesis of specific language impairment (SLI) by comparing children's performance in two motor procedural learning tasks and an implicit verbal sequence learning task. Participants were 7- to 11-year-old children with SLI (n = 48), typically developing age-matched children (n = 20) and younger typically developing children matched for receptive grammar (n = 28). In a serial reaction time task, the children with SLI performed at the same level as the grammar-matched children, but poorer than age-matched controls in learning motor sequences. When tested with a motor procedural learning task that did not involve learning sequential relationships between discrete elements (i.e. pursuit rotor), the children with SLI performed comparably with age-matched children and better than younger grammar-matched controls. In addition, poor implicit learning of word sequences in a verbal memory task (the Hebb effect) was found in the children with SLI. Together, these findings suggest that SLI might be characterized by deficits in learning sequence-specific information, rather than generally weak procedural learning. © 2014 The Authors. Developmental Science Published by John Wiley & Sons Ltd.


Kapit E.,University of Oxford
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

I describe a lattice of asymmetrical qubit pairs in arbitrary dimension, with couplings arranged so that the motion of single-qubit excited states mimics the behavior of charged lattice bosons hopping in a magnetic field. I show, in particular, that one can choose the parameters of the many-body circuit to reach a regime where the complex hopping phase between any two elements can be tuned to any value by simply adjusting the relative phases of two applied oscillating voltage signals. I also propose specific realizations of our model using coupled three junction flux qubits or transmon qubits, in which one can reach the strongly interacting bosonic quantum Hall limit where one will find anyonic excitations. This model could also be studied in trapped ions, and the superconducting circuits could be used for topological quantum computation. © 2013 American Physical Society.


Jones J.A.,University of Oxford
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

Composite pulses, originally developed in nuclear magnetic resonance (NMR), have found widespread use in experimental quantum information processing (QIP) to reduce the effects of systematic errors. Most pulses used so far have simply been adapted from existing NMR designs, and while techniques have been developed for designing composite pulses with arbitrary precision, the results have been quite complicated and have found little application. Here, I describe techniques for designing short but effective composite pulses to implement robust not gates, bringing together existing insights from NMR and QIP, and present some composite pulses. © 2013 American Physical Society.


Amso D.,Brown University | Scerif G.,University of Oxford
Nature Reviews Neuroscience | Year: 2015

Visual attention functions as a filter to select environmental information for learning and memory, making it the first step in the eventual cascade of thought and action systems. Here, we review studies of typical and atypical visual attention development and explain how they offer insights into the mechanisms of adult visual attention. We detail interactions between visual processing and visual attention, as well as the contribution of visual attention to memory. Finally, we discuss genetic mechanisms underlying attention disorders and how attention may be modified by training. © 2015 Macmillan Publishers Limited.


Kaye J.,University of Oxford
Annual Review of Genomics and Human Genetics | Year: 2012

Next-generation sequencing and global data sharing challenge many of the governance mechanisms currently in place to protect the privacy of research participants. These challenges will make it more difficult to guarantee anonymity for participants, provide information to satisfy the requirements of informed consent, and ensure complete withdrawal from research when requested. To move forward, we need to improve the current governance systems for research so that they are responsive to individual privacy concerns but can also be effective at a global level. We need to develop a system of e-governance that can complement existing governance systems but that places greater reliance on the use of technology to ensure compliance with ethical and legal requirements. These new governance structures must be able to address the concerns of research participants while at the same time ensuring effective data sharing that promotes public trust in genomics research. © 2012 by Annual Reviews. All rights reserved.


To date, the majority of studies which consider transport from a social exclusion perspective have been conducted in the context of the developed world where both income poverty and lack of transport are relative rather absolute states. In a unique departure from these previous studies, this paper explores the relationship between transport and social disadvantage in the development context, the key difference being that income poverty is absolute and where there is much lower access to both private and public transportation generally. Thus, it seeks to explore whether the concept of social exclusion remains valid, when it is the majority of the population that is experiencing transport and income poverty compared with the minority who do so in advanced economies.The paper is based on a scoping study for the Republic of South Africa Department of Transport (RSA DOT), which primarily involved focus group discussions with a range of socially deprived urban and peri-urban population groups living in the Tshwane region of South Africa. In a second departure from previous studies which consider transport and social disadvantage in the development context, the study takes a primarily urban focus. The rationale for this is that theoretically low income urban settlements do not suffer from the lack of transport infrastructure and motorised transport services in the way that more remote rural areas do. The policy issue is therefore less a question of addressing a deficit in supply and more one of addressing particular aspects of public transit service failure, which are more readily amenable to relatively low cost, manageable, small-scale national and local policy interventions.A primary aim for the study was to reinvigorate cross-government debate of these issues in the hope of breaking South African government's long-standing and persistent policy inertia in the delivery of equitable and socially sustainable urban transport systems. © 2011 Elsevier Ltd.


Banister D.,University of Oxford
Journal of Transport Geography | Year: 2011

Societies gain enormous benefits from travel, as economies have become more globalised and as the new communications infrastructure allows international networking and travel at a low cost. There has been a true internationalisation of all activities, and travel forms an essential part of that process. However, this mobility is fuelled by carbon, and there is clear scientific agreement that carbon emissions are affecting the global climate with irreversible long term consequences. Transport is the one sector where a reduction in energy use and emissions is proving to be extraordinarily difficult to achieve despite some success in urban areas. This paper focuses on cities, mobility and climate change, highlighting recent trends in both developed and developing countries. It is argued that the current situation is unsustainable, and that transport must contribute fully to achieving carbon reduction targets. An alternative is presented, based on the sustainable mobility paradigm (Banister, 2008) that looks at ways to reduce the need to travel in cities. The belief that high mobility and technology provides the solution is misplaced, as technological innovation can only get us part of the way to sustainable transport, and this may facilitate more travel. There are opportunities for cities to switch to low carbon transport futures, where vision and action are based on a combination of economic, planning and technological innovations working in mutually supporting ways. Potentially, the future is bright for low carbon transport in cities, but the real question is whether there is the commitment and leadership to follow such a path. © 2011.


Cipriani A.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Bipolar disorder is a recurrent illness that is amongst the top 30 causes of disability worldwide and is associated with significant healthcare costs. In the past, emphasis was placed solely on the Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) (to January 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE, (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). No language restrictions were applied. Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies marketing valproate and experts in this field were contacted for supplemental data. Randomised controlled trials allocating participants with bipolar disorder to long-term treatment with valproate or any other mood stabiliser, or antipsychotic drugs, or placebo. Maintenance treatment was defined as treatment instituted specifically or mainly to prevent further episodes of illness. Three review authors independently extracted data. A double-entry procedure was employed by two review authors. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. For dichotomous data, risk ratios were calculated with 95% confidence intervals (CIs). For statistically significant results, we calculated the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH). For continuous data, mean differences (MDs) or standardised mean differences (SMDs) were calculated along with 95% CIs. MDs were used when the same scale was used to measure an outcome; SMDs were employed when different scales were used to measure the same outcome. The primary analysis used a fixed-effect model. Binary outcomes were calculated on a strict intention-to-treat (ITT) basis; dropouts were included in this analysis. When data were missing and the method of "last observation carried forward" (LOCF) had been used to do an ITT analysis, then the LOCF data were used. Six randomised controlled trials (overall 876 participants) lasting 6 to 24 months were included. Two studies (overall 312 participants) compared valproate with placebo, four studies (overall 618 participants) valproate with lithium, one study (overall 23 participants) valproate with olanzapine and one study (overall 220 participants) valproate with the combination of valproate plus lithium. In terms of study quality, most studies reported the methods used to generate random sequence; however, only one study reported enough details on allocation concealment. Four of six included studies described their design as "double blind", but only two trials reported full details about blinding. Valproate was more effective than placebo in preventing study withdrawal due to any mood episode (RR 0.68, 95% CI 0.49 to 0.93; NNTB 8), but no difference in efficacy was found between valproate and lithium (RR 1.02, 95% CI 0.87 to 1.20). Valproate was associated with fewer participants dropping out of treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively). However, combination therapy with lithium plus valproate was more likely to prevent relapse than was monotherapy with valproate (RR 0.78, 95% CI 0.63 to 0.96). Significant differences in adverse event frequencies were found, and lithium was associated with more frequent diarrhoea, polyuria, increased thirst and enuresis, whereas valproate was associated with increased sedation and infection. Limited evidence supports the efficacy of valproate in the long-term treatment of bipolar disorder. Clinicians and patients should consider acceptability and tolerability profile when choosing between lithium and valproate-their combination or other agents-as long-term treatment for bipolar disorder.


Crow T.J.,University of Oxford
Clinical Genetics | Year: 2012

The psychoses (schizophrenia and bipolar disorder) occur in all populations with approximately uniform incidence and sex-dependent age of onset. Core symptoms involve aspects of language; brain structural deviations are sex and hemisphere-related. Genetic predisposition is unaccounted for by linkage or association. The hypothesis is proposed that the 'missing heritability' is epigenetic in form and generated in meiosis on a species-specific XY chromosomal template. A duplication from Xq21.3 to Yp11.2 that occurred 6 million years ago is proposed as critical to hominin evolution. Within this block of homology the Protocadherin11XY gene pair is expressed as a cell surface adhesion factor in both X and Y forms; it has undergone a series of coding changes (16 in the Y sequence and 5 in the X including two to cysteines) in the hominin lineage. According to the hypothesis these sequence changes, together with one or more deletions and a paracentric inversion in the Y block, were successively selected; late events in this series established cerebral asymmetry (the 'torque') as the defining characteristic of the human brain. Built around this reference frame, an epigenetic message channels early development of the embryo in a sapiens-specific format. Diversity in meiotic pairing is postulated as the basis for species-specific deviations in development associated with psychosis. © 2012 John Wiley & Sons A/S.


Jones P.J.,University of Oxford
Monthly Notices of the Royal Astronomical Society | Year: 2014

Analysis of plasma acceleration in pulsars with positive corotational charge density has shown that any element of area on the polar cap is bi-stable: it can be in phases either of pure proton emission or of mixed ions and protons (the ion phase). Ion-phase zones are concentrated near the edge of the polar cap, and are physical bases for the coherent radio emission observed as components within the mean pulse profile. The state of the polar cap is generally chaotic, but organized linear motion of ion zones in a peripheral band is possible and is the likely source of subpulse drift. It is shown that several patterns of limited movement are possible and can account for the varied phenomena observed including mirror and bi-directional drifting. © 2013 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society.


Thomson D.R.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Axillary dissection is commonly performed for breast carcinoma. It is uncertain whether insertion of a drain reduces complication rates. To assess the effects of wound drainage after axillary dissection for breast carcinoma on the incidence of postoperative seroma formation. Secondary outcome measures include the incidence of infection and length of hospital stay. We searched the Cochrane Wound and Breast Cancer Group's Specialised Registers (22 February 2013), MEDLINE (1950 to 22 February 2013), EMBASE (1966 to 22 February 2013), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov (22 February 2013) for all prospectively registered and ongoing trials (22 February 2013). Reference lists of included studies were handsearched by two independent review authors to look for additional eligible trials. All randomised controlled trials (RCTs) comparing wound drainage versus no wound drainage in individuals after axillary dissection for the treatment of breast carcinoma were included. All disease stages were considered. Breast-conserving surgery and mastectomy were considered. Patients undergoing sentinel node biopsy without axillary dissection were not included. No limits were applied to language or study location. Two review authors independently determined the eligibility of each study. Two review authors independently extracted data for each included study using a predesigned data extraction proforma and assessed risk of bias using The Cochrane Collaboration's 'Risk of bias' tool. Discrepancies were resolved by consensus discussion with a third review author. Dichotomous variables were analysed using a Mantel-Haenszel model to produce odds ratios (ORs). Continuous variables were analysed using an inverse variance model to produce a mean difference (MD). Seven RCTs including 960 participants were identified. The quality of trials was generally low, with several studies at risk of selection bias, and no studies used blinding during treatment or outcome assessment. There was a high level of statistical variation between the studies, which therefore reduces the reliability of the evidence. The OR for seroma formation was 0.46 (95% confidence interval (CI) 0.23 to 0.91, P = 0.03) in favour of a reduced incidence of seroma in participants with drains inserted. There was no significant difference in infection rates between drainage and no drainage groups (OR = 0.70; 95% CI 0.44 to 1.12, P = 0.14). The mean difference in length of hospital stay, reported in four trials consisting of 600 participants, was 1.47 days greater in the drained population (95% CI 0.67 to 2.28, P = 0.0003). A mean difference of 0.79 fewer postoperative seroma aspirations was found in the drained population (95% CI 1.23 to 0.35 fewer, P = 0.0004) in two trials including 212 participants. No significant difference in volume of seroma aspirations was reported (MD -19.44, 95% CI -59.45 to 20.57, P = 0.34) in three trials including 519 participants. No significant difference in the incidence of lymphoedema was noted (OR 2.31 favouring no drainage, 95% CI 0.47 to 11.37, P = 0.30), with only six instances reported in three trials of 360 participants, nor was any significant difference in the incidence of haematoma observed (OR 1.68, 95% CI 0.33 to 8.51, P = 0.53), with only five instances reported in two trials of 314 participants. There is limited quality evidence that insertion of a drain following axillary lymphadenectomy reduced the odds of developing a seroma and reduced the number of post-operative seroma aspirations. These benefits should be balanced against an increased length of hospital stay in the drained population.


Noble D.,University of Oxford
Heart Rhythm | Year: 2011

Mathematical models of the electrical activity of the heart using equations for protein ion channels and other transporters began with the Noble 1962 model. These models then developed over a period of about 50 years. Cell types in all regions have been modeled and now are available for download from the CellML website (www.cellml.org). Simulation is a necessary tool of analysis in attempting to understand biological complexity. We often learn as much from the failures as from the successes of mathematical models. It is the iterative interaction between experiment and simulation that is important. © 2011 Heart Rhythm Society. All rights reserved.


Derry S.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Fixed-dose combinations of ibuprofen and oxycodone are available, and the drugs may be separately used in combination in some acute pain situations. To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus oxycodone for moderate to severe postoperative pain. We searched the Cochrane Central Register of Controlled Trials, (CENTRAL), on The Cochrane Library, (Issue 4 of 12, 2013), MEDLINE (1950 to 21st May 2013), EMBASE (1974 to 21st May 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. Randomised, double-blind clinical trials of single dose, oral ibuprofen plus oxycodone compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults. Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus oxycodone, ibuprofen alone, oxycodone alone, or placebo with at least 50% pain relief over six hours, using validated equations. We calculated relative risk (RR) and number needed to treat to benefit (NNT). We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. Searches identified three studies involving 1202 participants. All examined the same dose combination. Included studies provided data from 603 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with placebo, 717 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with ibuprofen 400 mg alone, and 471 participants for the comparison of ibuprofen 400 mg + oxycodone 5 mg with oxycodone 5 mg alone.The proportion of participants achieving at least 50% pain relief over 6 hours was 60% with ibuprofen 400 mg + oxycodone 5 mg and 17% with placebo, giving an NNT of 2.3 (2.0 to 2.8). For ibuprofen 400 mg alone the proportion was 50%, producing no significant difference between ibuprofen 400 mg + oxycodone 5 mg and ibuprofen 400 mg alone. For oxycodone 5 mg alone the proportion was 23%, giving an NNT for ibuprofen 400 mg + oxycodone 5 mg compared with oxycodone alone of 2.9 (2.3 to 4.0).Ibuprofen + oxycodone resulted in longer times to remedication than with placebo. The median time to use of rescue medication was more than 5 hours for ibuprofen 400 mg + oxycodone 5 mg, and 2.3 hours or less with placebo. Fewer participants needed rescue medication with ibuprofen + oxycodone combination than with placebo or ibuprofen alone. The proportion was 40% with ibuprofen 400 mg + oxycodone 5 mg, 83% with placebo, 53% with ibuprofen alone, and 83% with oxycodone alone, giving NNT to prevent one patient needing rescue medication of 2.4 (2.0 to 2.9), 11 (6.1 to 56), and 2.6 (2.1 to 3.4) for comparisons of ibuprofen 400 mg + oxycodone 5 mg with placebo, ibuprofen alone, and oxycodone alone, respectively.The proportion of participants experiencing one or more adverse events was 25% with ibuprofen 400 mg + oxycodone 5 mg, 25% with placebo, 26% with ibuprofen alone, and 35% with oxycodone alone; they were not significantly different. Serious adverse events were reported only after abdominal surgery 6/169 with the combination, 1/175 with ibuprofen alone, 3/52 with oxycodone alone, and 1/60 with placebo. Withdrawals for reasons other than lack of efficacy were fewer than 5% and balanced across treatment arms. The combination of ibuprofen 400mg + oxycodone 5mg provided analgesia for longer than oxycodone alone, but not ibuprofen alone (at the same dose). There was also a smaller chance of needing additional analgesia over about eight hours, and with no greater chance of experiencing an adverse event.


Stead L.F.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Healthcare professionals frequently advise people to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. The aims of this review were to assess the effectiveness of advice from physicians in promoting smoking cessation; to compare minimal interventions by physicians with more intensive interventions; to assess the effectiveness of various aids to advice in promoting smoking cessation, and to determine the effect of anti-smoking advice on disease-specific and all-cause mortality. We searched the Cochrane Tobacco Addiction Group trials register in January 2013 for trials of interventions involving physicians. We also searched Latin American databases through BVS (Virtual Library in Health) in February 2013. Randomised trials of smoking cessation advice from a medical practitioner in which abstinence was assessed at least six months after advice was first provided. We extracted data in duplicate on the setting in which advice was given, type of advice given (minimal or intensive), and whether aids to advice were used, the outcome measures, method of randomisation and completeness of follow-up.The main outcome measure was abstinence from smoking after at least six months follow-up. We also considered the effect of advice on mortality where long-term follow-up data were available. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. People lost to follow-up were counted as smokers. Effects were expressed as relative risks. Where possible, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. We identified 42 trials, conducted between 1972 and 2012, including over 31,000 smokers. In some trials, participants were at risk of specified diseases (chest disease, diabetes, ischaemic heart disease), but most were from unselected populations. The most common setting for delivery of advice was primary care. Other settings included hospital wards and outpatient clinics, and industrial clinics.Pooled data from 17 trials of brief advice versus no advice (or usual care) detected a significant increase in the rate of quitting (relative risk (RR) 1.66, 95% confidence interval (CI) 1.42 to 1.94). Amongst 11 trials where the intervention was judged to be more intensive the estimated effect was higher (RR 1.84, 95% CI 1.60 to 2.13) but there was no statistical difference between the intensive and minimal subgroups. Direct comparison of intensive versus minimal advice showed a small advantage of intensive advice (RR 1.37, 95% CI 1.20 to 1.56). Direct comparison also suggested a small benefit of follow-up visits. Only one study determined the effect of smoking advice on mortality. This study found no statistically significant differences in death rates at 20 years follow-up. Simple advice has a small effect on cessation rates. Assuming an unassisted quit rate of 2 to 3%, a brief advice intervention can increase quitting by a further 1 to 3%. Additional components appear to have only a small effect, though there is a small additional benefit of more intensive interventions compared to very brief interventions.


Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and a range of anxiety disorders [1,2]. Preclinical models have been relatively successful at elucidating the key neurochemical effects of these serotonergic agents; however, a lack of understanding exists of the functional mechanisms by which these drugs exert their effects on mood and anxiety. Elucidating the link between the neurochemical effects of these drugs and their therapeutic action is an essential step in further understanding some of the current limitations of SSRIs, and in developing novel agents that are more selectively designed to target the symptoms they treat. An increasingly popular experimental method within psychopharmacological research is the use of functional neuroimaging techniques to investigate the pharmacological modulation of task-induced brain activity by psychoactive drugs. Such an approach offers an exciting opportunity to investigate the mechanisms of drug action and, in this way, bridge the gap between preclinical and clinical studies. Applying this approach to the study of SSRIs has highlighted that direct modulation of activity in neural areas involved in emotional processing may represent a key functional mechanism through which these agents exert their antidepressant clinical effects. This review summarises the cognitive and neuroimaging evidence suggesting the critical role that disruptions in emotion-related processing play in depression and anxiety disorders. It then examines the functional neuroimaging evidence, from both patient and healthy volunteer studies, to suggest that the amelioration of such disruptions is a key mechanism through which SSRIs exert their therapeutic effects. © 2010 Bentham Science Publishers Ltd.


Magnus C.,University of Oxford
PLoS Computational Biology | Year: 2013

Antibodies binding to the surface of virions can lead to virus neutralisation. Different theories have been proposed to determine the number of antibodies that must bind to a virion for neutralisation. Early models are based on chemical binding kinetics. Applying these models lead to very low estimates of the number of antibodies needed for neutralisation. In contrast, according to the more conceptual approach of stoichiometries in virology a much higher number of antibodies is required for virus neutralisation by antibodies. Here, we combine chemical binding kinetics with (virological) stoichiometries to better explain virus neutralisation by antibody binding. This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus. Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves. In addition, we can identify important parameters that will make further analysis of kinetic neutralisation curves more valuable in the context of estimating stoichiometries. Our model gives a more subtle explanation of kinetic neutralisation curves in terms of single-hit and multi-hit kinetics. © 2013 Magnus.


Electronic gaming machines (EGMs) offer significant revenue streams for mercantile gambling. However, limited clinical and experimental evidence suggests that EGMs are associated with heightened risks of clinically problematic patterns of play. Little is known about the neural structures that might mediate the transition from exploratory EGM play to the 'addictive' play seen in problem gamblers; neither is it known how personality traits associated with gambling activity (and gambling problems) influence reinforcement processing while playing EGMs. Using functional magnetic resonance imaging in healthy participants, we show that a single episode of slot-machine play is subsequently associated with reduced amplitudes of blood-oxygenation-level-dependent signals within reinforcement-related structures, such as the ventral striatum and caudate nucleus, following winning game outcomes; but increased amplitudes of anticipatory signals within the ventral striatum and amygdala while watching the game reels spin. Trait impulsivity enhanced positive signals within the ventral striatum and amygdala following the delivery of winning outcomes but diminished positive signals following the experience of almost-winning ('near-misses'). These results indicate that a single episode of slot-machine play engages the well-characterised reinforcement-learning mechanisms mediated by ascending dopamine mesolimbic and mesostriatal pathways, to shift reward value of EGMs away from game outcomes towards anticipatory states. Impulsivity, itself linked to problem gambling and heightened vulnerability to other addictive disorders, is associated with divergent coding of winning outcomes and almost-winning experiences within the ventral striatum and amygdala, potentially enhancing the reward value of successful slot-machine game outcomes but, at the same time, modulating the aversive motivational consequences of near-miss outcomes.


Glitsch M.,University of Oxford
Physiology | Year: 2011

Ion channels and G-protein-coupled receptors (GPCRs) play a fundamental role in cancer progression by influencing Ca2+ influx and signaling pathways in transformed cells. Transformed cells thrive in a hostile environment that is characterized by extracellular acidosis that promotes the pathological phenotype. The pathway(s) by which extracellular protons achieve this remain unclear. Here, a role for proton-sensing ion channels and GPCRs as mediators of the effects of extracellular protons in cancer cells is discussed. © 2011 Int. Union Physiol. Sci./Am. Physiol. Soc.


Altman D.G.,University of Oxford
American Journal of Gastroenterology | Year: 2013

Reports of randomized controlled trials (RCTs) inform the care of future patients and are especially important to clinicians and systematic reviewers. Readers should satisfy themselves that the study methods were sound. Clinicians should consider the relevance to their own patients, both benefits and harms, and absolute as well as relative effects. Trial reports should provide a clear, transparent, and complete report of what was done and what was found. Unfortunately, bad reporting of RCTs is common, which has serious consequences for clinical practice, research, policy making, and ultimately for patients. RCT reports should adhere to the CONSORT Statement, a minimum set of items that should be addressed. Authors, peer reviewers, and editors should all work to ensure that research reports maximize the value derived from the cost and effort of conducting a trial. © 2013 by the American College of Gastroenterology.


Hermoso M.,University of Oxford
Paleoceanography | Year: 2015

The present work examines the relationship between pH-induced changes in growth and stable isotopic composition of coccolith calcite in two coccolithophore species with a geological perspective. These species (Gephyrocapsa oceanica and Coccolithus pelagicus) with differing physiologies and vital effects possess a growth optimum corresponding to average pH of surface seawater in the geological period during their first known occurrence. The "ancestral" C. pelagicus has much wider pH tolerance in terms of growth rates than the more recently evolved G. oceanica. Diminished growth rates are explained by the challenge of proton translocation into the extracellular environment at low pH and enhanced aqueous CO2 limitation at high pH. Reducing the cell dynamics in this way leads to a lower degree of oxygen isotopic disequilibrium in G. oceanica. In contrast, the slower growing species C. pelagicus, which typically precipitates near-equilibrium calcite, does not show any modulation of oxygen isotope signals with changing pH. Overall, carbon and oxygen isotope compositions are best explained by the degree of utilization of the internal dissolved inorganic carbon (DIC) pool and the dynamics of isotopic reequilibration inside the cell. Thus, the "carbonate ion effect" may not apply to coccolithophores. This difference with foraminifera can be traced to different modes of DIC incorporation into these two distinct biomineralizing organisms. From a geological perspective, these findings have implications for refining the use of oxygen isotopes to infer more reliable sea surface temperatures (SSTs) from fossil carbonates and contribute to a better understanding of how climate-relevant parameters are recorded in the sedimentary archive. ©2015. American Geophysical Union. All Rights Reserved.


Farine D.R.,University of Oxford
Methods in Ecology and Evolution | Year: 2013

Summary: The sampling of animals for the purpose of measuring associations and interactions between individuals has led to the development of several statistical methods to deal with biases inherent in these data. However, these methods are typically computationally intensive and complex to implement. Here, I provide a software package that supports a range of these analyses in the R statistical computing environment. This package includes a novel approach to estimating re-association rates of time between frequently sampled individuals. I include extended demonstration of the syntax and examples of the ability for this software to interface with existing network analysis packages in R. This bridges a gap in the tools that are available to biologists wishing to analyse animal social networks in R. © 2013 British Ecological Society.


Baxi R.,University of Oxford
The Cochrane database of systematic reviews | Year: 2014

Children's exposure to other people's cigarette smoke (environmental tobacco smoke, or ETS) is associated with a range of adverse health outcomes for children. Parental smoking is a common source of children's exposure to ETS. Older children are also at risk of exposure to ETS in child care or educational settings. Preventing exposure to cigarette smoke in infancy and childhood has significant potential to improve children's health worldwide. To determine the effectiveness of interventions aiming to reduce exposure of children to ETS. We searched the Cochrane Tobacco Addiction Group Specialized Register and conducted additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, EMBASE, CINAHL, ERIC, and The Social Science Citation Index & Science Citation Index (Web of Knowledge). Date of the most recent search: September 2013. Controlled trials with or without random allocation. Interventions must have addressed participants (parents and other family members, child care workers and teachers) involved with the care and education of infants and young children (aged 0 to 12 years). All mechanisms for reduction of children's ETS exposure, and smoking prevention, cessation, and control programmes were included. These include health promotion, social-behavioural therapies, technology, education, and clinical interventions. Two authors independently assessed studies and extracted data. Due to heterogeneity of methodologies and outcome measures, no summary measures were possible and results were synthesised narratively. Fifty-seven studies met the inclusion criteria. Seven studies were judged to be at low risk of bias, 27 studies were judged to have unclear overall risk of bias and 23 studies were judged to have high risk of bias. Seven interventions were targeted at populations or community settings, 23 studies were conducted in the 'well child' healthcare setting and 24 in the 'ill child' healthcare setting. Two further studies conducted in paediatric clinics did not make clear whether the visits were to well or ill children, and another included both well and ill child visits. Thirty-six studies were from North America, 14 were in other high income countries and seven studies were from low- or middle-income countries. In only 14 of the 57 studies was there a statistically significant intervention effect for child ETS exposure reduction. Of these 14 studies, six used objective measures of children's ETS exposure. Eight of the studies had a high risk of bias, four had unclear risk of bias and two had a low risk of bias. The studies showing a significant effect used a range of interventions: seven used intensive counselling or motivational interviewing; a further study used telephone counselling; one used a school-based strategy; one used picture books; two used educational home visits; one used brief intervention and one study did not describe the intervention. Of the 42 studies that did not show a significant reduction in child ETS exposure, 14 used more intensive counselling or motivational interviewing, nine used brief advice or counselling, six used feedback of a biological measure of children's ETS exposure, one used feedback of maternal cotinine, two used telephone smoking cessation advice or support, eight used educational home visits, one used group sessions, one used an information kit and letter, one used a booklet and no smoking sign, and one used a school-based policy and health promotion. In 32 of the 57 studies, there was reduction of ETS exposure for children in the study irrespective of assignment to intervention and comparison groups. One study did not aim to reduce children's tobacco smoke exposure, but rather aimed to reduce symptoms of asthma, and found a significant reduction in symptoms in the group exposed to motivational interviewing. We found little evidence of difference in effectiveness of interventions between the well infant, child respiratory illness, and other child illness settings as contexts for parental smoking cessation interventions. While brief counselling interventions have been identified as successful for adults when delivered by physicians, this cannot be extrapolated to adults as parents in child health settings. Although several interventions, including parental education and counselling programmes, have been used to try to reduce children's tobacco smoke exposure, their effectiveness has not been clearly demonstrated. The review was unable to determine if any one intervention reduced parental smoking and child exposure more effectively than others, although seven studies were identified that reported motivational interviewing or intensive counselling provided in clinical settings was effective.


Watkin D.J.,University of Oxford
Crystallography Reviews | Year: 2010

X-ray single crystal structure analysis has become a gold standard for the determination of molecular geometry. The reliability of the technique is a triumph for science and technology working together. The uniqueness of well-crystalline material intrigued early natural philosophers, and their examinations, followed by the discovery of the diffraction of X-rays by crystals, led to the powerful technology that we now enjoy. For about three quarters of a century molecular structure determination has been a driving force for crystallographic research, but now that the science has matured into a technology, interest is returning in trying to understand the nature of crystals themselves. © 2010 Taylor & Francis.


It has been proposed that endogenous H2S mediates oxygen sensing in chemoreceptors; this study investigates the mechanisms by which H 2S excites carotid body type 1 cells. H2S caused a rapid reversible increase in intracellular calcium with EC50≈6 μM. This [Ca2+]i response was abolished in Ca-free Tyrode. In perforated patch current clamp recordings, H2S depolarised type 1 cells from -59 to -35 mV; this was accompanied by a robust increase in [Ca 2+]i. Voltage clamping at the resting membrane potential abolished the H2S-induced rise in [Ca2+]i. H2S inhibited background K+current in whole cell perforated patch and reduced background K+ channel activity in cell-attached patch recordings. It is concluded that H2S excites type 1 cells through the inhibition of background (TASK) potassium channels leading to membrane depolarisation and voltage-gated Ca2+ entry. These effects mimic those of hypoxia. H2S also inhibited mitochondrial function over a similar concentration range as assessed by NADH autofluorescence and measurement of intracellular magnesium (an index of decline in MgATP). Cyanide inhibited background K channels to a similar extent to H2S and prevented H2S exerting any further influence over channel activity. These data indicate that the effects of H2S on background K channels are a consequence of inhibition of oxidative phosphorylation. Whilst this does not preclude a role for endogenous H2S in oxygen sensing via the inhibition of cytochrome oxidase, the levels of H2S required raise questions as to the viability of such a mechanism. © Springer-Verlag 2012.


Vallance C.,University of Oxford
Physical Chemistry Chemical Physics | Year: 2011

The gas phase is generally defined as a state of matter in which atoms or molecules are in constant, rapid, random Brownian motion. However, a range of techniques exist for preparing distributions of gas phase atoms and molecules whose motion is far from random, and whose orientation in space is well defined. In this Perspective, we will explore the nature of atomic and molecular alignment and orientation, the various techniques by which samples of spatially oriented species may be prepared and characterised, and some of the ways in which oriented molecules are being exploited to further our knowledge of molecular structure and dynamics. © the Owner Societies 2011.


Satija R.,University of Oxford | Satija R.,The Broad Institute of MIT and Harvard | Bradley R.K.,Fred Hutchinson Cancer Research Center
Genome Research | Year: 2012

Highly overlapping patterns of genome-wide binding of many distinct transcription factors have been observed in worms, insects, and mammals, but the origins and consequences of this overlapping binding remain unclear. While analyzing chromatin immunoprecipitation data sets from 21 sequence-specific transcription factors active in the Drosophila embryo, we found that binding of all factors exhibits a dose-dependent relationship with "TAGteam" sequence motifs bound by the zinc finger protein Vielfaltig, also known as Zelda, a recently discovered activator of the zygotic genome. TAGteam motifs are present and well conserved in highly bound regions, and are associated with transcription factor binding even in the absence of canonical recognition motifs for these factors. Furthermore, levels of binding in promoters and enhancers of zygotically transcribed genes are correlated with RNA polymerase II occupancy and gene expression levels. Our results suggest that Vielfaltig acts as a master regulator of early development by facilitating the genome-wide establishment of overlapping patterns of binding of diverse transcription factors that drive global gene expression. © 2012 by Cold Spring Harbor Laboratory Press.


Backens M.,University of Oxford
New Journal of Physics | Year: 2014

The ZX-calculus is a graphical calculus for reasoning about quantum systems and processes. It is known to be universal for pure state qubit quantum mechanics (QM), meaning any pure state, unitary operation and post-selected pure projective measurement can be expressed in the ZX-calculus. The calculus is also sound, i.e. any equality that can be derived graphically can also be derived using matrix mechanics. Here, we show that the ZX-calculus is complete for pure qubit stabilizer QM, meaning any equality that can be derived using matrices can also be derived pictorially. The proof relies on bringing diagrams into a normal form based on graph states and local Clifford operations. © 2014 IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.


Lezaun J.,University of Oxford
Environment and Planning D: Society and Space | Year: 2011

Over the last decade the flying patterns and foraging behavior of bees have become a matter of public policy in the European Union. Determined to establish a system where transgenic crops can 'coexist' with conventional and organic farming, the EU has begun to erect a system of demarcations and separations designed to minimize the extent of 'gene flow' from genetically modified plants. As the European landscape is regimented through the introduction of isolation distances and buffer zones, bees and other pollinating insects have become vectors of 'genetic pollution', disrupting the project of cohabitation and purification devised by European authorities. Drawing on the work of Michel Serres on parasitism, this paper traces the emergence of bees as an object of regulatory scrutiny and as an interruptor of the 'coexistence' project. Along with bees, however, another uninvited guest arrived unexpectedly on the scene: the beekeeper, who came to see his traditional relationship to bees, crops, and consumers at risk. The figure of the parasite connects the two essential dynamics described in this paper: an escalation of research and the intensification of political attributes. © 2011 Pion Ltd and its Licensors.


Wiffen P.J.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

This is an update of the original Cochrane review entitled Lamotrigine for acute and chronic pain published in Issue 2, 2007, and updated in Issue 2, 2011. Some antiepileptic medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This updated review adds no new additional studies looking at evidence for lamotrigine as an effective treatment for chronic neuropathic pain or fibromyalgia. The update uses higher standards of evidence than previously. To assess the analgesic efficacy of lamotrigine in the treatment of chronic neuropathic pain and fibromyalgia, and to evaluate adverse effects reported in the studies. We identified randomised controlled trials (RCTs) of lamotrigine for chronic neuropathic pain and fibromyalgia (including cancer pain) from MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). We ran searches for the original review in 2006, in 2011 for the first update, and subsequent searches in August 2013 for this update. We sought additional studies from the reference lists of the retrieved papers. The original review and first update included acute pain, but no acute pain studies were identified. RCTs investigating the use of lamotrigine (any dose, by any route, and for any study duration) for the treatment of chronic neuropathic pain or fibromyalgia. Assessment of pain intensity or pain relief, or both, using validated scales. Participants were adults aged 18 and over. We included only full journal publication articles. Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. The first tier used data where studies reported the outcome of at least 50% pain reduction from baseline, lasted at least eight weeks, had a parallel group design, included 200 or more participants in the comparison, and reported an intention-to-treat analysis. First-tier studies did not use last observation carried forward (LOCF) or other imputational methods for dropouts. The second tier used data that failed to meet this standard and second-tier results were therefore subject to potential bias. Twelve included studies in 11 publications (1511 participants), all with chronic neuropathic pain: central post-stroke pain (1), chemotherapy-induced neuropathic pain (1), diabetic neuropathy (4), HIV-related neuropathy (2), mixed neuropathic pain (2), spinal cord injury-related pain (1), and trigeminal neuralgia (1). We did not identify any additional studies. Participants were aged between 26 and 77 years. Study duration was two weeks in one study and at least six weeks in the remainder; eight were of eight-week duration or longer.No study provided first-tier evidence for an efficacy outcome. There was no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of 200 mg to 400 mg daily. Almost 10% of participants taking lamotrigine reported a skin rash. Large, high-quality, long-duration studies reporting clinically useful levels of pain relief for individual participants provided no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of about 200 to 400 mg daily. Given the availability of more effective treatments including antiepileptics and antidepressant medicines, lamotrigine does not have a significant place in therapy based on the available evidence. The adverse effect profile of lamotrigine is also of concern.


Paton R.S.,University of Oxford
Organic and Biomolecular Chemistry | Year: 2014

Substrate association and asymmetric induction in oxazaborolidinium- catalyzed cycloadditions of maleimides are shown to depend strongly on the catalyst's aromatic substituents. Favourable dispersive forces bias complexation to the catalyst's convex (exo) face exposing a single diastereoface of the substrate preferentially. © 2014 The Royal Society of Chemistry.


Banister D.,University of Oxford
Journal of Transport Geography | Year: 2011

Over the recent past there has been a dramatic increase in travel, mainly driven by the desire to move faster and over ever greater distances. This growth is unsustainable, and the continued growth in levels of mobility needs to be reassessed through substantially reducing the levels of consumption (energy and carbon) in transport. This means that travel activities should be based on shorter distances and slower speeds, with a more flexible interpretation of time constraints. Transport geographers should have a strong and instrumental role to play in this debate. This paper outlines the changing patterns of movement, before concentrating on urban areas where most daily travel takes place, and it examines the trilogy of distance, speed and time. The focus of the paper is on distance, and the role that land use planning and development, and technology can play in encouraging new forms of travel in cities, but there are strong implications on the ways in which speed and time are conceptualised. The conventional transport paradigm is heavily embedded in the belief that travel time needs to be minimised and consequently speeds need to be increased. The resulting impacts on travel distances have not been part of that debate, but reducing travel distances is central to sustainable transport. © 2010 Elsevier Ltd.


Derry C.J.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. Some combinations of ibuprofen and paracetamol are available for use without prescription in some acute pain situations. To assess the efficacy and adverse effects of single dose oral ibuprofen plus paracetamol for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4 of 12, 2013), MEDLINE (1950 to May 21st 2013), EMBASE (1974 to May 21st 2013), the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. Randomised, double-blind clinical trials of single dose, oral ibuprofen plus paracetamol compared with placebo or the same dose of ibuprofen alone for acute postoperative pain in adults. Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used validated equations to calculate the area under the pain relief versus time curve and derive the proportion of participants with at least 50% of maximum pain relief over six hours. We calculated relative risk (RR) and number needed to treat to benefit (NNT) for ibuprofen plus paracetamol, ibuprofen alone, or placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. Searches identified three studies involving 1647 participants. Each of them examined several dose combinations. Included studies provided data from 508 participants for the comparison of ibuprofen 200 mg + paracetamol 500 mg with placebo, 543 participants for the comparison of ibuprofen 400 mg + paracetamol 1000 mg with placebo, and 359 participants for the comparison of ibuprofen 400 mg + paracetamol 1000 mg with ibuprofen 400 mg alone.The proportion of participants achieving at least 50% maximum pain relief over 6 hours was 69% with ibuprofen 200 mg + paracetamol 500 mg, 73% with ibuprofen 400 mg + paracetamol 1000 mg, and 7% with placebo, giving NNTs of 1.6 (1.5 to 1.8) and 1.5 (1.4 to 1.7) for the lower and higher doses respectively compared with placebo. For ibuprofen 400 mg alone the proportion was 52%, giving an NNT for ibuprofen 400 mg + paracetamol 1000 mg compared with ibuprofen alone of 5.4 (3.5 to 12).Ibuprofen + paracetamol at the 200/500 mg and 400/1000 mg doses resulted in longer times to remedication than placebo. The median time to use of rescue medication was 7.6 hours for ibuprofen 200 mg + paracetamol 500 mg, 8.3 hours with ibuprofen 400 mg + paracetamol 1000 mg, and 1.7 hours with placebo. Fewer participants needed rescue medication with ibuprofen + paracetamol combination than with placebo or ibuprofen alone. The proportion was 34% with ibuprofen 200 mg + paracetamol 500 mg, 25% with ibuprofen 400 mg + paracetamol 1000 mg, and 79% with placebo, giving NNTs to prevent use of rescue medication of 2.2 (1.8 to 2.9) and 1.8 (1.6 to 2.2) respectively compared with placebo. The proportion of participants using rescue medication with ibuprofen 400 mg was 48%, giving an NNT to prevent use for ibuprofen 400 mg + paracetamol 1000 mg compared with ibuprofen alone of 4.3 (3.0 to 7.7).The proportion of participants experiencing one or more adverse events was 30% with ibuprofen 200 mg + paracetamol 500 mg, 29% with ibuprofen 400 mg + paracetamol 1000 mg, and 48% with placebo, giving NNT values in favour of the combination treatment of 5.4 (3.6 to 10.5) and 5.1 (3.5 to 9.5) for the lower and higher doses respectively. No serious adverse events were reported in any of the included studies. Withdrawals for reasons other than lack of efficacy were fewer than 5% and balanced across treatment arms. Ibuprofen plus paracetamol combinations provided better analgesia than either drug alone (at the same dose), with a smaller chance of needing additional analgesia over about eight hours, and with a smaller chance of experiencing an adverse event.


Cahill K.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention. Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments. NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting. Combination NRT and varenicline are equally effective as quitting aids. Nortriptyline also improves the chances of quitting. On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use. Further research is warranted into the safety of varenicline and into cytisine's potential as an effective and affordable treatment, but not into the efficacy and safety of NRT.


Perera R.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2006.Otitis media with effusion (OME) or 'glue ear' is an accumulation of fluid in the middle ear, in the absence of acute inflammation or infection. It is the commonest cause of acquired hearing loss in childhood and the usual reason for insertion of 'grommets'. Potential treatments include decongestants, mucolytics, steroids, antihistamines and antibiotics. Autoinflation devices have been proposed as a simple mechanical means of improving 'glue ear'. To assess the effectiveness of autoinflation compared with no treatment in children and adults with otitis media with effusion. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 12 April 2013. We selected randomised controlled trials that compared any form of autoinflation to no autoinflation in individuals with 'glue ear'. Two review authors independently assessed studies for inclusion, assessed risk of bias and extracted data from included studies. Eight studies, with a total of 702 participants, met the inclusion criteria. Overall, the studies were predominantly assessed as being at low or unclear risk of bias; unclear risk was mainly due lack of information. There was no evidence of selective reporting.Pooled estimates favoured the intervention, but did not show a significant effect on tympanometry (type C2 and B) at less than one month, nor at more than one month. Similarly, there were no significant changes for discrete pure-tone audiometry and non-discrete audiometry. Pooled estimates favoured, but not significantly, the intervention for the composite measure of tympanogram or audiometry at less than one month; at more than one month the result became significant (RRI 1.74, 95% CI 1.22 to 2.50). Subgroup analysis based on the type of intervention showed a significant effect using a Politzer device under one month (RRI 7.07, 95% CI 3.70 to 13.51) and over one month (RRI 2.25, 95% CI 1.67 to 3.04).None of the studies demonstrated a significant difference in the incidence of side effects between interventions. All of the studies were small, of limited treatment duration and had short follow-up. However, because of the low cost and absence of adverse effects it is reasonable to consider autoinflation whilst awaiting natural resolution of otitis media with effusion. Primary care could prove a beneficial place to evaluate such interventions and there is ongoing research in this area. Further research should also consider the duration of treatment, the long-term impact on developmental outcomes in children and additional quality of life outcome measures for children and families.


Derry S.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

This is an update of a review first published in The Cochrane Library in Issue 4, 2008, and updated in Issue 3, 2012. Celecoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor usually prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis. Celecoxib is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). Its effectiveness in acute pain was demonstrated in the earlier reviews. To assess analgesic efficacy and adverse effects of a single oral dose of celecoxib for moderate to severe postoperative pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, and ClinicalTrials.gov. The most recent search was to 31 May 2013. We included randomised, double-blind, placebo-controlled trials (RCTs) of adults prescribed any dose of oral celecoxib or placebo for acute postoperative pain. Two review authors assessed studies for quality and extracted data. We converted summed pain relief (TOTPAR) or pain intensity difference (SPID) into dichotomous information, yielding the number of participants with at least 50% pain relief over four to six hours. We used this to calculate the relative benefit (RB) and number needed to treat to benefit (NNT), for one patient to achieve at least 50% of maximum pain relief with celecoxib who would not have done so with placebo. We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. Ten studies (1785 participants) met the inclusion criteria. The two new studies in this update had been identified in the earlier update, but data were not available. There remain three potentially relevant unpublished studies for which data are not available at this time.The NNT for celecoxib 200 mg and 400 mg compared with placebo for at least 50% of maximum pain relief over four to six hours was 4.2 (95% confidence interval (CI) 3.4 to 5.6) and 2.6 (95% CI 2.3 to 3.0) respectively. The median time to use of rescue medication was 6.6 hours with celecoxib 200 mg, 8.4 hours with celecoxib 400 mg, and 2.3 hours with placebo. The proportion of participants requiring rescue medication over 24 hours was 74% with celecoxib 200 mg, 63% for celecoxib 400 mg, and 91% for placebo. The NNT to prevent one patient using rescue medication was 4.8 (95% CI 3.5 to 7.7) and 3.5 (95% CI 2.9 to 4.6) for celecoxib 200 mg and 400 mg respectively. Adverse events were generally mild to moderate in severity, and were experienced by a similar proportion of participants in the celecoxib and placebo groups. One serious adverse event that was probably related to celecoxib was reported. Single-dose oral celecoxib is an effective analgesic for postoperative pain relief. Indirect comparison suggests that the 400 mg dose has similar efficacy to ibuprofen 400 mg.


Wang Q.,Beijing Forestry University | O'Hare D.,University of Oxford
Chemical Communications | Year: 2013

A facile method for the synthesis of Zn2Al-borate and Mg 3Al-borate layered double hydroxides (LDHs) with extremely high specific surface areas of 458.6 and 263 m2 g-1 and containing delaminated nanosheets is reported. To the best of our knowledge, this is the first report of LDH powders that still remain exfoliated on drying. © 2013 The Royal Society of Chemistry.


Jones P.B.,University of Oxford
Monthly Notices of the Royal Astronomical Society | Year: 2014

Radio luminosities have been estimated from published data for a well-defined homogeneous set of 29 normal pulsars. The radio frequency energies per unit charge in the primary accelerated particle beam are given for each pulsar and form a distribution more than two orders of magnitude in width. The values found show that pulsars are extremely efficient generators of radiation below 1-10GHz given the kinematic constraints which are obtained here in the cases of electron-positron and ion-proton plasmas. Our conclusion is that only the ion-proton plasma source is consistent with the spectra of normal and millisecond pulsars and we list and describe the factors which together support this conclusion. © 2014 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society.


This review discusses ambivalent and ambiphilic molecules, which includes transition metals and main group molecules (or ions). It encompasses ambivalent ligands such as NO, NR, N2R; ambiphilic molecules such as SO 2, I2 and ambiphilic transition metal complexes, e.g. [IrCl(CO)(PPh3)2]. Adducts of these ambivalent molecules are able to change geometries according to the number of electrons which they formally donate or accept. It is proposed that they be described as ambivalent (ambiphilic) Lewis acids/ bases with symmetry signatures. The structures of adducts formed by ambivalent and ambiphilic molecules are discussed and the chemical implications of these properties are discussed. The symmetry signatures may be observed at the ligand, at the metal, or at the ligand and the metal simultaneously. The geometric changes which result at the ligand are consistent with VSEPR considerations and at the transition metal with the Complementary Spherical Electron Density Model. The chemical and dynamical implications of the ambivalency and ambiphilicity are indicated. When the same ligand displays ambivalent properties within the same molecule then their interconversion provides an interesting inorganic example of valence tautomerism. The paper also introduces an alternative notation to that described previously by Enemark and Feltham for nitrosyl complexes which may be extended to a wide range of complexes containing ambivalent and ambiphilic ligands. The paper also connects complexes of ambivalent ligands with those of polyene and carborane organometallics which display ambivalency by disconnecting one or more of the double bonds or by undergoing slip distortions. The implications of symmetry signatures to reactivity are also discussed. © 2013 Elsevier B.V. All rights reserved.


Shepperd S.,University of Oxford
Cochrane database of systematic reviews (Online) | Year: 2013

Discharge planning is a routine feature of health systems in many countries. The aim of discharge planning is to reduce hospital length of stay and unplanned readmission to hospital, and improve the co-ordination of services following discharge from hospital. To determine the effectiveness of planning the discharge of individual patients moving from hospital. We updated the review using the Cochrane EPOC Group Trials Register, MEDLINE, EMBASE and the Social Science Citation Index (last searched in March 2012). Randomised controlled trials (RCTs) that compared an individualised discharge plan with routine discharge care that was not tailored to the individual patient. Participants were hospital inpatients. Two authors independently undertook data analysis and quality assessment using a pre designed data extraction sheet. Studies are grouped according to patient group (elderly medical patients, patients recovering from surgery and those with a mix of conditions) and by outcome. Our statistical analysis was done on an intention to treat basis, we calculated risk ratios for dichotomous outcomes and mean differences for continuous data using fixed-effect meta-analysis. When combining outcome data was not possible, because of differences in the reporting of outcomes, we have presented the data in narrative summary tables. We included twenty-four RCTs (8098 patients); three RCTS were identified in this update. Sixteen studies recruited older patients with a medical condition, four recruited patients with a mix of medical and surgical conditions, one recruited patients from a psychiatric hospital, one from both a psychiatric hospital and from a general hospital, and two trials patients admitted to hospital following a fall (110 patients). Hospital length of stay and readmissions to hospital were statistically significantly reduced for patients admitted to hospital with a medical diagnosis and who were allocated to discharge planning (mean difference length of stay -0.91, 95% CI -1.55 to -0.27, 10 trials; readmission rates RR 0.82, 95% CI 0.73 to 0.92, 12 trials). For elderly patients with a medical condition there was no statistically significant difference between groups for mortality (RR 0.99, 95% CI 0.78 to 1.25, five trials) or being discharged from hospital to home (RR 1.03, 95% CI 0.93 to 1.14, two trials). This was also the case for trials recruiting patients recovering from surgery and a mix of medical and surgical conditions. In three trials, patients allocated to discharge planning reported increased satisfaction. There was little evidence on overall healthcare costs. The evidence suggests that a discharge plan tailored to the individual patient probably brings about reductions in hospital length of stay and readmission rates for older people admitted to hospital with a medical condition. The impact of discharge planning on mortality, health outcomes and cost remains uncertain.


James A.C.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

A previous Cochrane review (James 2005) showed that cognitive behavioural therapy (CBT) was effective in treating childhood anxiety disorders; however, questions remain regarding (1) the relative efficacy of CBT versus non-CBT active treatments; (2) the relative efficacy of CBT versus medication and the combination of CBT and medication versus placebo; and (3) the long-term effects of CBT.  To examine (1) whether CBT is an effective treatment for childhood and adolescent anxiety disorders in comparison with (a) wait-list controls; (b) active non-CBT treatments (i.e. psychological placebo, bibliotherapy and treatment as usual (TAU)); and (c) medication and the combination of medication and CBT versus placebo; and (2) the long-term effects of CBT. Searches for this review included the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and Neurosis Group Register, which consists of relevant randomised controlled trials from the bibliographic databasesThe Cochrane Library (1970 to July 2012), EMBASE, (1970 to July 2012) MEDLINE (1970 to July 2012) and PsycINFO (1970 to July 2012). All randomised controlled trials (RCTs) of CBT versus waiting list, active control conditions, TAU or medication were reviewed. All participants must have met the criteria of the Diagnostic and Statistical Manual (DSM) or the International Classification of Diseases (ICD) for an anxiety diagnosis, excluding simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder and elective mutism. The methodological quality of included trials was assessed by three reviewers independently. For the dichotomous outcome of remission of anxiety diagnosis, the odds ratio (OR) with 95% confidence interval (CI) based on the random-effects model, with pooling of data via the inverse variance method of weighting, was used. Significance was set at P < 0.05. Continuous data on each child's anxiety symptoms were pooled using the standardised mean difference (SMD). Forty-one studies consisting of 1806 participants were included in the analyses. The studies involved children and adolescents with anxiety of mild to moderate severity in university and community clinics and school settings. For the primary outcome of remission of any anxiety diagnosis for CBT versus waiting list controls, intention-to-treat (ITT) analyses with 26 studies and 1350 participants showed an OR of 0.13 (95% CI 0.09 to 0.19, Z = 10.26, P < 0.0001), but with evidence of moderate heterogeneity (P = 0.04, I2 = 33%). The number needed to treat (NNT) was 6.0 (95% CI 7.5 to 4.6). No difference in outcome was noted between individual, group and family/parental formats. ITT analyses revealed that CBT was no more effective than non-CBT active control treatments (six studies, 426 participants) or TAU in reducing anxiety diagnoses (two studies, 88 participants). The few controlled follow-up studies (n = 4) indicate that treatment gains in the remission of anxiety diagnosis are not statistically significant. Cognitive behavioural therapy is an effective treatment for childhood and adolescent anxiety disorders; however, the evidence suggesting that CBT is more effective than active controls or TAU or medication at follow-up, is limited and inconclusive.


Kirthi V.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

This is an updated version of the original Cochrane review published in Issue 4, 2010 (Kirthi 2010). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine headaches. To determine the efficacy and tolerability of aspirin, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 10 March 2010 for the original review and to 31 January 2013 for the update. We included randomised, double-blind, placebo-controlled or active-controlled studies, or both, using aspirin to treat a migraine headache episode, with at least 10 participants per treatment arm. Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. No new studies were found for this update. Thirteen studies (4222 participants) compared aspirin 900 mg or 1000 mg, alone or in combination with metoclopramide 10 mg, with placebo or other active comparators, mainly sumatriptan 50 mg or 100 mg. For all efficacy outcomes, all active treatments were superior to placebo, with NNTs of 8.1, 4.9 and 6.6 for 2-hour pain-free, 2-hour headache relief, and 24-hour headache relief with aspirin alone versus placebo, and 8.8, 3.3 and 6.2 with aspirin plus metoclopramide versus placebo. Sumatriptan 50 mg did not differ from aspirin alone for 2-hour pain-free and headache relief, while sumatriptan 100 mg was better than the combination of aspirin plus metoclopramide for 2-hour pain-free, but not headache relief; there were no data for 24-hour headache relief.Adverse events were mostly mild and transient, occurring slightly more often with aspirin than placebo.Additional metoclopramide significantly reduced nausea (P < 0.00006) and vomiting (P = 0.002) compared with aspirin alone. We found no new studies since the last version of this review. Aspirin 1000 mg is an effective treatment for acute migraine headaches, similar to sumatriptan 50 mg or 100 mg. Addition of metoclopramide 10 mg improves relief of nausea and vomiting. Adverse events were mainly mild and transient, and were slightly more common with aspirin than placebo, but less common than with sumatriptan 100 mg.


Hadley G.,University of Oxford
The Cochrane database of systematic reviews | Year: 2013

Opioid drugs have been used for many years to relieve pain. Transdermal fentanyl offers one option for delivering and maintaining pain relief in patients with moderate or severe cancer pain. To determine the analgesic efficacy of transdermal fentanyl for relief of cancer pain, and to assess the adverse events associated with the use of transdermal fentanyl for relief of cancer pain. The following databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4 of 12); MEDLINE (1966 to May 2013); EMBASE (1974 to May 2013; CANCERLIT (PubMED) (November 2012); and ClinicalTrials.gov (May 2013). Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of transdermal fentanyl in adults and children with cancer pain. Studies with fewer than 10 participants were excluded. Data were extracted independently by two review authors. We extracted any available data on the number or proportion of patients with 'no worse than mild pain' or treatment success (very satisfied, or very good or excellent on patient global impression scales), together with information about adverse events and withdrawals. We identified nine studies meeting the inclusion criteria, including a Turkish study that is awaiting formal translation. There were 1244 participants randomised in classically designed RCTs, of whom 1197 had evaluable data, and 138 patients enrolled in an enriched enrolment, randomised withdrawal (EERW) trial. Overall, 600 participants were treated with transdermal fentanyl patches, 382 with various formulations of morphine, 36 with methadone, and 221 with paracetamol plus codeine. There were major sources of potential bias, including lack of blinding, small size, high levels of attrition, and inconsistent reporting.We could not compare data in a meaningful analysis regarding adverse events such as nausea, abdominal pain, gastrointestinal bleeding, and confusion. These events may have been attributable to the underlying disease process.There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNT) for the analgesic effect. In seven studies with 461 participants reporting pain intensity results after about two weeks, the mean or median pain scores were on the borderline of mild and moderate pain. Most participants would have had no worse than mild pain on treatment. Another reported that 77% of participants using transdermal fentanyl had an undefined successful outcome. Fewer participants experienced constipation with transdermal fentanyl (28%) than with oral morphine (46%), giving a risk ratio of 0.61 (95% CI 0.47 to 0.78); the NNT to prevent constipation was 5.5 (95% CI 3.8 to 10). The randomised trial literature for effectiveness of transdermal fentanyl is limited, but it is an important medicine. Most studies recruited fewer than 100 participants and did not provide data appropriate for meta-analysis. Only a few reported how many patients had good pain relief but, where data were reported, a majority had no worse than mild pain within a reasonably short time period. The evidence pointed to a useful and significant reduction in complaints about constipation for transdermal fentanyl compared with oral morphine.


Derry S.,University of Oxford
Cochrane database of systematic reviews (Online) | Year: 2013

Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams.High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, normally under local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made. To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-concentration (8%) capsaicin in chronic neuropathic pain in adults. We searched CENTRAL, MEDLINE, EMBASE and clinicaltrials.gov to December 2012. Randomised, double-blind, placebo-controlled studies of at least six weeks' duration, using topical capsaicin to treat neuropathic pain. Two review authors independently assessed trial quality and validity, and extracted data on numbers of participants with pain relief (clinical improvement) after at least six weeks, and with local skin reactions. We calculated risk ratio and numbers needed to treat to benefit (NNT) and harm (NNH). We sought details of definition of pain relief and specific adverse events.Efficacy outcomes reflecting long-duration pain relief after a single drug application were from the patient global impression of change (PGIC) at specific points, usually eight and 12 weeks. We regarded these outcomes as first-tier evidence. We regarded average pain scores over weeks 2 to 8 and 2 to 12 and the number and/or percentage of participants with pain intensity reduction of at least 30% or at least 50% over baseline as second-tier evidence. We included six studies, involving 2073 participants; they were of generally good reporting quality; the control was 0.04% topical capsaicin to help maintain blinding. Efficacy outcomes were inconsistently reported between studies, however, resulting in analyses for most outcomes being based on less than complete data.Four studies involved 1272 participants with postherpetic neuralgia. All efficacy outcomes were significantly better than control. At both eight and 12 weeks there was a significant benefit for high-concentration over low-concentration topical capsaicin for participants reporting themselves to be much or very much better, with point estimates of the NNTs of 8.8 (95% confidence interval (CI) 5.3 to 26) and 7.0 (95% CI 4.6 to 15) respectively. More participants had average 2 to 8-week and 2 to 12-week pain intensity reductions over baseline of at least 30% and at least 50% with active treatment than control, with NNT values between 10 and 12.Two studies involved 801 participants with painful HIV-neuropathy. In a single study the NNT at 12 weeks for participants to be much or very much better was 5.8 (95% CI 3.8 to 12). Over both studies more participants had average 2 to 12-week pain intensity reductions over baseline of at least 30% with active treatment than control, with an NNT of 11.Local adverse events were common, but not consistently reported. Serious adverse events were no more common with active treatment (4.1%) than control (3.2%). Adverse event withdrawals did not differ between groups, but lack of efficacy withdrawals were somewhat more common with control than active treatment, based on small numbers of events. No deaths were judged to be related to study medication. High-concentration topical capsaicin used to treat postherpetic neuralgia and HIV-neuropathy generates more participants with high levels of pain relief than does control treatment using a much lower concentration of capsaicin. The additional proportion who benefit over control is not large, but for those who do obtain high levels of pain relief there are additional improvements in sleep, fatigue, depression and an improved quality of life. High-concentration topical capsaicin is therefore similar to other therapies for chronic pain. In this case, the high cost of single and repeated applications suggest that high-concentration topical capsaicin is likely to be used when other available therapies have failed, and that it should probably not be used repeatedly without substantial documented pain relief. Even when efficacy is established, there are unknown risks, especially on epidermal innervation, of repeated application of long periods.


McQuillan A.,Tel Aviv University | Mazeh T.,Tel Aviv University | Aigrain S.,University of Oxford
Astrophysical Journal, Supplement Series | Year: 2014

We analyzed three years of data from the Kepler space mission to derive rotation periods of main-sequence stars below 6500 K. Our automated autocorrelation-based method detected rotation periods between 0.2 and 70 days for 34,030 (25.6%) of the 133,030 main-sequence Kepler targets (excluding known eclipsing binaries and Kepler Objects of Interest), making this the largest sample of stellar rotation periods to date. In this paper we consider the detailed features of the now well-populated period-temperature distribution and demonstrate that the period bimodality, first seen by McQuillan et al. in the M-dwarf sample, persists to higher masses, becoming less visible above 0.6 M⊙. We show that these results are globally consistent with the existing ground-based rotation-period data and find that the upper envelope of the period distribution is broadly consistent with a gyrochronological age of 4.5 Gyr, based on the isochrones of Barnes, Mamajek, & Hillenbrand and Meibom et al. We also performed a detailed comparison of our results to those of Reinhold et al. and Nielsen et al., who measured rotation periods of field stars observed by Kepler. We examined the amplitude of periodic variability for the stars with detection rotation periods, and found a typical range between 950 ppm (5th percentile) and 22,700 ppm (95th percentile), with a median of 5600 ppm. We found typically higher amplitudes for shorter periods and lower effective temperatures, with an excess of low-amplitude stars above 5400 K. © 2014. The American Astronomical Society. All rights reserved..


Pinsker F.,University of Oxford
Annals of Physics | Year: 2015

In this work I generalize and apply an analytical approximation to analyze 1D states of non-equilibrium spinor polariton Bose-Einstein condensates (BEC). Solutions for the condensate wave functions carrying black solitons and half-dark solitons are presented. The derivation is based on the non-conservative Lagrangian formalism for complex Ginzburg-Landau type equations (cGLE), which provides ordinary differential equations for the parameters of the dark soliton solutions in their dynamic environment. Explicit expressions for the stationary dark soliton solution are stated. Subsequently the method is extended to spin sensitive polariton condensates, which yields ordinary differential equations for the parameters of half-dark solitons. Finally a stationary case with explicit expressions for half-dark solitons is presented. © 2015 Elsevier Inc.


Golestanian R.,University of Oxford
Physical Review Letters | Year: 2015

Enzymes have been recently found to exhibit enhanced diffusion due to their catalytic activities. A recent experiment [C. Riedel et al., Nature (London) 517, 227 (2015)] has found evidence that suggests this phenomenon might be controlled by the degree of exothermicity of the catalytic reaction involved. Four mechanisms that can lead to this effect, namely, self-thermophoresis, boost in kinetic energy, stochastic swimming, and collective heating are critically discussed, and it is shown that only the last two can be strong enough to account for the observations. The resulting quantitative description is used to examine the biological significance of the effect. © 2015 American Physical Society.


Angus S.,University of Oxford
Journal of High Energy Physics | Year: 2014

Abstract: Dark radiation is a compelling extension to ΛCDM: current experimental results hint at ΔNeff ≳0.5, which is increased to ΔNeff ≃1 if the recent BICEP2 results are included. In recent years dark radiation has been considered in the context of string theory models such as the LARGE Volume Scenario of type IIB string theory, forging a link between present-day cosmological observations and models of physics at the Planck scale. In this paper I consider an extension of the LARGE Volume Scenario in which the bulk volume is stabilised by two moduli instead of one. Consequently, the lightest modulus no longer corresponds to the compactification volume but instead to a transverse direction in the bulk geometry. I focus on scenarios in which sequestering of soft masses is achieved by localising the Standard Model on D3 branes at a singularity. The fraction of dark radiation produced in such models vastly exceeds experimental bounds, ruling out the sequestered LARGE Volume Scenario with two bulk moduli as a model of the early Universe. © 2014, The Author(s).


Gauld R.,University of Oxford
Journal of High Energy Physics | Year: 2014

The forward LHCb acceptance opens interesting possibilities of studying precision Standard Model hard processes in a kinematical region beyond the reach of ATLAS and CMS. In this paper we perform a feasibility study for cross-section measurements of top quark pairs with the LHCb detector, with an analysis of signal and background rates for selected final states, and determine the potential precision achievable at √ s = 7 and 14TeV. We then study the dependence of theoretical uncertainties on the pseudorapidity distribution of top quarks produced in pair production at NLO, and observe that a crosssection measurement at high pseudorapidity has enhanced sensitivity to probe the high-x gluon PDF as compared to measurements in the central-region. Based on simulated pseudodata, the impact of a 14TeV cross-section measurement on the gluon PDF and charge asymmetry is quantified. © 2014 The Authors.


He L.,University of Oxford
Progress in Aerospace Sciences | Year: 2010

Rapid increase in computing power has made a huge difference in scales and complexities of the problems in turbomachinery that we can tackle by use of computational fluid dynamics (CFD). It is recognised, however, that there is always a need for developing efficient methods for applications to blade designs. In a design cycle, a large number of flow solutions are sought to interact iteratively or concurrently with various options, opportunities and constraints from other disciplines. This basic requirement for fast prediction methods in a multi-disciplinary design environment remains unchanged, regardless of computer speed. And it must be recognised that the multi-disciplinary nature of blading design increasingly influences outcomes of advanced gas turbine and aeroengine developments. Recently there has been considerable progress in the Fourier harmonic modelling method development for turbomachinery applications. The main driver is to develop efficient and accurate computational methodologies and working methods for prediction and analysis of unsteady effects on aerothermal performance (loading and efficiency) and aeroelasticity (blade vibration due to flutter and forced response) in turbomachinery. In this article, the developments and applications of this type of methods in the past 20 years or so are reviewed. The basic modelling assumptions and various forms of implementations for the temporal Fourier modelling approach are presented and discussed. Computational examples for realistic turbomachinery configurations/flow conditions are given to illustrate the validity and effectiveness of the approach. Although the major development has been in the temporal Fourier harmonic modelling, some recent progress in use of the spatial Fourier modelling is also described with demonstration examples. © 2010 Elsevier Ltd. All rights reserved.


Darby S.,University of Oxford
Building Research and Information | Year: 2010

The argument for the implementation of 'smart' metering, which is an elastic term, varies according to circumstance and place. In some countries, the business case for establishing an advanced metering infrastructure (AMI) relies in part on improving consumption feedback to customers and assisting in the transition to lower-impact energy systems. There is an expectation that AMI will lead to reductions in both the demand and the cost to serve customers through improved communication, but little evidence exists to show overall demand reduction. To what extent might smart meters improve the prospects for customer engagement? To assess this question, end-user perceptions and practices must be considered along with metering hardware and economics. Using the theory of affordances, qualitative research is examined to understand how householders have used consumption feedback, with and without smart meters. Although AMI offers possibilities for household energy management and customer-utility relations, there is little evidence to suggest it will automatically achieve a significant reduction in energy demand. For that, there has to be a determined focus on overall demand reduction (rather than on peak electricity demand reduction), on designing customer interfaces for ease of understanding, and on guiding occupants towards appropriate action. Appropriate forms of interface, feedback, narrative, and support will be needed to reach diverse populations. © 2010 Taylor & Francis.


Rothwell P.M.,University of Oxford | Algra A.,University Utrecht | Amarenco P.,University Paris Diderot
The Lancet | Year: 2011

Stroke is a major cause of death and disability worldwide. Without improvements in prevention, the burden will increase during the next 20 years because of the ageing population, especially in developing countries. Major advances have occurred in secondary prevention during the past three decades, which demonstrate the broader potential to prevent stroke. We review the main medical treatments that should be considered for most patients with transient ischaemic attack or ischaemic stroke in the acute phase and the long term, and draw attention to recent developments. © 2011 Elsevier Ltd.


Gauld R.,University of Oxford
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

The forward LHCb acceptance offers the possibility of measuring the top-quark pair asymmetry in a kinematic region that does not receive overwhelming dilution from the symmetric gluon-fusion channel. To investigate this possibility, two leptonic final states are identified, and analysis strategies are proposed for each channel with 14 TeV data. Leading fixed-order predictions are then provided for the relevant leptonic asymmetry variables in each channel. If backgrounds can be experimentally constrained, statistically, a nonzero asymmetry is estimated to be observable beyond 5σ confidence level with the full LHCb 14 TeV data. © 2015 American Physical Society.


Noller J.,University of Oxford
Journal of Cosmology and Astroparticle Physics | Year: 2015

The only known fully ghost-free and consistent Lorentz-invariant kinetic term for a graviton (or indeed for any spin-2 field) is the Einstein-Hilbert term. Here we propose and investigate a new candidate family of kinetic interactions and their extensions to derivative interactions involving several spin-2 fields. These new terms generically break diffeomorphism invariance(s) and as a result can lead to the propagation of 5 degrees of freedom for a single spin-2 field - analogous to ghost-free Massive Gravity. We discuss under what circumstances these new terms can be used to build healthy effective field theories and in the process establish the 'Jordan' and 'Einstein' frame pictures for Massive-, Bi- and Multi-Gravity. © 2015, IOP. All rights reserved.


There is concern that the internet is playing an increasing role in self-harm and suicide. In this study we systematically review and analyse research literature to determine whether there is evidence that the internet influences the risk of self-harm or suicide in young people. An electronic literature search was conducted using the PsycINFO, MEDLINE, EMBASE, Scopus, and CINAHL databases. Articles of interest were those that included empirical data on the internet, self-harm or suicide, and young people. The articles were initially screened based on titles and abstracts, then by review of the full publications, after which those included in the review were subjected to data extraction, thematic analysis and quality rating. Youth who self-harm or are suicidal often make use of the internet. It is most commonly used for constructive reasons such as seeking support and coping strategies, but may exert a negative influence, normalising self-harm and potentially discouraging disclosure or professional help-seeking. The internet has created channels of communication that can be misused to 'cyber-bully' peers; both cyber-bullying and general internet use have been found to correlate with increased risk of self-harm, suicidal ideation, and depression. Correlations have also been found between internet exposure and violent methods of self-harm. Internet use may exert both positive and negative effects on young people at risk of self-harm or suicide. Careful high quality research is needed to better understand how internet media may exert negative influences and should also focus on how the internet might be utilised to intervene with vulnerable young people.


MacMahon M.,Leiden University | Garlaschelli D.,Leiden University | Garlaschelli D.,University of Oxford
Physical Review X | Year: 2015

A challenging problem in the study of complex systems is that of resolving, without prior information, the emergent, mesoscopic organization determined by groups of units whose dynamical activity is more strongly correlated internally than with the rest of the system. The existing techniques to filter correlations are not explicitly oriented towards identifying such modules and can suffer from an unavoidable information loss. A promising alternative is that of employing community detection techniques developed in network theory. Unfortunately, this approach has focused predominantly on replacing network data with correlation matrices, a procedure that we show to be intrinsically biased because of its inconsistency with the null hypotheses underlying the existing algorithms. Here, we introduce, via a consistent redefinition of null models based on random matrix theory, the appropriate correlation-based counterparts of the most popular community detection techniques. Our methods can filter out both unit-specific noise and systemwide dependencies, and the resulting communities are internally correlated and mutually anticorrelated. We also implement multiresolution and multifrequency approaches revealing hierarchically nested subcommunities with "hard" cores and "soft" peripheries. We apply our techniques to several financial time series and identify mesoscopic groups of stocks which are irreducible to a standard, sectorial taxonomy; detect "soft stocks" that alternate between communities; and discuss implications for portfolio optimization and risk management.


Taggart D.P.,University of Oxford
Current Opinion in Cardiology | Year: 2011

Purpose of review: The SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) trial is the most important trial of surgery and stents in patients with severe coronary artery disease (CAD) and reflects real clinical practice. This review describes its key findings at 3 years with particular reference to what is already known on this topic. Recent findings: Taking together the SYNTAX randomized trial and its registry component, almost 79% of patients with three-vessel CAD and almost two-thirds of patients with left main stem (LMS) disease have a survival benefit and marked reduction in the need for repeat revascularization with coronary artery bypass grafting (CABG) in comparison to stents, implying that CABG is still the treatment of choice for most of these patients. This conclusion, at odds with results of previous trials of stenting and surgery but consistent with findings of large propensity-matched registries, can be explained by the fact that SYNTAX enrolled 'real life' patients rather than the highly select patients in previous trials. SYNTAX also shows that for patients with less severe CAD there is no difference in survival between CABG and stents but a lower incidence of repeat revascularization with CABG. Summary: The results of the SYNTAX trial confirm that at 3 years CABG remains the treatment of choice for most patients with three-vessel and LMS disease and especially in those with the most severe disease. SYNTAX will have a profound effect on practice recommendations for the foreseeable future and already has had a major effect on the new European Society for Cardiology/European Association for Cardiothoracic Surgery guidelines for myocardial revascularization. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Brockdorff N.,University of Oxford
RNA | Year: 2013

A plethora of noncoding (nc) RNAs has been revealed through the application of high-throughput analysis of the transcriptome, and this has led to an intensive search for possible biological functions attributable to these transcripts. A major category of functional ncRNAs that has emerged is for those that are implicated in coordinate gene silencing, either in cis or in trans. The archetype for this class is the well-studied long ncRNA Xist which functions in cis to bring about transcriptional silencing of an entire X chromosome in female mammals. An important step in X chromosome inactivation is the recruitment of the Polycomb repressive complex PRC2 that mediates histone H3 lysine 27 methylation, a hallmark of the inactive X chromosome, and recent studies have suggested that this occurs as a consequence of PRC2 interacting directly with Xist RNA. Accordingly, other ncRNAs have been linked to PRC2 targeting either in cis or in trans, and here also the mechanism has been proposed to involve direct interaction between PRC2 proteins and the different ncRNAs. In this review, I discuss the evidence for and against this hypothesis, in the process highlighting alternative models and discussing experiments that, in the future, will help to resolve existing discrepancies. Copyright © 2013 RNA Society.


Empirical work on the relationship between environmental stress and human migration has blossomed over the last 10 years. While such work has provided important insights into this relationship, there has been, to date, limited effort expended on generating a generalisable framework for apprehending such interactions. This paper seeks to address this deficit. Based on semi-structured interviews in two sending and four receiving areas in northern Ethiopia, it explores dominant mobility narratives among populations whose livelihoods are exposed to a range of environmental stresses. Analysis of these narratives corroborates findings from other empirical studies on the subject, highlighting how the impact of environmental stress on human mobility can only be understood within the context in which it occurs. To this end the paper attempts to generate a typology of interactions between environmental and non-environmental factors shaping mobility. The typology is based on four effects: additive, enabling, vulnerability and barrier effects. It is thought to provide a generalisable conceptual language which is capable of describing the role of environmental stress in mobility decisions and thereby offering a systematic means for thinking through the processes by which environmental stress impacts upon mobility. While the framework is hypothesised to be suitably generalisable to account for other contexts and other environmental stresses, this still needs to be tested. In addition it is acknowledged that the framework suffers from some major limitations. Most notable is reliance on a conceptually false distinction between environmental and non-environmental factors, and the inability to account for the non-environmental features which shape perceptions of migration. © 2013 Elsevier Ltd.


Rorsman P.,University of Oxford | Braun M.,University of Alberta
Annual Review of Physiology | Year: 2013

Pancreatic β cells secrete insulin, the body's only hormone capable of lowering plasma glucose levels. Impaired or insufficient insulin secretion results in diabetes mellitus. The β cell is electrically excitable; in response to an elevation of glucose, it depolarizes and starts generating action potentials. The electrophysiology of mouse β cells and the cell's role in insulin secretion have been extensively investigated. More recently, similar studies have been performed on human β cells. These studies have revealed numerous and important differences between human and rodent β cells. Here we discuss the properties of human pancreatic β cells: their glucose sensing, the ion channel complement underlying glucose-induced electrical activity that culminates in exocytotic release of insulin, the cellular control of exocytosis, and the modulation of insulin secretion by circulating hormones and locally released neurotransmitters. Finally, we consider the pathophysiology of insulin secretion and the interactions between genetics and environmental factors that may explain the current diabetes epidemic. Copyright © 2013 by Annual Reviews. All rights reserved.


Freeman D.,University of Oxford
Schizophrenia Research | Year: 2011

A clear challenge for schizophrenia research is to improve markedly the efficacy of psychological treatments for delusional beliefs. Effect sizes for the first generation of cognitive approaches are weak to moderate. These therapies now lag behind the transformation over the past ten years in understanding the causes of delusions. This paper advocates an interventionist-causal model approach: to focus on one putative causal factor at a time, show that an intervention can change it, and examine the subsequent effects on the delusional beliefs. A number of new studies that illustrate this approach with patients with schizophrenia spectrum disorders who have not responded to previous treatment are reviewed. These early stage studies show great promise in terms of efficacy, although remain to be subjected to methodologically rigorous evaluation. The advantages and difficulties of the interventionist approach applied to psychosis are considered, and future studies are highlighted. The importance for clinical services of cognitive approaches to psychosis will increase further if the theoretical advances can be translated into treatment. © 2011 Elsevier B.V.


Barr F.A.,University of Oxford
Journal of Cell Biology | Year: 2013

Rab GTPases are highly conserved components of vesicle trafficking pathways that help to ensure the fusion of a vesicle with a specific target organelle membrane. Specific regulatory pathways promote kinetic proofreading of membrane surfaces by Rab GTPases, and permit accumulation of active Rabs only at the required sites. Emerging evidence indicates that Rab activation and inactivation are under complex feedback control, suggesting that ultrasensitivity and bistability, principles established for other cellular regulatory networks, may also apply to Rab regulation. Such systems can promote the rapid membrane accumulation and removal of Rabs to create timelimited membrane domains with a unique composition, and can explain how Rabs define the identity of vesicle and organelle membranes. © 2013 Barr.


Parsons J.L.,University of Liverpool | Dianov G.L.,University of Oxford
DNA Repair | Year: 2013

Base excision repair (BER) is a major DNA repair pathway employed in mammalian cells that is required to maintain genome stability, thus preventing several human diseases, such as ageing, neurodegenerative diseases and cancer. This is achieved through the repair of damaged DNA bases, sites of base loss and single strand breaks of varying complexity that are continuously induced endogenously or via exogenous mutagens. Whilst the enzymes involved in BER are now well known and characterised, the role of the co-ordination of BER enzymatic activities in the cellular response to DNA damage and the mechanisms regulating this process are only now being revealed. Post-translational modifications of BER proteins, including ubiquitylation and phosphorylation, are increasingly being identified as key processes that regulate BER. In this review we will summarise recent evidence discovering novel mechanisms that are involved in maintaining genome stability by regulation of the key BER proteins in response to DNA damage. © 2013 Elsevier B.V.


Przybylski A.K.,University of Oxford
Pediatrics | Year: 2014

BACKGROUND AND OBJECTIVES: The rise of electronic games has driven both concerns and hopes regarding their potential to influence young people. Existing research identifies a series of isolated positive and negative effects, yet no research to date has examined the balance of these potential effects in a representative sample of children and adolescents. The objective of this study was to explore how time spent playing electronic games accounts for significant variation in positive and negative psychosocial adjustment using a representative cohort of children aged 10 to 15 years.METHODS: A large sample of children and adolescents aged 10 to 15 years completed assessments of psychosocial adjustment and reported typical daily hours spent playing electronic games. Relations between different levels of engagement and indicators of positive and negative psychosocial adjustment were examined, controlling for participant age and gender and weighted for population representativeness.RESULTS: Low levels (<1 hour daily) as well as high levels (>3 hours daily) of game engagement was linked to key indicators of psychosocial adjustment. Low engagement was associated with higher life satisfaction and prosocial behavior and lower externalizing and internalizing problems, whereas the opposite was found for high levels of play. No effects were observed for moderate play levels when compared with non-players.CONCLUSIONS: The links between different levels of electronic game engagement and psychosocial adjustment were small (<1.6% of variance) yet statistically significant. Games consistently but not robustly associated with children's adjustment in both positive and negative ways, findings that inform policy-making as well as future avenues for research in the area.


Knight J.C.,University of Oxford
Trends in Genetics | Year: 2013

Our understanding of immunity has historically been informed by studying heritable mutations in both the adaptive and innate immune responses, including primary immunodeficiency and autoimmune diseases. Recent advances achieved through the application of genomic and epigenomic approaches are reshaping the study of immune dysfunction and opening up new avenues for therapeutic interventions. Moreover, applying genomic techniques to resolve functionally important genetic variation between individuals is providing new insights into immune function in health. This review describes progress in the study of rare variants and primary immunodeficiency diseases arising from whole-exome sequencing (WES), and discusses the application, success, and challenges of applying genome-wide association studies (GWAS) to disorders of immune function and how they may inform more rational use of therapeutics. In addition, the application of expression quantitative-trait mapping to immune phenotypes, progress in understanding MHC disease associations, and insights into epigenetic mechanisms at the interface of immunity and the environment are reviewed. © 2012 Elsevier Ltd.


Hobson K.,University of Oxford
Environmental Politics | Year: 2013

Debates about how to foster green/environmental citizenship have been central to environmental politics research in the past few decades. While a great deal of this work draws its central tenets from liberal political theory more recently researchers have adopted broadly post-structural analytical frameworks to explore how diverse forms of (environmental) citizenship are formed and enacted. But what can and does this 'green governmentality' literature contribute to our understanding of environmental citizenship? In exploring such a question, some key environment and citizenship debates, including the recent post-structural turn, are examined. Research into domestic sustainable consumption and public deliberation around climate change is drawn upon to outline how both forms of intervention worked to produce incomplete and conditional expressions of intent and commitment that could be viewed as environmental citizenship. Green governmentality analysis thus highlights some conceptual and empirical blind spots in prevailing environmental citizenships frameworks whilst raising further questions about appropriate and effective public intervention mechanisms. © 2013 Copyright Taylor and Francis Group, LLC.


Huang C.,Wuhan University | Hesselbo S.P.,University of Oxford
Gondwana Research | Year: 2014

The Early Toarcian Oceanic Anoxic Event (OAE) in the Early Jurassic Period is associated with a major negative carbon isotope excursion (CIE), mass extinction, marine transgression and global warming. The Toarcian OAE is thought to have been caused by flood basalt magmatism, and may have been a trigger for mass extinction. However, these proposed causes of the Toarcian OAE and associated biotic crisis are not adequately resolved by a precise chronology. The duration of the Toarcian OAE has been estimated to be anywhere from ~. 0.12 to ~. 0.9. Myr, most recently 0.74 to 3.26. Myr from U-Pb dating. The CIE associated with the Toarcian OAE has a similar pattern at numerous localities, and there is evidence that the marine carbon isotope variations recorded astronomical forcing signals. Here we estimate a duration of ~. 620. kyr for the main negative CIE, ~. 860. kyr for the polymorphum zone and >. 1.58. Myr for the levisoni zone based on 405-kyr astronomical eccentricity tuning of the marine section at Peniche (Portugal). This 405-kyr tuned series provides a ~. 2.5. Myr continuous high-resolution chronology through the Early Toarcian. There are 6, or possibly 7 short eccentricity cycles in the main CIE interval at Peniche. To confirm this astronomically based estimate, we analyzed three other sections at Yorkshire (UK), Dotternhausen (Germany), and Valdorbia (Italy) from marine carbon isotopic series. These four stratigraphic sections from Early Jurassic western Tethys record the Toarcian OAE with ~. 6 prominent carbon isotope cycles in the CIE that span a 600. ±. 100. kyr duration. The Peniche 405-kyr tuned series indicates that the pre- and post-CIE intervals experienced strong precession-eccentricity-forced climate change, whereas the CIE interval is marked by dominant obliquity forcing. These dramatic and abrupt changes in astronomical response in the carbon isotopes point to fundamental shifting in the Early Toarcian paleoclimate system that was directly linked to the global carbon cycle. © 2013 International Association for Gondwana Research.


Warrell D.A.,University of Oxford
Infectious Disease Clinics of North America | Year: 2012

This article discusses the epidemiology, prevention, clinical features, first aid and medical treatment of venomous bites by snakes, lizards, and spiders; stings by fish, jellyfish, echinoderms, and insects; and poisoning by fish and molluscs, in all parts of the world. Of these envenoming and poisonings, snake bite causes the greatest burden of human suffering, killing 46,000 people each year in India alone and more than 100,000 worldwide and resulting in physical handicap in many survivors. Specific antidotes (antivenoms/antivenins) are available to treat envenoming by many of these taxa but supply and distribution is inadequate in many tropical developing countries. © 2012 .


Hill A.V.S.,University of Oxford
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case-control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.


Rebonato R.,University of Oxford
Journal of Computational Finance | Year: 2015

This paper presents a simple, yet surprisingly effective, approximation for the noarbitrage drifts that appear in Libor market model-SABR-family term structure models. The approximation reduces the burden of the computational bottleneck for these models by one order of magnitude. As the size of the problem increases it becomes asymptotically exact for a wide class of correlation structures.We show the effectiveness of the approximation in a particularly severe stress case. © 2015 Incisive Risk Information (IP) Limited.


Fones H.,Free University of Berlin | Preston G.M.,University of Oxford
FEMS Microbiology Reviews | Year: 2013

Metals play essential roles in many biological processes but are toxic when present in excess. This makes their transport and homoeostatic control of particular importance to living organisms. Within the context of plant-pathogen interactions the availability and toxicity of transition metals can have a substantial impact on disease development. Metals are essential for defensive generation of reactive oxygen species and other plant defences and can be used directly to limit pathogen growth. Metal-based antimicrobials are used in agriculture to control plant disease, and there is increasing evidence that metal hyperaccumulating plants use accumulated metal to limit pathogen growth. Pathogens and hosts compete for available metals, with plants possessing mechanisms to withhold essential metals from invading microbes. Pathogens, meanwhile, use low-metal conditions as a signal to recognise and respond to the host environment. Consequently, metal-sensing systems such as fur (iron) and zur (zinc) regulate the expression of pathogenicity and virulence genes; and pathogens have developed sophisticated strategies to acquire metal during growth in plant tissues, including the production of multiple siderophores. This review explores the impact of transition metals on the processes that determine the outcome of bacterial infection in plants, with a particular emphasis on zinc, iron and copper. This review discusses the pivotal role of transition metals such as zinc, copper and iron in determining the outcome of plant-pathogen interactions, both as essential mineral nutrients for plant and pathogen, and as anti-microbial agents that inhibit pathogen growth. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.


Allison K.,University of Oxford
Journal of High Energy Physics | Year: 2014

A non-minimal coupling ξ of the Standard Model Higgs field to gravity can give rise to inflation, but large ξ is required and thus leads to a violation of perturbative unitarity at MPl/ξ, which is well below the inflationary scale MP1/√ξ. We re-examine this claim for a Higgs mass in the range 125-126 GeV for which λeff(μ) runs to very small values near the Planck scale and can significantly reduce the value of ξ required for inflation. Using the two-loop renormalization group equations and effective potential for Higgs ξ-inflation, we find that familiar inflationary solutions can have a non-minimal coupling as small as ξ ∼ 400 without the potential developing a second minimum. We also find a new observationally allowed region of Higgs ξ-inflation with ξ ∼ 90 and distinct inflationary predictions, including an observable level of the tensor-to-scalar ratio r.


Herron T.J.,University of Michigan | Lee P.,University of Oxford | Jalife J.,University of Michigan
Circulation Research | Year: 2012

Cardiac optical mapping has proven to be a powerful technology for studying cardiovascular function and disease. The development and scientific impact of this methodology are well-documented. Because of its relevance in cardiac research, this imaging technology advances at a rapid pace. Here, we review technological and scientific developments during the past several years and look toward the future. First, we explore key components of a modern optical mapping set-up, focusing on: (1) new camera technologies; (2) powerful light-emitting-diodes (from ultraviolet to red) for illumination; (3) improved optical filter technology; (4) new synthetic and optogenetic fluorescent probes; (5) optical mapping with motion and contraction; (6) new multiparametric optical mapping techniques; and (7) photon scattering effects in thick tissue preparations. We then look at recent optical mapping studies in single cells, cardiomyocyte monolayers, atria, and whole hearts. Finally, we briefly look into the possible future roles of optical mapping in the development of regenerative cardiac research, cardiac cell therapies, and molecular genetic advances. © 2012 American Heart Association, Inc.


Williams R.J.P.,University of Oxford
FEBS Letters | Year: 2012

Iron chemistry in the environment and in organisms is entwined. The iron surface minerals in solution for the first billion years of the planet were ferrous compounds. This ion became and has remained a major participant in organisms. The evolution of iron was due to its oxidation to insoluble ferric ions by oxygen released from organisms. The evolution of cellular iron chemistry then required uptake from this oxidised state. Use was expanded from the mainly electron transfer properties in the original reductive cell interior to employment in external oxidative chemistry. The environment/organisms evolution is that of one predictable chemical system. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Price C.P.,University of Oxford
Clinical Biochemist Reviews | Year: 2012

The principles of Evidence-Based Medicine have been established for about two decades, with the need for evidence-based clinical practice now being accepted in most health systems around the world. These principles can be employed in laboratory medicine. The key steps in evidence-based practice, namely (i) formulating the question; (ii) searching for evidence; (iii) appraising evidence; (iv) applying evidence; and (v) assessing the experience are all accepted but, as yet, translation into daily clinical and laboratory practice has been slow. Furthermore, the demand for evidence-based laboratory medicine (EBLM) has been slow to develop. There are many contrasting observations about laboratory medicine, for example (i) there is too much testing vs insufficient testing; (ii) testing is expensive vs laboratories are expected to generate income; and (iii) test results have little impact on outcomes vs test results are crucial to clinical decision making. However, there is little evidence to support any of these observations. Integrating the principles of EBLM into routine practice will help to resolve some of these issues by identifying (a) where laboratory medicine fits into the care pathway; (b) where testing is appropriate; (c) the nature and quality of evidence required to demonstrate the clinical utility of a test; (d) how the test result impacts on clinical actions; (e) where changes in the care pathway will occur; and (f) where benefit/value can be achieved. These answers will help to establish the culture of EBLM in clinical and laboratory practice.


Calderwood D.A.,Yale University | Campbell I.D.,University of Oxford | Critchley D.R.,University of Leicester
Nature Reviews Molecular Cell Biology | Year: 2013

Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling. © 2013 Macmillan Publishers Limited. All rights reserved.


Trowsdale J.,University of Cambridge | Knight J.C.,University of Oxford
Annual Review of Genomics and Human Genetics | Year: 2013

Over several decades, various forms of genomic analysis of the human major histocompatibility complex (MHC) have been extremely successful in picking up many disease associations. This is to be expected, as the MHC region is one of the most gene-dense and polymorphic stretches of human DNA. It also encodes proteins critical to immunity, including several controlling antigen processing and presentation. Single-nucleotide polymorphism genotyping and human leukocyte antigen (HLA) imputation now permit the screening of large sample sets, a technique further facilitated by high-throughput sequencing. These methods promise to yield more precise contributions of MHC variants to disease. However, interpretation of MHC-disease associations in terms of the functions of variants has been problematic. Most studies confirm the paramount importance of class I and class II molecules, which are key to resistance to infection. Infection is likely driving the extreme variation of these genes across the human population, but this has been difficult to demonstrate. In contrast, many associations with autoimmune conditions have been shown to be specific to certain class I and class II alleles. Interestingly, conditions other than infections and autoimmunity are also associated with the MHC, including some cancers and neuropathies. These associations could be indirect, owing, for example, to the infectious history of a particular individual and selective pressures operating at the population level. Copyright © 2013 by Annual Reviews. All rights reserved.


Heyes C.,University of Oxford
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Many comparative and developmental psychologists believe thatwe are Homo imitans; humans are more skilled and prolific imitators than other animals, becausewe have a special, inborn ‘intermodal matching’ mechanism that integrates representations of others with representations of the self. In contrast, the associative sequence learning (ASL) model suggests that human infants learn to imitate using mechanisms that they share with other animals, and the rich resources provided by their sociocultural environments. This article answers seven objections to the ASL model: (i) it presents evidence that newborns do not imitate; (ii) argues that infants receive a plentiful supply of the kind of experience necessary for learning to imitate; (iii) suggests that neither infants nor adults can imitate elementally novel actions; (iv) explains why non-human animals have a limited capacity for imitation; (v) discusses the goaldirectedness of imitation; (vi) presents evidence that improvement in imitation depends on visual feedback; and (vii) reflects on the view that associative theories steal ‘the soul of imitation’. The empirical success of the ASL model indicates that the mechanisms which make imitation possible, by aligning representations of self with representations of others, have been tweaked by cultural evolution, not built from scratch by genetic evolution. © 2015 The Author(s) Published by the Royal Society. All rights reserved.


Wilkinson D.,University of Oxford
Archives of Pediatrics and Adolescent Medicine | Year: 2011

Physicians sometimes refer to a "window of opportunity" for withdrawing lifesustaining treatment in patients with acute severe brain injury. There is a period of critical illness and physiological instability when treatment withdrawal is likely to be followed by death but prognosis is uncertain. If decisions are delayed, greater prognostic certainty can be achieved, but with the risk that the patient is no longer dependent on life support and survives with very severe disability. In this article I draw on the example of birth asphyxia and highlight the role that the window of opportunity sometimes plays in decisions about lifesustaining treatment in intensive care. I outline the potential arguments in favor of and against taking the window into account. I argue that it is, at least sometimes, ethical and appropriate for physicians and parents to be influenced by the window of opportunity in their decisions about life-sustaining treatment. ©2011 American Medical Association. All rights reserved.


Rezayi E.H.,California State University, Los Angeles | Simon S.H.,University of Oxford
Physical Review Letters | Year: 2011

We perform numerical studies to determine if the fractional quantum Hall state observed at a filling factor of ν=5/2 is the Moore-Read wave function or its particle-hole conjugate, the so-called anti-Pfaffian. Using a truncated Hilbert space approach we find that, for realistic interactions, including Landau-level mixing, the ground state remains fully polarized and the anti-Pfaffian is strongly favored. © 2011 American Physical Society.


Draper S.J.,University of Oxford | Heeney J.L.,University of Cambridge
Nature Reviews Microbiology | Year: 2010

Recent developments in the use of viruses as vaccine vectors have been facilitated by a better understanding of viral biology. Advances occur as we gain greater insight into the interrelationship of viruses and the immune system. Viral-vector vaccines remain the best means to induce cellular immunity and are now showing promise for the induction of strong humoral responses. The potential benefits for global health that are offered by this field reflect the scope and utility of viruses as vaccine vectors for human and veterinary applications, with targets ranging from certain types of cancer to a vast array of infectious diseases. © 2010 Macmillan Publishers Limited. All rights reserved.


Fagotti M.,University of Oxford
Physical Review B - Condensed Matter and Materials Physics | Year: 2013

We consider the time evolution after sudden quenches of global parameters in translational invariant Hamiltonians and study the time average expectation values and entanglement entropies in finite chains. We show that in noninteracting models the time average of spin correlation functions is asymptotically equal to the infinite time limit in the infinite chain, which is known to be described by a generalized Gibbs ensemble. The equivalence breaks down considering nonlocal operators, and we establish that this can be traced back to the existence of conservation laws common to the Hamiltonian before and after the quench. We develop a method to compute the leading finite-size corrections. We find that the finite-size corrections are generally large in observables with large relaxation timescales. © 2013 American Physical Society.


Wheeler R.J.,University of Oxford
Trends in Parasitology | Year: 2010

The Trypanosoma brucei subspecies T. brucei brucei is non-human infective due to susceptibility to lysis by trypanolytic factor (TLF) in human serum. Reviewed here are the advances which have revealed apolipoprotein L1 (ApoL1), found in high density lipoprotein, as the lysis-inducing component of TLF, the means of uptake via haptoglobin-related protein receptor and the mechanism of resistance in T. b. rhodesiense via its serum resistance-associated (SRA) protein. The first practical steps to application of these discoveries are now in progress; transgenic animals expressing either baboon or minimally truncated human ApoL1 show resistance to both T. b. brucei and T. b. rhodesiense. This has major implications for treatment and prevention of human and animal African trypanosomiasis. © 2010 Elsevier Ltd.


Noble D.,University of Oxford
Progress in Biophysics and Molecular Biology | Year: 2013

This article explores the relativistic principle that there is no privileged scale of causality in biology to clarify the relationships between genomes and phenotypes. The idea that genetic causes are primary views the genome as a program. Initially, that view was vindicated by the discovery of mutations and knockouts that have large and specific effects on the phenotype. But we now know that these form the minority of cases. Many changes at the genome level are buffered by robust networks of interactions in cells, tissues and organs. The 'differential' view of genetics therefore fails because it is too restrictive. An 'integral' view, using reverse engineering from systems biological models to quantify contributions to function, can solve this problem. The article concludes by showing that far from breaking the supervenience principle, downward causation requires that it should be obeyed. © 2012 Elsevier Ltd.


Melham T.,University of Oxford
Progress in Biophysics and Molecular Biology | Year: 2013

Systems biology is centrally engaged with computational modelling across multiple scales and at many levels of abstraction. Formal modelling, precise and formalised abstraction relationships, and computation also lie at the heart of computer science-and over the past decade a growing number of computer scientists have been bringing their discipline's core intellectual and computational tools to bear on biology in fascinating new ways. This paper explores some of the apparent points of contact between the two fields, in the context of a multi-disciplinary discussion on conceptual foundations of systems biology. © 2012 Elsevier Ltd.


Roberts J.V.,University of Oxford
British Journal of Criminology | Year: 2011

Sentencing guideline schemes require courts to sentence within the guidelines - or give reasons why a different sentence is appropriate. Most US schemes require courts to find 'substantial and compelling' grounds for departing from the guidelines. The duty of a court with respect to sentencing guidelines in England and Wales changed significantly in 2010 as a result of the Coroners and Justice Act 2009. This article explores the evolution of the duty of courts to comply with the English sentencing guidelines. As will be seen, the language of the duty of a court provision has become more robust: henceforth, courts 'must follow' definitive guidelines rather than merely 'have regard to' them. At the same time, the government significantly increased the range of sentence within which courts must sentence. The essay provides some international context, drawing upon experiences in the jurisdiction in which guidelines have been longest in existence, and explores the limited compliance statistics collected in England and Wales to date. The consequences of the latest changes for sentencing in England and Wales are discussed. © The Author 2011. Published by Oxford University Press. All rights reserved.


Evans N.H.,Lancaster University | Beer P.D.,University of Oxford
Angewandte Chemie - International Edition | Year: 2014

Since the start of this millennium, remarkable progress in the binding and sensing of anions has been taking place, driven in part by discoveries in the use of hydrogen bonding, as well as the previously under-exploited anion-π interactions and halogen bonding. However, anion supramolecular chemistry has developed substantially beyond anion recognition, and now encompasses a diverse range of disciplines. Dramatic advance has been made in the anion-templated synthesis of macrocycles and interlocked molecular architectures, while the study of transmembrane anion transporters has flourished from almost nothing into a rapidly maturing field of research. The supramolecular chemistry of anions has also found real practical use in a variety of applications such as catalysis, ion extraction, and the use of anions as stimuli for responsive chemical systems. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Robson A.,University of Oxford
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The movement of molecules inside living cells is a fundamental feature of biological processes. The ability to both observe and analyse the details of molecular diffusion in vivo at the single-molecule and single-cell level can add significant insight into understanding molecular architectures of diffusing molecules and the nanoscale environment in which the molecules diffuse. The tool of choice for monitoring dynamic molecular localization in live cells is fluorescence microscopy, especially so combining total internal reflection fluorescence with the use of fluorescent protein (FP) reporters in offering exceptional imaging contrast for dynamic processes in the cell membrane under relatively physiological conditions compared with competing single-molecule techniques. There exist several different complex modes of diffusion, and discriminating these from each other is challenging at the molecular level owing to underlying stochastic behaviour. Analysis is traditionally performed using mean square displacements of tracked particles; however, this generally requires more data points than is typical for single FP tracks owing to photophysical instability. Presented here is a novel approach allowing robust Bayesian ranking of diffusion processes to discriminate multiple complex modes probabilistically. It is a computational approach that biologists can use to understand single-molecule features in live cells.


Kevin Baird J.,Eijkman Oxford Clinical Research Unit | Kevin Baird J.,University of Oxford
Clinical Microbiology Reviews | Year: 2013

Vivax malaria threatens patients despite relatively low-grade parasitemias in peripheral blood. The tenet of death as a rare outcome, derived from antiquated and flawed clinical classifications, disregarded key clinical evidence, including (i) high rates of mortality in neurosyphilis patients treated with vivax malaria; (ii) significant mortality from zones of endemicity; and (iii) the physiological threat inherent in repeated, very severe paroxysms in any patient, healthy or otherwise. The very well-documented course of this infection, with the exception of parasitemia, carries all of the attributes of "perniciousness" historically linked to falciparum malaria, including severe disease and fatal outcomes. A systematic analysis of the parasite biomass in severely ill patients that includes blood, marrow, and spleen may ultimately explain this historic misunderstanding. Regardless of how this parasite is pernicious, recent data demonstrate that the infection comes with a significant burden of morbidity and associated mortality. The extraordinary burden of malaria is not heavily weighted upon any single continent by a single species of parasite-it is a complex problem for the entire endemic world, and both species are of fundamental. © 2013, American Society for Microbiology. All Rights Reserved.


Helm D.,University of Oxford
Energy Policy | Year: 2014

European energy and climate change policy rests on two main pillars: the internal energy market (IEM), and the climate change package (CCP). The IEM aimed at third party access and unbundling, neglecting the physical infrastructure and the basis for asset valuations and hence the harmonisation of network charges. The Commission plans to complete the IEM by 2014-almost a quarter of a century after embarking on the policy. Yet even if all the IEM directives are implemented, the EU will remain far from a single competitive market. The CCP was grounded on short term targets (the 2020-20-20 programme) on the assumption that fossil fuel prices would rise, making renewables competitive, and hence yielding a competitive advantage to the EU. The EUETS was intended to lead the way to a global trading system and an international agreement at Copenhagen. The EU has reduced the production of carbon emissions, but only as a result of de-industrialisation and slow growth, and at the expense of rising carbon consumption. Renewables have not led to green growth, but rather to a further eroding of competitiveness. The EUETS price has collapsed. In order for the EU to put the IEM and the CCP back on track, both need to be radically reconsidered. The IEM requires a refocusing on physical infrastructure, common accounting rules and an EU-wide approach to capacity markets and renewables trading. The CCP requires a refocusing on carbon consumption, on limiting the dash-for-coal, and on future rather than current renewables. © 2013 Elsevier Ltd.


Achieving food system sustainability is a global priority but there are different views on how it might be achieved. Broadly three perspectives are emerging, defined here as: efficiency oriented, demand restraint and food system transformation. These reflect different conceptualisations on what is practically achievable, and what is desirable, underpinned by different values and ideologies about the role of technology, our relationship with nature and fundamentally what is meant by a 'good life.' This paper describes these emerging perspectives and explores their underlying values; highlights LCA's role in shaping these perspectives; and considers how LCA could be oriented to clarify thinking and advance policy-relevant knowledge. It argues that more work is needed to understand the values underlying different approaches to the food sustainability problem. This can shed light on why stakeholders disagree, where there are genuine misunderstandings, and where common ground is possible and ways forward agreed. © 2013 Elsevier Ltd. All rights reserved.


Axon et al., (2012) argue that maximizing the potential for energy efficiency and demand reduction in tenanted commercial properties requires a "building communities" approach. This paper develops and extends Axon et al.'s proposed framework in two ways. First, by extending its applicability from tenanted to owner-occupied properties. Second, by situating it within the literature related to organizational culture, occupant behaviours, and technology adoption. The paper begins with a brief review of the existing research on people, energy and commercial buildings. This literature tends to address either organizational choices, or occupant behavior, but it rarely crosses the analytical boundaries between these two groups. The paper then explores these different levels of analysis within a 3Cs - "concern, capacity, and conditions" - framework, which was developed to describe and distinguish organizational responses to an energy crisis. The combination of the "building communities" and 3Cs frames reveals gaps and grey areas between organizational culture, occupant behaviour, and technology adoption where further conservation opportunities may lie. These understudied areas suggest that there may be "social potential" for change that is between and beyond the frames used by previous research in the field. © 2013 Elsevier Ltd.


Romano F.,University of Oxford | Sciortino F.,University of Rome La Sapienza
Physical Review Letters | Year: 2015

We design an all-DNA system that behaves like vitrimers, innovative plastics with self-healing and stress-releasing properties. The DNA sequences are engineered to self-assemble first into tetra- and bifunctional units which, upon further cooling, bind to each other forming a fully bonded network gel. An innovative design of the binding regions of the DNA sequences, exploiting a double toehold-mediated strand displacement, generates a network gel which is able to reshuffle its bonds, retaining at all times full bonding. As in vitrimers, the rate of bond switching can be controlled via a thermally activated catalyst, which in the present design is very short DNA strands. © 2015 American Physical Society.


Stern J.,University of Oxford
Energy Policy | Year: 2014

In Continental Europe and LNG importing Asia, international gas prices reflect the market fundamentals of the 1970s-1990s when gas was replacing oil products and crude oil in energy balances. By the end of the 2000s, fundamentals in both these regions had changed significantly, but gas price formation mechanisms had not. This created major problems for buyers locked into long term contracts indexed to crude oil and oil product prices, which had risen to levels far above gas market fundamentals. By 2013, the transition to hub-based pricing was well advanced in Europe and dominant in the large markets in the north west of the Continent. In Asia the "crisis of fundamentals" was only just starting to be addressed with a transition to market pricing an urgent imperative, but still a distant prospect. © 2013 Elsevier Ltd.


Can M.,University of Michigan | Armstrong F.A.,University of Oxford | Ragsdale S.W.,University of Michigan
Chemical Reviews | Year: 2014

The structure, function, and mechanism of the nickel metalloenzymes, CO dehydrogenase (CODH), and acetyl-CoA synthase was reviewed. CODH also is a wonderful system to explore how chemical bond forming and breaking interfaces with redox chemistry. This enzyme, especially coupled to ACS and other enzymes of the Wood-Ljungdahl pathway, offers great potential for biotechnology through the conversion of simple abundant compounds into needed chemicals and fuels. It will be extremely important to understand how the activities of CODH and ACS are coordinated in the complex and to increase our understanding of the dynamics and mechanics of the tunnel that carries CO from the C-cluster to the A-cluster. With both CODH and ACS, it is important to understand the movement of domains and how these proteins interact with other components of the Wood-Ljungdahl pathway, especially the CFeSP. Future high-impact papers will emerge that provide an understanding of the structures of complexes between CODH/ACS and the CFeSP.


Holland P.W.H.,University of Oxford
Wiley Interdisciplinary Reviews: Developmental Biology | Year: 2013

Many homeobox genes encode transcription factors with regulatory roles in animal and plant development. Homeobox genes are found in almost all eukaryotes, and have diversified into 11 gene classes and over 100 gene families in animal evolution, and 10 to 14 gene classes in plants. The largest group in animals is the ANTP class which includes the well-known Hox genes, plus other genes implicated in development including ParaHox (Cdx, Xlox, Gsx), Evx, Dlx, En, NK4, NK3, Msx, and Nanog. Genomic data suggest that the ANTP class diversified by extensive tandem duplication to generate a large array of genes, including an NK gene cluster and a hypothetical ProtoHox gene cluster that duplicated to generate Hox and ParaHox genes. Expression and functional data suggest that NK, Hox, and ParaHox gene clusters acquired distinct roles in patterning the mesoderm, nervous system, and gut. The PRD class is also diverse and includes Pax2/5/8, Pax3/7, Pax4/6, Gsc, Hesx, Otx, Otp, and Pitx genes. PRD genes are not generally arranged in ancient genomic clusters, although the Dux, Obox, and Rhox gene clusters arose in mammalian evolution as did several non-clustered PRD genes. Tandem duplication and genome duplication expanded the number of homeobox genes, possibly contributing to the evolution of developmental complexity, but homeobox gene loss must not be ignored. Evolutionary changes to homeobox gene expression have also been documented, including Hox gene expression patterns shifting in concert with segmental diversification in vertebrates and crustaceans, and deletion of a Pitx1 gene enhancer in pelvic-reduced sticklebacks. © 2012 Wiley Periodicals, Inc.


Dianov G.L.,University of Oxford | Hubscher U.,University of Zurich
Nucleic Acids Research | Year: 2013

Base excision repair (BER) is a frontline repair system that is responsible for maintaining genome integrity and thus preventing premature aging, cancer and many other human diseases by repairing thousands of DNA lesions and strand breaks continuously caused by endogenous and exogenous mutagens. This fundamental and essential function of BER not only necessitates tight control of the continuous availability of basic components for fast and accurate repair, but also requires temporal and spatial coordination of BER and cell cycle progression to prevent replication of damaged DNA. The major goal of this review is to critically examine controversial and newly emerging questions about mammalian BER pathways, mechanisms regulating BER capacity, BER responses to DNA damage and their links to checkpoint control of DNA replication. © The Author(s) 2013. Published by Oxford University Press.


Simmonds M.J.,University of Oxford
Nature Reviews Endocrinology | Year: 2013

The ability of the immune system to protect the body from attack by foreign antigens is essential for human survival. The immune system can, however, start to attack the body's own organs. An autoimmune response against components of the thyroid gland affects 2-5% of the general population. Considerable familial clustering is also observed in autoimmune thyroid disease (AITD). Teasing out the genetic contribution to AITD over the past 40 years has helped unravel how immune disruption leads to disease onset. Breakthroughs in genome-wide association studies (GWAS) in the past decade have facilitated screening of a greater proportion of the genome, leading to the identification of a before unimaginable number of AITD susceptibility loci. This Review will focus on the new susceptibility loci identified by GWAS, what insights these loci provide about the pathogenesis of AITD and how genetic susceptibility loci shared between different autoimmune diseases could help explain disease co-clustering within individuals and families. This Review also discusses where future efforts should be focused to translate this step forward in our understanding of the genetic contribution to AITD into a better understanding of disease presentation and progression, and improved therapeutic options.© 2013 Macmillan Publishers Limited. All rights reserved.


Soni A.,University of Oxford
Arthritis and rheumatism | Year: 2012

To describe the temporal patterns of knee pain in a community-based cohort over 12 years. Data on self-reported knee pain at 4 time points over 12 years were analyzed in participants from the Chingford Women's Study of osteoarthritis (OA) and osteoporosis. Pain status was defined as any pain in the preceding month and pain on most days in the preceding month. This status was used to classify participants according to pain patterns of asymptomatic, persistent, incident, or intermittent pain. Multinomial logistic regression was used to identify baseline predictors for each pain pattern. Among the 489 women with complete followup data, the median age at baseline was 52 years (interquartile range [IQR] 48-58 years), the median body mass index (BMI) was 24.39 kg/m(2) (IQR 22.46-27.20), and 11.7% of the women had a Kellgren/Lawrence radiographic OA severity grade of ≥2 in at least one knee. Among subjects reporting any pain in the preceding month versus those reporting pain on most days in the preceding month, 9% versus 2% had persistent pain, 24% versus 16% had incident pain, and 29% versus 18% had intermittent pain. A higher BMI was predictive of persistent pain (odds ratio [OR] 1.14, 95% confidence interval [95% CI] 1.04-1.25) and incident pain (OR 1.10, 95% CI 1.02-1.18). The presence of radiographic knee OA was predictive of persistent pain (OR 3.70, 95% CI 1.34-10.28; P = 0.012), and reported knee injury was predictive of both persistent pain (OR 4.13, 95% CI 1.34-12.66; P = 0.013) and intermittent pain (OR 4.25, 95% CI 1.81-9.98; P = 0.001). Significant variability in the temporal fluctuation of self-reported knee pain was seen in this community-based prospective study over a period of 12 years, with few women consistently reporting knee pain at each time point. Distinct baseline predictors for each pain pattern were identified and may explain the observed heterogeneity of self-reported knee pain when pain status is measured at only one time point. Copyright © 2012 by the American College of Rheumatology.


De Gier J.,University of Melbourne | Essler F.H.L.,University of Oxford
Physical Review Letters | Year: 2011

We consider the one-dimensional asymmetric exclusion process with particle injection and extraction at two boundaries. The model is known to exhibit four distinct phases in its stationary state. We analyze the current statistics at the first site in the low and high density phases. In the limit of infinite system size, we conjecture an exact expression for the current large deviation function. © 2011 American Physical Society.


Pattinson K.T.S.,University of Oxford
Thorax | Year: 2015

Discordance of clinical symptoms with markers of disease severity remains a conundrum in a variety of respiratory conditions. The breathlessness of chronic lung disease correlates poorly with spirometry, yet is a better predictor of mortality. In chronic cough, symptoms are often evident without clear physical cause. In asthma, the terms 'over perceivers' and 'under perceivers' are common parlance. In all these examples, aberrant brain mechanisms may explain the mismatch between symptoms and pathology. Functional MRI is a non-invasive method of measuring brain function. It has recently become significantly advanced enough to be useful in clinical research and to address these potential mechanisms. This article explains how FMRI works, current understanding from FMRI in breathlessness, cough and asthma and suggests possibilities for future research. © 2015 BMJ Publishing Group Ltd & British Thoracic Society.


Cohen Kadosh R.,University of Oxford
The Stimulated Brain: Cognitive Enhancement Using Non-Invasive Brain Stimulation | Year: 2014

The Stimulated Brain�which garnered an Honorable Mention for Biomedicine & Neuroscience at the 2015 PROSE Awards from the Association of American Publishers�presents the first integration of findings on brain stimulation from different research fields with a primary focus on Transcranial Electrical Stimulation (tES), one of the most frequently used noninvasive stimulation methods. The last decade has witnessed a significant increase in the amount of research exploring how noninvasive brain stimulation can not only modulate but also enhance cognition and brain functions. However, although Transcranial Magnetic Stimulation (TMS) and particularly tES have the potential to become more widely applicable techniques (as they come with none of the risks associated with deep brain stimulation) the reference literature on these neurotechnologies has been sparse. This resource provides a broad survey of current knowledge, and also marks future directions in cognitive and neuro-enhancement. It expands our understanding of basic research findings from animals and humans, including clear translational benefits for applied research and the therapeutic use of noninvasive brain stimulation methods. The books coverage includes a primer that paves the way to a more advanced knowledge of tES and its physiological basis; current research findings on cognitive and neuro-enhancement in animals and typical and atypical human populations, such as neurological patients; and discussions of future directions, including specific neuroethical issues and pathways for collaboration and entrepreneurialism. © 2014 Elsevier Inc. All rights reserved.


Robinson D.P.,University of Oxford
Geophysical Journal International | Year: 2011

Broad-band body and mantle wave data are used to study the 2004 December 23, Tasman Sea earthquake. In common with other strike-slip earthquakes studied in the same fashion, the mantle wave data indicates that there are two pure-double couple constrained solutions, along with a range of mechanisms between them, that fit the data almost equally well. Aftershocks relocated for this study indicate that the rupture occurred on a fracture zone which bends sharply in the epicentral region. Horizontally polarised S body waves and P body waves are used to determine the rupture parameters. A model with two faults best fits the data. The northern fault plane, with strike 160°, dip 86° and rake 5°, is compatible with the first motion solution found in this study and has a strike consistent with the fracture zone north of the bend. The southern fault plane, with strike 178°, dip 54° and rake 65°, has a strike consistent with the portion of the fracture zone to the south of the bend and has a dip which can be explained by the style of deformation that the region is undergoing. The centroid moment tensor solution of the broad-band model is calculated and found to be consistent with the region of low misfit in mantle wave solution space. The broad-band solution has a moment of 1.53 × 1021N m (Mw 8.1), again, consistent with the mantle wave data. Slip propagated bilaterally with an approximate rupture velocity of ~3 kms-1~80 per cent of local shear wave speed. The rupture front is less well resolved to the south of the epicentre than to the north. The majority (~75 per cent) of moment originated from slip on the northern fault. The broad-band data requires significant slip below the oceanic Moho with as much as 70 per cent of moment due to slip in the brittle uppermost mantle in the preferred model. © 2011 The Authors Geophysical Journal International © 2011 RAS.


Anderson E.A.,University of Oxford
Organic and Biomolecular Chemistry | Year: 2011

The efficient, stereocontrolled construction of polycyclic ring systems has long presented a formidable challenge to synthetic chemists. Cascade reactions offer a 'quick fix' - building multiple rings in a single step - and often dramatically shorten a synthetic route. In this Emerging Area article, a selection of the most recent and impressive examples of applications of this tactic to natural product synthesis are discussed, which demonstrate the ambition and achievements of the modern synthetic chemist. © 2011 The Royal Society of Chemistry.


Martin C.M.,University of Oxford
Geotechnique Letters | Year: 2011

The numerical method known as finite-element limit analysis (FELA) is generally employed as a tool for obtaining lower and upper bounds on the exact collapse load of a perfectly plastic structure or continuum. Most applications of FELA in geotechnical engineering have focused on plane strain problems involving the classical Tresca and Mohr-Coulomb yield criteria, and considerable computational effort has been expended on the calculation of lower- and upper-bound solutions for particular problems. This paper discusses and demonstrates an alternative use of FELA - as a tool for ascertaining slip-line fields for plane strain problems. A simple but effective strategy for adaptive mesh refinement is a key feature of the process; it allows the layout of plastic regions, rigid regions and velocity discontinuities to be determined by inspection of the FELA mesh. The corresponding slip-line field can then be constructed numerically in the usual way. The examples presented are restricted to purely cohesive soil, but the same approach is applicable in principle to frictional or cohesive-frictional materials.


Malhi Y.,University of Oxford
Journal of Ecology | Year: 2012

1. Tropical forests account for one-third of the total metabolic activity of the Earth's land surface. Hence, understanding the controls on tropical forest photosynthesis and respiration, and the allocation of the products of photosynthesis to canopy, woody tissue and rhizosphere, is important to understand global ecosystem functioning. 2.I review how studies in tropical ecosystem ecology have progressed since their inception in the 1960s towards developing a quantitative, mechanistic and global description of the carbon cycle of tropical vegetation. 3.I present a synthesis of studies in tropical forest sites in the Americas and Asia for which gross primary productivity (GPP) has been reported, and a subset of these sites for which net primary productivity (NPP) and ecosystem carbon use efficiency (CUE) have been estimated. GPP ranges between 30 and 40Mg C ha -1year -1 in lowland moist tropical forests and declines with elevation. CUE in tropical forests is at the low end of the global range reported for forests. 4.A pathway and framework are presented to explain the link between photosynthesis and tropical forest biomass, and to explain differences in carbon cycling and biomass between forests. Variation in CUE and allocation of NPP can be as important as variation in GPP in explaining differences in tropical forest growth rates between sites. 5. Finally, I explore some of the key questions surrounding the functioning and future of tropical forests in the rapidly changing conditions of the early Anthropocene. 6. Synthesis. There have been significant recent advances in quantifying the carbon cycle of tropical forests, but our understanding of causes of variation amongst forests is still poor. Moreover, we should expect all tropical forests in the 21st century, whether intact or disturbed, to be undergoing rapid change in function and composition; the key challenge for tropical ecosystem ecologists is to determine and understand the major and most fundamental aspects of this change. © 2012 The Author. Journal of Ecology © 2012 British Ecological Society.


Lau J.Y.F.,University of Oxford
Behaviour Research and Therapy | Year: 2013

Anxiety disorders in children and adolescents are common and impairing. As many patients do not benefit from - or have difficulties accessing - frontline treatments, novel, effective and easy-to-deliver interventions are needed. Cognitive Bias Modification of Interpretations (CBM-I) training has been used to treat adult anxiety disorders. CBM-I methods train individuals to endorse benign rather than negative resolutions of ambiguous cues. Developmental extensions of CBM-I are important for several reasons. First, implementing CBM-I in symptomatic children and adolescents may facilitate early preventative gains. Second, as training uses simple learning mechanisms, CBM-I may reflect a developmentally-suitable strategy for shaping adaptive processing styles. Third, as this age range involves protracted neurocognitive maturation and associated plasticity, administering CBM-I early could drive powerful, long-lasting benefits for emotional development. Finally, data from CBM-I studies could inform the cognitive mechanisms involved in the genesis of early-emerging anxiety. This paper provides the first organised review of CBM-I studies conducted in children and adolescents, and contains suggestions for future research that may help realise the therapeutic potential of early CBM-I interventions. © 2013 Elsevier Ltd.


Spence C.,University of Oxford
Cell | Year: 2015

The perception of flavor is perhaps the most multisensory of our everyday experiences. The latest research by psychologists and cognitive neuroscientists increasingly reveals the complex multisensory interactions that give rise to the flavor experiences we all know and love, demonstrating how they rely on the integration of cues from all of the human senses. This Perspective explores the contributions of distinct senses to our perception of food and the growing realization that the same rules of multisensory integration that have been thoroughly explored in interactions between audition, vision, and touch may also explain the combination of the (admittedly harder to study) flavor senses. Academic advances are now spilling out into the real world, with chefs and food industry increasingly taking the latest scientific findings on board in their food design. © 2015 Elsevier Inc.


Field R.W.,University of Oxford | Pearce G.K.,Membrane Consultancy Associates
Advances in Colloid and Interface Science | Year: 2011

Critical flux theory evolved as a description of the upper bound in the operating envelope for controlled steady state environments such as cross-flow systems. However, in the application of UF membranes in the water industry, dead-end (direct-flow) designs are used. Direct-flow is a pseudo steady state operation with different fouling characteristics to cross-flow, and thus the critical flux concept has limited applicability. After a review of recent usage of the critical flux theory, an alternative concept for providing design guidelines for direct-flow systems namely that of the threshold flux is introduced. The concept of threshold flux can also be applicable to cross-flow systems. In more general terms the threshold flux can be taken to be the flux that divides a low fouling region from a high fouling region. This may be linked both to the critical flux concept and to the concept of a sustainable flux. The sustainable flux is the one at which a modest degree of fouling occurs, providing a compromise between capital expenditure (which is reduced by using high flux) and operating costs (which are reduced by restricting the fouling rate). Whilst the threshold flux can potentially be linked to physical phenomena alone, the sustainable flux also depends upon economic factors and is thus of a different nature to the critical and threshold fluxes. This distinction will be illustrated using some MBR data. Additionally the utility of the concept of a threshold flux will be illustrated using pilot plant data obtained for UF treatment of four sources of water. © 2011 Elsevier B.V. All rights reserved.


Singh B.,University Malaysia Sarawak | Daneshvar C.,University of Oxford
Clinical Microbiology Reviews | Year: 2013

Plasmodium knowlesi is a malaria parasite that is found in nature in long-tailed and pig-tailed macaques. Naturally acquired human infections were thought to be extremely rare until a large focus of human infections was reported in 2004 in Sarawak, Malaysian Borneo. Human infections have since been described throughout Southeast Asia, and P. knowlesi is now recognized as the fifth species of Plasmo-dium causing malaria in humans. The molecular, entomological, and epidemiological data indicate that human infections with P. knowlesi are not newly emergent and that knowlesi malaria is primarily a zoo-nosis. Human infections were undiagnosed until molecular detection methods that could distinguish P. knowlesi from the morphologically similar human malaria parasite P. malariae became available. P. knowlesi infections cause a spectrum of disease and are potentially fatal, but if detected early enough, infections in humans are readily treatable. In this review on knowlesi malaria, we describe the early studies on P. knowlesi and focus on the epidemiology, diagnosis, clinical aspects, and treatment of knowlesi malaria. We also discuss the gaps in our knowledge and the challenges that lie ahead in studying the epidemiology and pathogenesis of knowlesi malaria and in the prevention and control of this zoonotic infection. © 2013, American Society for Microbiology. All Rights Reserved.


Boyd I.L.,University of St. Andrews | Freer-Smith P.H.,Japan Forestry and Forest Products Research Institute | Gilligan C.A.,University of Cambridge | Godfray H.C.J.,University of Oxford
Science | Year: 2013

Trees and forests provide a wide variety of ecosystem services in addition to timber, food, and other provisioning services. New approaches to pest and disease management are needed that take into account these multiple services and the different stakeholders they benefit, as well as the likelihood of greater threats in the future resulting from globalization and climate change. These considerations will affect priorities for both basic and applied research and how trade and phytosanitary regulations are formulated.


Adland E.,University of Oxford
PloS one | Year: 2013

Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.


Gilbert S.C.,University of Oxford
Influenza and other Respiratory Viruses | Year: 2013

Despite the widespread availability and use of influenza vaccines, influenza still poses a considerable threat to public health. Vaccines against seasonal influenza do not offer protection against pandemic viruses, and vaccine efficacy against seasonal viruses is reduced in seasons when the vaccine composition is not a good match for the predominant circulating viruses. Vaccine efficacy is also reduced in older adults, who are one of the main target groups for vaccination. The continual threat of pandemic influenza, with the known potential for rapid spread around the world and high mortality rates, has prompted researchers to develop a number of novel approaches to providing immunity to this virus, focusing on target antigens which are highly conserved between different influenza A virus subtypes. Several of these have now been taken into clinical development, and this review discusses the progress that has been made, as well as considering the requirements for licensing these new vaccines and how they might be used in the future. © 2012 John Wiley & Sons Ltd.


Galione A.,University of Oxford
Cold Spring Harbor perspectives in biology | Year: 2011

Of the established Ca(2+) mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations. Recent studies have identified a new class of calcium release channel, the two-pore channels (TPCs), as the likely targets for NAADP. These channels are endolysosomal in localization where they mediate local Ca(2+) release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca(2+) mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca(2+) release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca(2+)-induced Ca(2+) release (CICR) channels at lysosomal-ER junctions. The third is to regulate plasma membrane excitability by the targeting of Ca(2+) release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca(2+)-activated channels. In this review, I discuss the role of NAADP-mediated Ca(2+) release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca(2+) signaling.


English K.,National University of Ireland, Maynooth | Wood K.J.,University of Oxford
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cellbased immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.© 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Adler M.J.,University of Oxford
Current topics in microbiology and immunology | Year: 2011

Small molecules which can mimic the key structural facets of protein secondary structure, in particular the α-helix, β-strand, and β-sheet, have been shown to be potent disruptors of protein-protein interactions. Researchers have recently taken the organizational imitation of protein secondary structure to a new level by using intramolecular hydrogen bonds as stabilizing forces in these small molecule mimetics. The inclusion of these interactions invokes a conformational bias of the system, allowing for greater control of the appearance, and thus often function, of these molecules by design.


Campbell I.D.,University of Oxford
Cold Spring Harbor perspectives in biology | Year: 2011

Integrins are large, membrane-spanning, heterodimeric proteins that are essential for a metazoan existence. All members of the integrin family adopt a shape that resembles a large "head" on two "legs," with the head containing the sites for ligand binding and subunit association. Most of the receptor dimer is extracellular, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains. These domains initiate the assembly of large signaling complexes and thereby bridge the extracellular matrix to the intracellular cytoskeleton. To allow cells to sample and respond to a dynamic pericellular environment, integrins have evolved a highly responsive receptor activation mechanism that is regulated primarily by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.


Salio M.,Weatherall Institute of Molecular Medicine | Silk J.D.,Weatherall Institute of Molecular Medicine | Yvonne Jones E.,University of Oxford | Cerundolo V.,Weatherall Institute of Molecular Medicine
Annual Review of Immunology | Year: 2014

Over the past 15 years, investigators have shown that T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules but also foreign and self-lipids in association with the nonclassical MHC class I-like molecules, CD1 proteins. In this review, we describe the most recent events in the field, with particular emphasis on (a) structural and functional aspects of lipid presentation by CD1 molecules, (b) the development of CD1d-restricted invariant natural killer T (iNKT) cells and transcription factors required for their differentiation, (c) the ability of iNKT cells to modulate innate and adaptive immune responses through their cross talk with lymphoid and myeloid cells, and (d) MR1-restricted and group I (CD1a, CD1b, and CD1c)-restricted T cells. © 2014 by Annual Reviews. All rights reserved.


Bennett D.L.H.,University of Oxford | Woods C.G.,University of Cambridge
The Lancet Neurology | Year: 2014

The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Nav1.8 (SCN10A) and Nav1.9 (SCN11A) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively. Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development-eg, using human sensory neurons differentiated from human induced pluripotent stem cells. Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development. © 2014 Elsevier Ltd.


Lee A.W.,University of Oxford
Journal of Clinical Epidemiology | Year: 2014

Objectives To identify and summarize published systematic reviews that report results of meta-analyses that combined direct and indirect comparisons. Study Design and Setting Narrative review of mixed treatment comparisons (MTCs) reported in systematic reviews of health interventions. MEDLINE, MEDLINE In-Process, Embase, CINAHL, DARE, the Cochrane Database of Systematic Reviews, and SIGLE were searched for reviews published up to June 2012 in which a meta-analysis had been conducted that combined direct and indirect comparisons among more than two interventions. Results Reviews reporting MTCs are difficult to identify when searching major databases. These databases offer no way to identify MTCs, and authors use various names when reporting them. Of the 201 eligible reviews identified, more than three-quarters had been published in full. MTC methods have been used to study a wide range of clinical topics. The reported use of these methods has increased rapidly since 2009, and results from MTCs are commonly used in health policy decisions, through the evidence considered in health technology assessments. Conclusion In view of the increasing use of MTCs, indexing of this study type in databases and a consensus on terminology and standards for conduct and reporting would be timely. © 2014 Elsevier Inc. All rights reserved.


Olver S.,University of Oxford
Foundations of Computational Mathematics | Year: 2011

We describe a new, spectrally accurate method for solving matrix-valued Riemann-Hilbert problems numerically. The effectiveness of this approach is demonstrated by computing solutions to the homogeneous Painlevé II equation. This can be used to relate initial conditions with asymptotic behavior. © 2010 SFoCM.


Green M.A.,University of New South Wales | Ho-Baillie A.,University of New South Wales | Snaith H.J.,University of Oxford
Nature Photonics | Year: 2014

The past two years have seen the unprecedentedly rapid emergence of a new class of solar cell based on mixed organic-inorganic halide perovskites. Although the first efficient solid-state perovskite cells were reported only in mid-2012, extremely rapid progress was made during 2013 with energy conversion efficiencies reaching a confirmed 16.2% at the end of the year. This increased to a confirmed efficiency of 17.9% in early 2014, with unconfirmed values as high as 19.3% claimed. Moreover, a broad range of different fabrication approaches and device concepts is represented among the highest performing devices-this diversity suggests that performance is still far from fully optimized. This Review briefly outlines notable achievements to date, describes the unique attributes of these perovskites leading to their rapid emergence and discusses challenges facing the successful development and commercialization of perovskite solar cells. © 2014 Macmillan Publishers Limited.


Sattentau Q.J.,University of Oxford
Current Opinion in HIV and AIDS | Year: 2014

Purpose of Review: This review aims to bring together recent developments relevant to the design of HIV-1 envelope glycoprotein-based immunogens to elicit broadly neutralizing antibodies (bNAbs). RECENT FINDINGS: The combined use of structural biology and deep sequencing of antigen-specific B-cell lineages has allowed cross-sectional and longitudinal views of antibody evolution towards broad and potent neutralization of HIV-1. Recent advances in molecular modelling allied with protein and glycoprotein engineering have fuelled the design of new-generation viral envelope glycoproteins (Env)-based antigens. SUMMARY: Although proof-of-principle for vaccine elicitation of bNAbs to HIV-1 is still lacking, many of the conceptual hurdles are being addressed. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


The three-dimensional structures of large biomolecules important in the function and mechanistic pathways of all living systems and viruses can be determined by x-ray diffraction from crystals of these molecules and their complexes. This area of crystallography is continually expanding and evolving, and the introduction of new methods that use the latest technology is allowing the elucidation of ever larger and more complex biological systems, which are now becoming tractable to structure solution. This review looks back at what has been achieved and forward at how current and future developments may allow technical challenges to be overcome.


Whittington R.,University of Oxford
Journal of Strategic Information Systems | Year: 2014

This review applauds the initiative to bring together Information Systems Strategy and Strategy-as-Practice research, as in this Special Issue. It highlights especially promising features of each of the empirical articles and develops an agenda for taking some of the themes further. In particular, the review points to opportunities for the intimate comparative investigation of episodes of Information Systems strategizing, for example by videoethnography; focus on the under-examined impacts of new or taken-for-granted Information Systems in strategy, for example big data, social media and Excel; and consideration of the political and discursive competence of Information Systems strategists in action, by comparison with other specialists. This agenda would be effectively advanced by joint work on the part of Information Systems and Strategy-as-Practice researchers.© 2014 Elsevier B.V. All rights reserved.


Ross G.G.,University of Oxford
European Physical Journal C | Year: 2014

Given that there is currently no direct evidence for supersymmetric particles at the LHC it is timely to re-evaluate the need for low scale supersymmetry and to ask whether it is likely to be discoverable by the LHC running at its full energy. We review the status of simple SUSY extensions of the Standard Model in the light of the Higgs discovery and the non-observation of evidence for SUSY at the LHC. The need for large radiative corrections to drive the Higgs mass up to 126 GeV and for the coloured SUSY states to be heavy to explain their non-observation introduces a little hierarchy problem and we discuss how to quantify the associated fine tuning. The requirement of low fine tuning requires non-minimal SUSY extensions and we discuss the nature and phenomenology of models which still have perfectly acceptable low fine tuning. A brief discussion of SUSY flavour-changing and CP-violation problems and their resolution is presented. © 2014 The Author(s).


Michl J.,University of Oxford
Nature Structural and Molecular Biology | Year: 2016

The tumor suppressor BRCA2 plays a key role in genome integrity by promoting replication-fork stability and homologous recombination (HR) DNA repair. Here we report that human cancer cells lacking BRCA2 rely on the Fanconi anemia protein FANCD2 to limit replication-fork progression and genomic instability. Our results identify a new role of FANCD2 in limiting constitutive replication stress in BRCA2-deficient cells, thereby affecting cell survival and treatment responses. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Hameroff S.,University of Arizona | Penrose R.,University of Oxford
Physics of Life Reviews | Year: 2014

The nature of consciousness, the mechanism by which it occurs in the brain, and its ultimate place in the universe are unknown. We proposed in the mid 1990's that consciousness depends on biologically 'orchestrated' coherent quantum processes in collections of microtubules within brain neurons, that these quantum processes correlate with, and regulate, neuronal synaptic and membrane activity, and that the continuous Schrödinger evolution of each such process terminates in accordance with the specific Diósi-Penrose (DP) scheme of 'objective reduction' ('OR') of the quantum state. This orchestrated OR activity ('Orch OR') is taken to result in moments of conscious awareness and/or choice. The DP form of OR is related to the fundamentals of quantum mechanics and space-time geometry, so Orch OR suggests that there is a connection between the brain's biomolecular processes and the basic structure of the universe. Here we review Orch OR in light of criticisms and developments in quantum biology, neuroscience, physics and cosmology. We also introduce a novel suggestion of 'beat frequencies' of faster microtubule vibrations as a possible source of the observed electro-encephalographic ('EEG') correlates of consciousness. We conclude that consciousness plays an intrinsic role in the universe. © 2013 Elsevier B.V.


Barua M.,University of Oxford
Biodiversity and Conservation | Year: 2011

Misrepresentation of terminology is a major impediment for attempts at enhancing public conservation literacy. Despite being critically important for improving conservation practice, there have been few systematic analyses of the popular use of conservation terminology. This paper draws from science communication studies and metaphor analysis, to examine how keystone, flagship and umbrella species concepts are used and represented in non-academic contexts. 557 news articles containing these terms were systematically analyzed. Mammals featured in 60% of articles on keystones, 55% on flagships and 63% on umbrella species. Number of articles explaining the terms keystone (35%) and flagship (31%) was low, and keystones were the most misrepresented term. Keystones were metaphorically linked with balance, flagships with representation and umbrella species with protection. These metaphors influenced public interpretation of scientific terminology, oriented actions towards select species, and led to a valuation of such actions. Together, the findings highlight three important aspects of popular use of conservation terminology: (1) communication is largely biased towards mammals, (2) everyday language plays a vital role in the interpretation of concepts, and (3) metaphors influence peoples' actions and understanding. Conservation biologists need to engage with issues of language if public conservation literacy is to be improved. Further evaluations of concepts with high public and policy relevance, systematic identification of communication shortfalls, and linguistic assessments prior to promoting new terms are potential ways of achieving this. © Springer Science+Business Media B.V.2011.


Nivette A.,University of Oxford
Theoretical Criminology | Year: 2014

One of the primary components of state stability and order is that citizens consider those in power just and legitimate. Citizens who perceive the state as legitimate are likely to consider its institutions a valid source of morality and social control. Theoretically, legitimacy should play an important role in criminal offending across countries. This link between state power and citizens-that is, legitimacy-has the potential to be an important social mechanism connecting state actions to individual criminal behaviours. With this in mind, this article explores how political legitimacy might affect levels of crime and violence across countries. A lack of legitimacy may lead citizens to (1) reject the monopoly of physical force to employ self-help and/or (2) withdraw commitment from institutions, breaking down social control. © The Author(s) 2013.


Didelot X.,University of Warwick | Maiden M.C.J.,University of Oxford
Trends in Microbiology | Year: 2010

Genetic exchange plays a defining role in the evolution of many bacteria. The recent accumulation of nucleotide sequence data from multiple members of diverse bacterial genera has facilitated comparative studies that have revealed many features of this process. Here we focus on genetic exchange that has involved homologous recombination and illustrate how nucleotide sequence data have furthered our understanding of: (i) the frequency of recombination; (ii) the impact of recombination in different parts of the genome; and (iii) patterns of gene flow within bacterial populations. Summarizing the results obtained for a range of bacteria, we survey evidence indicating that the extent and nature of recombination vary widely among microbiological species and often among lineages assigned to the same microbiological species. These results have important implications in studies ranging from epidemiological investigations to examination of the bacterial species problem. © 2010 Elsevier Ltd.


Bowness P.,University of Oxford
Annual Review of Immunology | Year: 2015

Possession of the human leukocyte antigen (HLA) class I molecule B27 is strongly associated with ankylosing spondylitis (AS), but the pathogenic role of HLA-B27 is unknown. Two broad theories most likely explain the role of HLA-B27 in AS pathogenesis. The first is based on the natural immunological function of HLA-B27 of presenting antigenic peptides to cytotoxic T cells. Thus, HLA-B27-restricted immune responses to self-antigens, or arthritogenic peptides, might drive immunopathology. B27 can also "behave badly," misfolding during assembly and leading to endoplasmic reticulum stress and autophagy responses. β2m-free B27 heavy chain structures including homodimers (B272) can also be expressed at the cell surface following endosomal recycling of cell surface heterotrimers. Cell surface free heavy chains and B272 bind to innate immune receptors on T, NK, and myeloid cells with proinflammatory effects. This review describes the natural function of HLA-B27, its disease associations, and the current theories as to its pathogenic role. © 2015 by Annual Reviews. All rights reserved.


Rutz C.,University of Oxford
Current Biology | Year: 2012

The fundamental currency of normative models of animal decision making is Darwinian fitness. In foraging ecology, empirical studies typically assess foraging strategies by recording energy intake rates rather than realized reproductive performance [1]. This study provides a rare empirical link, in a vertebrate predator-prey system, between a predator's foraging behavior and direct measures of its reproductive fitness. Goshawks Accipiter gentilis selectively kill rare color variants of their principal prey, the feral pigeon Columba livia, presumably because targeting odd-looking birds in large uniform flocks helps them overcome confusion effects and enhances attack success [2-4]. Reproductive performance of individual hawks increases significantly with their selectivity for odd-colored pigeons, even after controlling for confounding age effects. Older hawks exhibit more pronounced dietary preferences, suggesting that hunting performance improves with experience [5, 6]. Intriguingly, although negative frequency-dependent predation by hawks exerts strong selection against rare pigeon phenotypes [7], pigeon color polymorphism is maintained through negative assortative mating [8]. © 2012 Elsevier Ltd.


Faizal M.,University of Oxford
Classical and Quantum Gravity | Year: 2012

In this paper, we construct a model for group field cosmology. The classical equations of motion for the non-interactive part of this model generate the Hamiltonian constraint of loop quantum gravity for a homogeneous isotropic universe filled with a scalar matter field. The interactions represent topology changing processes that occur due to joining and splitting of universes. These universes in the multiverse are assumed to obey both bosonic and fermionic statistics, and so a supersymmetric multiverse is constructed using superspace formalism. We also introduce gauge symmetry in this model. The supersymmetry and gauge symmetry are introduced at the level of third quantized fields, and not the second quantized ones. This is the first time that supersymmetry has been discussed at the level of third quantized fields. © 2012 IOP Publishing Ltd.


Blundell S.J.,University of Oxford
Physical Review Letters | Year: 2012

An analysis is presented of the behavior of muons in the low-temperature state in spin ice. It is shown in detail how the behavior observed in some previous muon experiments on spin ice in a weak transverse field may result from the macroscopic stray field of magnetized spin ice. A model is presented which allows these macroscopic field effects to be simulated and the results agree with experiment. The persistent spin dynamics at low temperature originate from the sample and could be a muon-induced implantation effect that is operative in out-of-equilibrium systems with long relaxation times. © 2012 American Physical Society.


Cavalier-Smith T.,University of Oxford
Cold Spring Harbor Perspectives in Biology | Year: 2014

Three kinds of cells exist with increasingly complex membrane-protein targeting: Unibacteria (Archaebacteria, Posibacteria) with one cytoplasmic membrane (CM); Negibacteria with a two-membrane envelope (inner CM; outer membrane [OM]); eukaryotes with a plasma membrane and topologically distinct endomembranes and peroxisomes. I combine evidence from multigene trees, palaeontology, and cell biology to show that eukaryotes and archaebacteria are sisters, forming the clade neomura that evolved ~1.2 Gy ago from a posibacterium, whose DNA segregation and cell division were destabilized by murein wall loss and rescued by the evolving novel neomuran endoskeleton, histones, cytokinesis, and glycoproteins. Phagotrophy then induced coevolving serial major changes making eukaryote cells, culminating in two dissimilar cilia via a novel gliding-fishing-swimming scenario. I transfer Chloroflexi to Posibacteria, root the universal tree between them and Heliobacteria, and argue that Negibacteria are a clade whose OM, evolving in a green posibacterium, was never lost. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.


Ashrafian H.,University of Oxford
PLoS genetics | Year: 2010

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.


Viles H.A.,University of Oxford
Earth Surface Processes and Landforms | Year: 2013

Weathering is linked complexly to the erosion and evolution of rock slopes. Weathering influences both the strength of rock slopes and the stresses that act upon them. While weathering has often been portrayed in an over-simplified way by those studying rock slope instability, in reality it consists of multiple processes, acting over different spatial and temporal scales, with many complex inter-linkages. Through a demonstration of the sources of non-linearities in rock slope weathering systems and their implications for rock slope instability, this paper proposes five key linkages worthy of further study. © 2012 John Wiley & Sons, Ltd.


Goodwin A.L.,University of Oxford
Nature Materials | Year: 2010

Barbour and co-workers have defined a crystal of (S,S)-octa-3,5-diyn-2,7- diol, the packing arrangement of an organic dumbbell-shaped molecule, which is expected to bring about a large thermal contraction of its crystal lattice. The dumbbells stack such that the hydrogen bonds at their ends form helices running parallel to one of the crystal axes. This arrangement connects the molecules in a similar way to the flexible networks suggesting the large thermal expansion between molecules might also bring about NT. Barbour's crystal is held together between the molecules and hydrogen bonds between the OH groups at either end of the dumbells. The results of Barbour and co-workers highlight the importance of looking to weakly bound materials for extreme, and extremely useful, mechanical behavior.


Snaith H.J.,University of Oxford
Advanced Functional Materials | Year: 2010

For an ideal solar cell, a maximum solar-to-electrical power conversion efficiency of just over 30% is achievable by harvesting UV to near IR photons up to 1.1eV. Dye-sensitized solar cells (DSCs) are, however, not ideal. Here, the electrical and optical losses in the dye-sensitized system are reviewed, and the main losses in potential from the conversion of an absorbed photon at the optical bandgap of the sensitizer to the open-circuit voltage generated by the solar cell are specifically highlighted. In the first instance, the maximum power conversion efficiency attainable as a function of optical bandgap of the sensitizer and the "loss-in-potential" from the optical bandgap to the open-circuit voltage is estimated. For the best performing DSCs with current technology, the loss-in-potential is -0.75eV, which leads to a maximum power-conversion efficiency of 13.4% with an optical bandgap of 1.48 eV (840 nm absorption onset). Means by which the loss-in-potential could be reduced to 0.4 eV are discussed; a maximum efficiency of 20.25% with an optical bandgap of 1.31 eV (940 nm) is possible if this is achieved © 2010 WILEY-VCH Verlag GmbH & Co. KCaA.


Maiden M.C.,University of Oxford
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The development and implementation of conjugate polysaccharide vaccines against invasive bacterial diseases, specifically those caused by the encapsulated bacteria Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, has been one of the most effective public health innovations of the last 25 years. These vaccines have resulted in significant reductions in childhood morbidity and mortality worldwide, with their effectiveness due in large part to their ability to induce long-lasting immunity in a range of age groups. At the population level this immunity reduces carriage and interrupts transmission resulting in herd immunity; however, these beneficial effects can be counterbalanced by the selection pressures that immunity against carriage can impose, potentially promoting the emergence and spread of virulent vaccine escape variants. Studies following the implementation of meningococcal serogroup C vaccines improved our understanding of these effects in relation to the biology of accidental pathogens such as the meningococcus. This understanding has enabled the refinement of the implementation of conjugate polysaccharide vaccines against meningitis-associated bacteria, and will be crucial in maintaining and improving vaccine control of these infections. To date there is little evidence for the spread of virulent vaccine escape variants of the meningococcus and H. influenzae, although this has been reported in pneumococci.


Davies R.,University of Oxford
Journal of High Energy Physics | Year: 2012

Supersymmetric models in which the gauginos acquire Dirac masses, rather than Majorana masses, offer an appealing alternative to the minimal supersymmetric standard model, especially in the light of the bounds set on superpartner masses by the 2011 LHC data. Dirac gauginos require the presence of chiral multiplets in the adjoint representation of the gauge group, and the realisation of such scenarios in F-theory is the subject of this paper. The chiral adjoints drastically alter the usual picture of gauge coupling unifi- cation, but this is disturbed anyway in F-theory models with non-trivial hypercharge ux. The interplay between these two factors is explored, and it is found for example that viable F-theory unification can be achieved at around the reduced Planck scale, if there is an extra vector-like pair of singlet leptons with TeV-scale mass. I then discuss the conditions which must be satisffed by the geometry and hypercharge ux of an F-theory model with Dirac gauginos. One nice possibility is for the visible sector to be localised on a K3 surface, and this is discussed in some detail. Finally, I describe how to achieve an unbroken discrete R-symmetry in such compactifications, which is an important ingredient in many models with Dirac gauginos, and write down a simple example which has adjoint chiral multiplets, an appropriate R-symmetry, and allows for viable breaking of SU(5) by hypercharge ux. © 2012 SISSA.


Nutritional factors may influence the risk of developing prostate cancer, but understanding of this topic is poor. This chapter discusses research on this subject, mostly from the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort which includes 150,000 men recruited in the 1990s in eight European countries. So far the EPIC collaborators have published analyses of the relationship of prostate cancer risk with the intake of a range of foods and nutrients, and with blood-based markers of nutritional factors, on up to nearly 3,000 incident cases of prostate cancer. Most of the results of these analyses have been null, with no clear indication that the risk for prostate cancer is related to intakes of meat, fish, fruit, vegetables, fibre, fat or alcohol or with blood levels of fatty acids, carotenoids, tocopherols, B vitamins, vitamin D, or selenium. There is some evidence from EPIC that risk may be increased in men with a high intake of protein from dairy products, and analyses of hormone levels have shown that risk is higher in men with relatively high blood levels of insulin-like growth factor-I (IGF-I). More research is needed to better describe the relationships of prostate cancer risk with IGF-I and related hormones, and to better understand whether nutritional factors may influence risk through hormones or perhaps by other mechanisms. © 2014 Springer-Verlag Berlin Heidelberg.


Marzari N.,Theory and Simulation of Materials THEOS | Mostofi A.A.,Imperial College London | Yates J.R.,University of Oxford | Souza I.,University of the Basque Country | And 2 more authors.
Reviews of Modern Physics | Year: 2012

The electronic ground state of a periodic system is usually described in terms of extended Bloch orbitals, but an alternative representation in terms of localized "Wannier functions" was introduced by Gregory Wannier in 1937. The connection between the Bloch and Wannier representations is realized by families of transformations in a continuous space of unitary matrices, carrying a large degree of arbitrariness. Since 1997, methods have been developed that allow one to iteratively transform the extended Bloch orbitals of a first-principles calculation into a unique set of maximally localized Wannier functions, accomplishing the solid-state equivalent of constructing localized molecular orbitals, or "Boys orbitals" as previously known from the chemistry literature. These developments are reviewed here, and a survey of the applications of these methods is presented. This latter includes a description of their use in analyzing the nature of chemical bonding, or as a local probe of phenomena related to electric polarization and orbital magnetization. Wannier interpolation schemes are also reviewed, by which quantities computed on a coarse reciprocal-space mesh can be used to interpolate onto much finer meshes at low cost, and applications in which Wannier functions are used as efficient basis functions are discussed. Finally the construction and use of Wannier functions outside the context of electronic-structure theory is presented, for cases that include phonon excitations, photonic crystals, and cold-atom optical lattices. © 2012 American Physical Society.


Brown G.,University of Oxford
Journal of Inherited Metabolic Disease | Year: 2014

Thiamine, in the form of thiamine pyrophosphate, is a cofactor for a number of enzymes which play important roles in energy metabolism. Although dietary thiamine deficiency states have long been recognised, it is only relatively recently that inherited defects in thiamine uptake, activation and the attachment of the active cofactor to target enzymes have been described, and the underlying genetic defects identified. Thiamine is transported into cells by two carriers, THTR1 and THTR2, and deficiency of these results in thiamine-responsive megaloblastic anaemia and biotin-responsive basal ganglia disease respectively. Defective synthesis of thiamine pyrophosphate has been found in a small number of patients with episodic ataxia, delayed development and dystonia, while impaired transport of thiamine pyrophosphate into the mitochondrion is associated with Amish lethal microcephaly in most cases. In addition to defects in thiamine uptake and metabolism, patients with pyruvate dehydrogenase deficiency and maple syrup urine disease have been described who have a significant clinical and/or biochemical response to thiamine supplementation. In these patients, an intrinsic structural defect in the target enzymes reduces binding of the cofactor and this can be overcome at high concentrations. In most cases, the clinical and biochemical abnormalities in these conditions are relatively non-specific, and the range of recognised presentations is increasing rapidly at present as new patients are identified, often by genome sequencing. These conditions highlight the value of a trial of thiamine supplementation in patients whose clinical presentation falls within the spectrum of documented cases. © 2014 SSIEM and Springer Science+Business Media.


Rogers H.,University of Oxford
Oxford Review of Economic Policy | Year: 2011

In the early 2000s US gas production was in slow but steady decline despite increasing drilling activity. As US natural gas prices rose in response to the resulting tight market, the only supply-side solution appeared to lie in the development of liquefied natural gas (LNG) projects in the Middle East and Africa for importation to the North American market. Almost unnoticed in its early stages, the US shale gas phenomenon gathered momentum from 2004 onwards through the combination and application of two proven technologies, namely horizontal drilling and pressure-induced hydraulic fracturing or 'fracking'. The pioneers of this approach were not the majors but the much smaller, domestically focused 'independent' upstream companies who, together with a well-established and adaptable service sector, instigated what is now commonly referred to as the 'shale gas boom' and which has increased US natural gas production to the point where only minimal imports of LNG are expected to be required for the foreseeable future. This paper looks at the genesis of the US shale gas industry, the intensive nature of its operations, and the factors which have underpinned its success to date. It also addresses the question of whether similar developments might be expected in Europe and what specific challenges would need to be overcome. In a world where increased LNG supply has created trade flow and price linkages between regional gas markets, the paper also examines the impact US shale production has had on other markets through the re-direction of LNG originally intended for the US market. © The Author 2011. Published by Oxford University Press.


Glitsch M.D.,University of Oxford
FASEB Journal | Year: 2010

In the mammalian nervous system, stimulation of G-protein-coupled type I glutamate receptors triggers various forms of neuronal plasticity, including cerebellar long-term depression and hippocampal longterm potentiation. Activation of these receptors in the cerebellum also leads to a slow excitatory postsynaptic current mediated by nonselective TRPC3 cation channels. How TRPC3 channels are opened is unknown, although it is widely thought that channel gating requires phospholipase C activation. Using the patchclamp technique and immunohistochemistry in rat cerebellar slices, we show that metabotropic glutamate receptors activate TRPC3 channels through the small GTP-binding protein Rho and subsequent phospholipase D stimulation. TRPC3 channel gating is independent of phospholipase C activity. These results reveal a new mechanism for the gating of the ubiquitous TRPC3 channel and identify a key role for phospholipase D in the generation of the slow excitatory postsynaptic current in cerebellar Purkinje cells. © FASEB.


Garman E.F.,University of Oxford
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

Infection by the influenza virus depends firstly on cell adhesion via the sialic-acid-binding viral surface protein, haemagglutinin, and secondly on the successful escape of progeny viruses from the host cell to enable the virus to spreadto other cells.To achieve the latter, influenza uses another glycoprotein, the enzyme neuraminidase (NA), to cleave the sialic acid receptors from the surface of the original host cell. This paper traces the development of anti-influenza drugs, from the initial suggestion by MacFarlane Burnet in 1948 that an effective ‘competitive poison’ of the virus’ NA might be useful in controlling infection by the virus, through to the determination of the structure of NA by X-ray crystallography and the realization of Burnet’s idea with the design of NA inhibitors. A focus is the contribution of the late William Graeme Laver, FRS, to this research. © 2014 The Author(s) Published by the Royal Society. All rights reserved.


One of the principal aims of modern drug design is the targeted delivery of drugs within the body, such as to the central nervous system, combined with their exclusion from the liver and kidneys, which break down foreign molecules and subsequently eliminate them. Many of the commonly prescribed drugs are transported into cells and across the plasma membrane via endogenous membrane transporters, whose principal roles are the uptake of essential nutrients for metabolism. In many cases, such drug transport is serendipitous as they are simply mistaken as 'natural' compounds. Many of these transporters could, however, be targeted more efficiently, improving drug absorption, distribution and retention. The molecular details of these drug-transporter interactions, however, are at best poorly understood, in large part through the absence of any high-resolution structural information. To address this issue, we recently determined the structure of a prokaryotic peptide transporter, PepTSo from Shewanella oneidensis, which shares a high degree of sequence similarity and functional characteristics with the human PepT1 and PepT2 proteins. PepT1 and PepT2 contribute significantly to the oral bioavailability and pharmacokinetic properties of a number of important drug families, including antibiotics, antivirals and anticancer agents. The crystal structure of PepTSo provides the first high-resolution model of a drug importer and provides the starting point for understanding drug and peptide transport within the human body. ©The Authors Journal compilation ©2011 Biochemical Society.


Heyes C.,University of Oxford
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Social learning strategies (SLSs) enable humans, non-human animals, and artificial agents to make adaptive decisions about when they should copy other agents, and who they should copy. Behavioural ecologists and economists have discovered an impressive range of SLSs, and explored their likely impact on behavioural efficiency and reproductive fitness while using the ‘phenotypic gambit’; ignoring, or remaining deliberately agnostic about, the nature and origins of the cognitive processes that implement SLSs. Here I argue that this ‘blackboxing’ of SLSs is no longer a viable scientific strategy. It has contributed, through the ‘social learning strategies tournament’, to the premature conclusion that social learning is generally better than asocial learning, and to a deep puzzle about the relationship between SLSs and cultural evolution. The puzzle can be solved by recognizing that whereas most SLSs are ‘planetary’—they depend on domain-general cognitive processes—some SLSs, found only in humans, are ‘cook-like’—they depend on explicit, metacognitive rules, such as copy digital natives. These metacognitive SLSs contribute to cultural evolution by fostering the development of processes that enhance the exclusivity, specificity, and accuracy of social learning. © 2016 The Author(s) Published by the Royal Society. All rights reserved.


Cowen P.J.,University of Oxford
British Journal of Psychiatry | Year: 2011

Fifty years ago pharmacological discoveries transformed psychiatry but progress since then has been relatively slow and there is unease about the role of industry. Despite this, the possibilities of pharmacological treatment have improved in recent years but exploiting developments for the benefit of patients requires psychotherapeutic skill as well as a high level of scientific knowledge.


McCormack D.P.,University of Oxford
Annals of the Association of American Geographers | Year: 2010

Remote sensing is an important geospatial technique employed across the discipline, yet it remains tangential to the conceptual and empirical concerns of cultural geographers. A modified understanding of remote sensing can, however, inform cultural geographical research into the persistence and circulation of spectral geographies. Revisiting a specific episode of Arctic exploration-the 1897 Andrée Balloon Expedition to the North Pole-provides a vehicle through which to substantiate this claim. The remains of the expedition, including objects, diaries, photographic film, and human remains, were found on a remote, ice-covered Arctic island in 1930. Over time these remains have become generative of a spectral afterlife: a dis