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Imperial College London is a public research university located in London, United Kingdom. As a former constituent college of the federal University of London, it became fully independent during the commemoration of its centenary on 9 July 2007. Imperial has grown through mergers, including with St Mary's Hospital Medical School , the National Heart and Lung Institute and the Charing Cross and Westminster Medical School . Imperial College Business School was established in 2003 and its building opened by the Queen of England in 2004.Imperial is organised into four main faculties: science, engineering, medicine and business; within the school there are over 40 departments, institutes and research centres. Imperial has around 13,500 students and 3,330 academic and research staff. Imperial's main campus is located in the South Kensington area of London, with additional campuses in Chelsea, Hammersmith, Paddington, Silwood Park, Wye College, and Singapore, making it one of the largest estates of any UK tertiary institution.Imperial is a major centre for biomedical research with the research staff having a total income of £822 million in 2012/13. Imperial is a founding member of the Francis Crick Institute and Imperial College Healthcare. Imperial is a member of the Association of Commonwealth Universities, the European University Association, the Association of MBAs, the G5, the League of European Research Universities, Oak Ridge Associated Universities and the Russell Group. Along with Cambridge and Oxford, Imperial, forms a corner of the "golden triangle" of British universities.Imperial is one of the most selective British universities. Imperial is consistently ranked among the top universities in the world, ranking 2nd in the 2014/15 QS World University Rankings and 9th in the 2014/15 Times Higher Education World University Rankings. In a corporate study carried out by The New York Times, its graduates were one of the most valued globally. Imperial's alumni and faculty include 15 Nobel laureates, 2 Fields Medalists, 70 Fellows of the Royal Society, 82 Fellows of the Royal Academy of Engineering, and 78 Fellows of the Academy of Medical science. Wikipedia.


Birch A.M.,Imperial College London
Biochemical Society Transactions | Year: 2014

Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD. The actual role of astrocytes in AD remains elusive, as they seem to adopt different functions dependent on disease progression and the extent of accompanying parenchymal inflammation. Astrocytes may contribute to the clearance of amyloid β-peptide (Aβ) and restrict the spread of inflammation in the brain. Conversely, they may contribute to neurodegeneration in AD by releasing neurotoxins and neglecting crucial metabolic roles. The present review summarizes current evidence on the multi-faceted functions of astrocytes in AD, highlighting the significant scope available for future therapeutic targets. ©The Authors Journal compilation ©2014 Biochemical Society.


Whilst the heritable nature of Type 2 diabetes has been recognized for many years, only in the past two decades have linkage analyses in families and genome-wide association studies in large populations begun to reveal the genetic landscape of the disease in detail. Whilst the former have provided a powerful means of identifying the genes responsible for monogenic forms of the disease, the latter highlight relatively large genomic regions. These often harbour multiple genes, whose relative contribution to exaggerated disease risk is uncertain. In the present study, the approaches that have been used to dissect the role of just a few (TCF7L2, SLC30A8, ADCY5, MTNR1B and CDKAL1) of the ~ 500 genes identified at dozens of implicated loci are described. These are usually selected based on the strength of their effect on disease risk, and predictions as to their likely biological role. Direct determination of the effects of identified polymorphisms on gene expression in disease-relevant tissues, notably the pancreatic islet, are then performed to identify genes whose expression is affected by a particular polymorphism. Subsequent functional analyses then involve perturbing gene expression in vitro in β-cell lines or isolated islets and in vivo in animal models. Although the majority of polymorphisms affect insulin production rather than action, and mainly affect the β cell, effects via other tissues may also contribute, requiring careful consideration in the design and interpretation of experiments in model systems. These considerations illustrate the scale of the task needed to exploit genome-wide association study data for the development of new therapeutic strategies. © 2014 Diabetes UK.


The last few years have witnessed a revolution in the diagnostic microbiology laboratory with the emergence of matrix assisted laser desorption/ionisation time-offlight mass spectrometry (MALDI- TOF MS) as an indispensible tool in microbial identification. In many laboratories this has superseded biochemical profiling. A mass spectrum is acquired from an unknown microorganism and this proteomic fingerprint is then compared with a database of reference spectra to ascertain the likely genus and species identity. The reproducibility of this method is facilitated by the analysis of continually produced, highly abundant proteins (mainly ribosomal proteins) in the mass range 2000 to 20 000 Da. MALDI- TOF MS is reliable and rapid and has the ability to determine the identity of an isolate from culture in a matter of minutes rather than the hours or days required by more traditional methods. In addition to microbial identification of cultured isolates, work is underway to extend the utility of MALDI- TOF MS to include bacterial identification directly from clinical samples as well as providing timely information regarding antibiotic resistance and typing of different micro-organisms.


Clark P.,Imperial College London
Thorax | Year: 2014

Ectodomain shedding is the proteolytic cleavage of cell surface proteins resulting in the loss of the extracellular domains. This mechanism is important in a variety of normal and pathological processes, including growth factor signalling, cell adhesion, inflammation and cell survival. Elevated protease activity in the lungs is a key pathological mechanism in emphysema which could enhance ectodomain shedding in lung cells. Here, the major steps and consequences of ectodomain shedding are reviewed.


Treat N.D.,Imperial College London | Chabinyc M.L.,University of California at Santa Barbara
Annual Review of Physical Chemistry | Year: 2014

Thin-film solar cells are an important source of renewable energy. The most efficient thin-film solar cells made with organic materials are blends of semiconducting polymers and fullerenes called the bulk heterojunction (BHJ). Efficient BHJs have a nanoscale phase-separated morphology that is formed during solution casting. This article reviews recent work to understand the nature of the phase-separation process resulting in the formation of the domains in polymer-fullerene BHJs. The BHJ is now viewed as a mixture of polymer-rich, fullerene-rich, and mixed polymer-fullerene domains. The formation of this structure can be understood through fundamental knowledge of polymer physics. The implications of this structure for charge transport and charge generation are given. Copyright © 2014 by Annual Reviews.


Dalakas M.C.,Imperial College London
Current Treatment Options in Neurology | Year: 2010

Polyneuropathies associated with IgM monoclonal gammopathies comprise a distinct entity. In spite of the apparent pathogenicity of the IgM antibodies and the specific immunoreactivity to myelin antigens, the disease has been difficult to treat. This review describes the clinical phenotype, addresses recent data on immunoreactivity of IgM to various nerve antigens, and discusses the latest progress on treatment. Most of these patients present with paresthesias and sensory ataxia followed by a varying degree of sensorimotor deficits. In more than 75% of the patients, the monoclonal IgM recognizes myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), best detected by ELISA, or other peripheral nerve glycolipids. Recent experiments have demonstrated that animals immunized with SGPG develop sensory ataxia, suggesting a pathogenic role for this antigen. Although cladribine, cyclophosphamide with prednisone, and intravenous immunoglobulin have offered transient benefits to some patients, most have remained treatment-resistant. Open label studies and a recent randomized controlled trial indicate that rituximab is emerging as the best agent available, providing long-term benefits to almost half of these patients. Rituximab appears to work by suppressing the IgM as well as the anti-MAG antibodies and by inducing immunoregulatory T cells. Patients with more sensory deficits and higher anti-MAG antibodies are more likely to respond but may require re-treatment after several months. These encouraging results need confirmation with a larger trial. Data on long-term efficacy and immune markers associated with response to therapy or need for re-treatment are still needed. © Springer Science+Business Media, LLC 2010.


Jayasena C.N.,Institute of Reproductive and Developmental Biology | Franks S.,Imperial College London
Nature Reviews Endocrinology | Year: 2014

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. The syndrome is typified by its heterogeneous presentation, which includes hirsutism (a function of hypersecretion of ovarian androgens), menstrual irregularity and infertility (that is due to infrequent or absent ovulation). Furthermore, PCOS predisposes patients to metabolic dysfunction and an increased risk of type 2 diabetes mellitus (T2DM). The aetiology of the syndrome has a major genetic component. Obesity exacerbates the insulin resistance that is a feature of PCOS in many women and amplifies the clinical and biochemical abnormalities. In clinical practice, the choice of investigations to be done depends mainly on the presenting symptoms. The approach to management is likewise dependent on the presenting complaint. Symptoms of androgen excess (hirsutism, acne and alopecia) require cosmetic measures, suppression of ovarian androgen function and anti-androgen therapy, alone or in combination. Ovulation rate is improved by diet and lifestyle intervention in overweight individuals but induction of ovulation by, in the first instance, anti-estrogens is usually required. Monitoring of glucose is important in overweight women and/or those with a family history of T2DM. Metformin is indicated for women with impaired glucose tolerance but whether this drug is otherwise useful in women with PCOS remains debatable. © 2014 Macmillan Publishers Limited. All rights reserved.


Pawar S.,Imperial College London
Advances in Ecological Research | Year: 2015

Body size determines key behavioral and life history traits across species, as well as interactions between individuals within and between species. Therefore, variation in sizes of immigrants, by exerting variation in trophic interaction strengths, may drive the trajectory and outcomes of community assembly. Here, I study the effects of size variation in the immigration pool on assembly dynamics and equilibrium distributions of sizes and consumer-resource size-ratios using a general mathematical model. I find that because small sizes both, improve the ability to invade and destabilize the community, invasibility and stability pull body size distributions in opposite directions, favoring an increase in both size and size-ratios during assembly, and ultimately yielding a right-skewed size and a symmetric size-ratio distribution. In many scenarios, the result at equilibrium is a systematic increase in body sizes and size-ratios with trophic level. Thus these patterns in size structure are 'signatures' of dynamically constrained, non-neutral community assembly. I also show that for empirically feasible distributions of body sizes in the immigration pool, immigration bias in body sizes cannot counteract dynamical constraints during assembly and thus signatures emerge consistently. I test the theoretical predictions using data from nine terrestrial and aquatic communities and find strong evidence that natural communities do indeed exhibit such signatures of dynamically constrained assembly. Overall, the results provide new measures to detect general, non-neutral patterns in community assembly dynamics, and show that in general, body size is dominant trait that strongly influences assembly and recovery of natural communities and ecosystems. © 2015 Elsevier Ltd.


Need A.C.,Imperial College London | Goldstein D.B.,Duke University
Neuron | Year: 2014

The new GWAS from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) clearly validates a genetic approach to understanding schizophrenia. The challenge now remains to track down the contributing genes and to develop appropriate models to elucidate the biological effects of the contributing variants. © 2014 Elsevier Inc.


Sherlock M.,Imperial College London
Physical Review Letters | Year: 2010

A generalized Ohm's law is derived for a system composed of a background magnetohydrodynamic plasma and a lower density relativistic charged-particle distribution. The interpretation of Ohmic electric fields occurring due to force balance breaks down for such a system and instead an approach based on Maxwell's equations along with the particle flux equations is necessary. Three additional terms arise in Ohm's law and each is verified numerically. © 2010 The American Physical Society.


Coppins M.,Imperial College London
Physical Review Letters | Year: 2010

A misty plasma is defined as a plasma containing small liquid droplets. In such a system, the droplets will undergo total electrostatic breakup if their charge exceeds the well-known Rayleigh limit. This imposes a minimum size on the droplets. Electrostatic breakup is a significant mechanism limiting droplet survival in a wide range of plasma applications, including plasma-enhanced chemical vapor deposition and fusion tokamaks. © 2010 The American Physical Society.


Hoare B.,Humboldt University of Berlin | Tseytlin A.A.,Imperial College London
Nuclear Physics B | Year: 2013

We consider superstring theory on AdS3×S3×T4 supported by a combination of RR and NSNS 3-form fluxes (with parameter of the NSNS 3-form q). This theory interpolates between the pure RR flux model (. q=0) whose spectrum is expected to be described by a (thermodynamic) Bethe ansatz and the pure NSNS flux model (. q=1) which is described by the supersymmetric extension of the SL(2,R)×SU(2) WZW model. As a first step towards the solution of this integrable theory for generic value of q we compute the corresponding tree-level S-matrix for massive BMN-type excitations. We find that this S-matrix has a surprisingly simple dependence on q: the diagonal amplitudes have exactly the same structure as in the q=0 case but with the BMN dispersion relation e2=p2+1 replaced by the one with shifted momentum and mass, e2=(p±q)2+1?q2. The off-diagonal amplitudes are then determined from the classical Yang-Baxter equation. We also construct the Pohlmeyer-reduced model corresponding to this superstring theory and find that it depends on q only through the rescaled mass parameter, μ→√1-q2μ, implying that its relativistic S-matrix is q-independent. © 2013 Elsevier B.V.


Rzepa H.S.,Imperial College London
Nature Chemistry | Year: 2010

The chemistry of helium has hitherto been confined to experimental and theoretical analysis of small molecules containing three to five atoms in the gas phase. Here a new suggestion is made for compounds of helium deriving from a recent proposal that five-coordinate carbon might be captured as a frozen SN2 transition state. A series of logical steps, originally discussed as postings and comments to two blogs, led to the outcome described here of a central hypervalent atom bound on one face by a small cyclic carbon ligand, with the other free face having an interaction to a helium atom with the topological properties of a charge-shift rather than a covalent bond. Although high-level theory predicts these helium bonds to be quite short with relatively high stretching frequencies, the kinetic barriers to the loss of helium are predicted to be small, and are not increased by the strategy of having bulky substituents on the ring ligand. © 2010 Macmillan Publishers Limited. All rights reserved.


Lucy L.B.,Imperial College London
Astronomy and Astrophysics | Year: 2012

A two-component phenomenological model developed originally for ζ Puppis is revised in order to model the outflows of late-type O dwarfs that exhibit the weak-wind phenomenon. With the theory's standard parameters for a generic weak-wind star, the ambient gas is heated to coronal temperatures ≈ 3 × 10 6 K at radii ≥ 1.4 R, with cool radiation-driven gas being then confined to dense clumps with filling factor ≈ 0.02. Radiative driving ceases at radius ≈ 2.1 R when the clumps are finally destroyed by heat conduction from the coronal gas. Thereafter, the outflow is a pure coronal wind, which cools and decelerates reaching ∞ with terminal velocity ≈ 1000 km-s -1. © 2012 ESO.


Wolz R.,Imperial College London
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention | Year: 2012

A robust automated segmentation of abdominal organs can be crucial for computer aided diagnosis and laparoscopic surgery assistance. Many existing methods are specialised to the segmentation of individual organs or struggle to deal with the variability of the shape and position of abdominal organs. We present a general, fully-automated method for multi-organ segmentation of abdominal CT scans. The method is based on a hierarchical atlas registration and weighting scheme that generates target specific priors from an atlas database by combining aspects from multi-atlas registration and patch-based segmentation, two widely used methods in brain segmentation. This approach allows to deal with high inter-subject variation while being flexible enough to be applied to different organs. Our results on a dataset of 100 CT scans compare favourable to the state-of-the-art with Dice overlap values of 94%, 91%, 66% and 94% for liver, spleen, pancreas and kidney respectively.


Vineis P.,Imperial College London | Wild C.P.,International Agency for Research on Cancer
The Lancet | Year: 2014

Cancer is a global and growing, but not uniform, problem. An increasing proportion of the burden is falling on low-income and middle-income countries because of not only demographic change but also a transition in risk factors, whereby the consequences of the globalisation of economies and behaviours are adding to an existing burden of cancers of infectious origin. We argue that primary prevention is a particularly effective way to fight cancer, with between a third and a half of cancers being preventable on the basis of present knowledge of risk factors. Primary prevention has several advantages: the effectiveness could have benefits for people other than those directly targeted, avoidance of exposure to carcinogenic agents is likely to prevent other non-communicable diseases, and the cause could be removed or reduced in the long term-eg, through regulatory measures against occupational or environmental exposures (ie, the preventive effort does not need to be renewed with every generation, which is especially important when resources are in short supply). Primary prevention must therefore be prioritised as an integral part of global cancer control.


Tan H.-L.,Imperial College London | Rosenthal M.,Royal Brompton Hospital
Thorax | Year: 2013

Interleukin 17 (IL-17) is a key proinflammatory cytokine in the T helper 17 pathway. While it is important in the clearance of certain pathogens, IL-17 has been shown to contribute to the pathogenesis of such inflammatory diseases as rheumatoid arthritis and psoriasis. In the lung, it has been postulated to be involved in the neutrophilic inflammation and airway remodelling of chronic respiratory conditions but the situation is increasingly complex. This review summarises the evidence for its role in several chronic inflammatory lung diseases: asthma, obliterative bronchiolitis, chronic obstructive pulmonary disease, sarcoidosis and cystic fibrosis.


Pournaras D.J.,Imperial College London
Current atherosclerosis reports | Year: 2013

The burden of type 2 diabetes is increasing. The prevention of the disease, improvement of metabolic control, and more importantly reduction in mortality remain a challenge for primary care doctors, diabetologists, researchers and policymakers. In this article, the available literature is reviewed with a focus on recent developments. Comparison between medical and surgical interventions is performed using mainly head-to-head trials where possible. Weight loss surgery is effective for glycaemic control. The need for level 1 data with hard end points such as cardiovascular risk and mortality is highlighted, and the prospect of the combination of existing therapy options is emphasized.


Shovlin C.L.,Imperial College London
Blood Reviews | Year: 2010

Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings. © 2010 Elsevier Ltd.


Wobbe L.,Bielefeld University | Nixon P.J.,Imperial College London
Nucleic Acids Research | Year: 2013

The molecular function of mTERFs (mitochondrial transcription termination factors) has so far only been described for metazoan members of the protein family and in animals they control mitochondrial replication, transcription and translation. Cells of photosynthetic eukaryotes harbour chloroplasts and mitochondria, which are in an intense cross-talk that is vital for photosynthesis. Chlamydomonas reinhardtii is a unicellular green alga widely used as a model organism for photosynthesis research and green biotechnology. Among the six nuclear C. reinhardtii mTERF genes is mTERF-like gene of Chlamydomonas (MOC1), whose inactivation alters mitorespiration and interestingly also light-acclimation processes in the chloroplast that favour the enhanced production of biohydrogen. We show here from in vitro studies that MOC1 binds specifically to a sequence within the mitochondrial rRNA-coding module S3, and that a knockout of MOC1 in the mutant stm6 increases read-through transcription at this site, indicating that MOC1 acts as a transcription terminator in vivo. Whereas the level of certain antisense RNA species is higher in stm6, the amount of unprocessed mitochondrial sense transcripts is strongly reduced, demonstrating that a loss of MOC1 causes perturbed mitochondrial DNA (mtDNA) expression. Overall, we provide evidence for the existence of mitochondrial antisense RNAs in C. reinhardtii and show that mTERF-mediated transcription termination is an evolutionary-conserved mechanism occurring in phototrophic protists and metazoans. © 2013 The Author(s) 2013. Published by Oxford University Press.


Summary: Recent major cancer genome sequencing studies have used whole-genome sequencing to detect various types of genomic variation. However, a number of these studies have continued to rely on SNP array information to provide additional results for copy number and loss-of-heterozygosity estimation and assessing tumour purity. OncoSNP-SEQ is a statistical model-based approach for inferring copy number profiles directly from high-coverage whole genome sequencing data that is able to account for unknown tumour purity and ploidy. © The Author 2013.


Ashton-Rickardt P.G.,Imperial College London
Cell Metabolism | Year: 2016

The development and function of cytotoxic CD8 T cells (CTLs), which provide immunity to viral infections, are regulated by changes in mitochondrial respiration. Champagne et al. (2016) describe a new mechanism through which mitochondrial metabolism controls production of ATP required for the secretion of critical anti-viral molecules by CTLs. © 2016 Elsevier Inc.


Williams M.,Imperial College London
Journal of Instrumentation | Year: 2010

Multivariate analyses play an important role in high energy physics. Such analyses often involve performing an unbinned maximum likelihood fit of a probability density function (p.d.f.) to the data. This paper explores a variety of unbinned methods for determining the goodness of fit of the p.d.f. to the data. The application and performance of each method is discussed in the context of a real-life high energy physics analysis (a Dalitz-plot analysis). Several of the methods presented in this paper can also be used for the non-parametric determination of whether two samples originate from the same parent p.d.f. This can be used, e.g., to determine the quality of a detector Monte Carlo simulation without the need for a parametric expression of the efficiency. © 2010IOP Publishing Ltd and SISSA.


Huckvale C.,Imperial College London
Quality & safety in health care | Year: 2010

BACKGROUND: Research on patient care has identified substantial variations in the quality and safety of healthcare and the considerable risks of iatrogenic harm as significant issues. These failings contribute to the high rates of potentially avoidable morbidity and mortality and to the rising levels of healthcare expenditure seen in many health systems. There have been substantial developments in information technology in recent decades and there is now real potential to apply these technological developments to improve the provision of healthcare universally. Of particular international interest is the use of eHealth applications. There is, however, a large gap between the theoretical and empirically demonstrated benefits of eHealth applications. While these applications typically have the technical capability to help professionals in the delivery of healthcare, inadequate attention to the socio-technical dimensions of their use can result in new avoidable risks to patients. RESULTS AND DISCUSSION: Given the current lack of evidence on quality and safety improvements and on the cost-benefits associated with the introduction of eHealth applications, there should be a focus on implementing more mature technologies; it is also important that eHealth applications should be evaluated against a comprehensive and rigorous set of measures, ideally at all stages of their application life cycle.


Aggarwal R.,Imperial College London
Quality & safety in health care | Year: 2010

Simulation-based medical education enables knowledge, skills and attitudes to be acquired for all healthcare professionals in a safe, educationally orientated and efficient manner. Procedure-based skills, communication, leadership and team working can be learnt, be measured and have the potential to be used as a mode of certification to become an independent practitioner. Simulation-based training initially began with life-like manikins and now encompasses an entire range of systems, from synthetic models through to high fidelity simulation suites. These models can also be used for training in new technologies, for the application of existing technologies to new environments and in prototype testing. The level of simulation must be appropriate to the learners' needs and can range from focused tuition to mass trauma scenarios. The development of simulation centres is a global phenomenon which should be encouraged, although the facilities should be used within appropriate curricula that are methodologically sound and cost-effective. A review of current techniques reveals that simulation can successfully promote the competencies of medical expert, communicator and collaborator. Further work is required to develop the exact role of simulation as a training mechanism for scholarly skills, professionalism, management and health advocacy.


Spratt B.G.,Imperial College London
Journal of Antimicrobial Chemotherapy | Year: 2012

In this review, based on my Garrod Lecture to the British Society for Antimicrobial Chemotherapy, I have given a brief outline of my career over the past 40 years, starting with research in the 1970s into the properties and functions of penicillin-binding proteins (PBPs), leading to the identification of the high molecular mass PBPs as the physiological targets of penicillin, and subsequent studies showing the emergence of low-affinity PBPs in penicillin-resistant clinical isolates by inter-species recombination and the generation of mosaic PBP genes. The studies of clinical isolates of gonococci, meningococci and pneumococci with PBP-mediated resistance to penicillin led to new interests in molecular epidemiology and the population and evolutionary biology of bacterial pathogens. The development (with colleagues) of multilocus sequence typing provided a method for the unambiguous characterization of bacterial strains that has proved to be very widely used, but the recent remarkable (and ongoing) developments in DNA sequencing technologies have provided the prospect of being able routinely to use whole genome sequences to characterize pathogen isolates. These developments will soon have major implications for diagnostic microbiology, outbreak investigations and our ability to follow the spread of strains of community-acquired and nosocomial pathogens at local, national and international levels. However, there are major barriers to be overcome, particularly with respect to how the avalanche of genome sequence data will be stored so that its transformative potential for molecular epidemiology and international public health are fully realized. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Majeed A.,Imperial College London
Journal of Ambulatory Care Management | Year: 2012

Many European countries have well-developed health systems that offer universal access to health services and which have a strong primary care sector. However, as the financial crisis in Europe progresses, it is leading to significant cutbacks in publicly funded health services. A key objective for primary care physicians will therefore be to work in an environment where resources will be much more limited than in the past. In the longer term, the role of primary care physicians in European health systems will continue to expand to meet the aim of shifting health services to the generally more cost-effective setting of primary care. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Burt A.,Imperial College London
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Mosquito-borne diseases are causing a substantial burden of mortality, morbidity and economic loss in many parts of the world, despite current control efforts, and new complementary approaches to controlling these diseases are needed. One promising class of new interventions under development involves the heritable modification of the mosquito by insertion of novel genes into the nucleus or of Wolbachia endosymbionts into the cytoplasm. Once released into a target population, these modifications can act to reduce one or more components of the mosquito population's vectorial capacity (e.g. the number of female mosquitoes, their longevity or their ability to support development and transmission of the pathogen). Some of the modifications under development are designed to be self-limiting, in that they will tend to disappear over time in the absence of recurrent releases (and hence are similar to the sterile insect technique, SIT), whereas other modifications are designed to be self-sustaining, spreading through populations even after releases stop (and hence are similar to traditional biological control). Several successful field trials have now been performed with Aedes mosquitoes, and such trials are helping to define the appropriate developmental pathway for this new class of intervention.


Intuitive and easily-described, "pick-the-highest" is often recommended for quantitative optimization of AV and especially VV delay settings of biventricular pacemakers (BVP; cardiac resynchronization therapy, CRT). But reliable selection of the optimum setting is challenged by beat-to-beat physiological variation, which "pick-the-highest" combats by averaging multiple heartbeats. Optimization is not optimization unless the optimum is identified confidently. This document shows how to calculate how many heartbeats must be averaged to optimize reliably by pick-the-highest. Any reader, by conducting a few measurements, can calculate for locally-available methods (i) biological scatter between replicate measurements, and (ii) curvature of the biological response. With these, for any clinically-desired precision of optimization, the necessary number of heartbeats can be calculated. To achieve 95% confidence of getting within ±Δx of the true optimum, the number of heartbeats needed is 2(scatter/curvature)2/Δx 4 per setting. Applying published scatter/curvature values (which readers should re-evaluate locally) indicates that optimizing AV, even coarsely with a 40 ms-wide band of precision, requires many thousand beats. For VV delay, the number approaches a million. Moreover, identifying the optimum twice as precisely requires 30-fold more beats. "Pick the highest" is quick to say but slow to do. We must not expect staff to do the impossible; nor criticise them for not doing so. Nor should we assume recommendations and published protocols are well-designed. Reliable AV or VV optimization, using "pick-the-highest" on commonly-recommended manual measurements, is unrealistic. Improving time-efficiency of the optimization process to become clinically realistic may need a curve-fitting strategy instead, with all acquired data marshalled conjointly. © 2012 Elsevier Ireland Ltd.


Gentleman S.M.,Imperial College London
Neuropathology and Applied Neurobiology | Year: 2013

Microglia cells have been implicated, to some extent, in the pathogenesis of all of the common neurodegenerative disorders involving protein aggregation such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. However, the precise role they play in the development of the pathologies remains unclear and it seems that they contribute to the pathological process in different ways depending on the specific disorder. A better understanding of their varied roles is essential if they are to be the target for novel therapeutic strategies. © 2013 British Neuropathological Society.


Pautasso M.,Imperial College London
Scientometrics | Year: 2010

The file-drawer problem is the tendency of journals to preferentially publish studies with statistically significant results. The problem is an old one and has been documented in various fields, but to my best knowledge there has not been attention to how the issue is developing in a quantitative way through time. In the abstracts of various major scholarly databases (Science and Social Science Citation Index (1991-2008), CAB Abstracts and Medline (1970s-2008), the file drawer problem is gradually getting worse, in spite of an increase in (1) the total number of publications and (2) the proportion of publications reporting both the presence and the absence of significant differences. The trend is confirmed for particular natural science topics such as biology, energy and environment but not for papers retrieved with the keywords biodiversity, chemistry, computer, engineering, genetics, psychology and quantum (physics). A worsening file-drawer problem can be detected in various medical fields (infection, immunology, malaria, obesity, oncology and pharmacology), but not for papers indexed with strings such as AIDS/HIV, epidemiology, health and neurology. An increase in the selective publication of some results against some others is worrying because it can lead to enhanced bias in meta-analysis and hence to a distorted picture of the evidence for or against a certain hypothesis. Long-term monitoring of the file-drawer problem is needed to ensure a sustainable and reliable production of (peer-reviewed) scientific knowledge. © 2010 Akadémiai Kiadó, Budapest, Hungary.


Vancheri C.,University of Catania | Du Bois R.M.,Imperial College London
European Respiratory Journal | Year: 2013

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease that results in increasing morbidity. To date there is only one licensed therapy for this condition and other agents are needed for this attritional disease. Efforts to study other agents have been obstructed by an increasing division of opinion about the most clinically meaningful end-point of phase III clinical trials to demonstrate efficacy. Many clinicians believe that an agent that impedes progression of the disease is more than acceptable and will encourage the pharmaceutical industry to further develop their IPF programmes. We have been impressed by the behavioural and biological similarities of cancer and IPF, and wondered if lessons could be learned about clinical trial design from lung cancer studies. Here, we set out our arguments that the similarities with cancer justify comparing the magnitude of therapeutic effects in clinical trials in nonsmall cell lung cancer with those in successful trials in IPF. We demonstrate that efficacy is of a similar magnitude in the two chronic lung diseases. We recommend that the demonstration of similar magnitudes of progression-free disease effect in IPF, using appropriate indices, should be considered as clinically meaningful benefit in future phase III clinical trials of novel therapies.


Gorog D.A.,Imperial College London | Fuster V.,Mount Sinai School of Medicine
Journal of the American College of Cardiology | Year: 2013

This review is a critical evaluation of publications in the past decade on the usefulness of platelet function tests (PFTs) in clinical cardiology, in aiding diagnosis, predicting risk, and monitoring therapy. The ideal PFT should: 1) detect baseline platelet hyperreactivity; 2) allow individualization of antiplatelet medication; 3) predict thrombotic risk; and 4) predict bleeding risk. The practicalities of clinical cardiology demand rapid, accurate, and reliable tests that are simple to operate at the bedside and available 24 h a day, 7 days a week. Point-of-care PFTs most widely evaluated clinically include PFA-100 and VerifyNow. None of these tests can reliably detect platelet hyperreactivity and thus identify a prothrombotic state. Identification of antiplatelet nonresponsiveness or hyporesponsiveness is highly test specific, and does not allow individualization of therapy. The power of PFTs in predicting thrombotic events for a given individual is variable and often modest, and alteration of antithrombotic treatment on the basis of the results of PFTs has not been shown to alter clinical outcome. PFTs in current mainstream use cannot reliably assess bleeding risk. These tests have been in use for over a decade, but the hopes raised by PFTs in clinical practice remain unfulfilled. Although physiologically relevant measurement of platelet function now is more important than ever, a critical reappraisal of available techniques in light of clinical requirements is needed. The use of native blood, global stimulus instead of individual agonists, contribution of thrombin generation by activated platelets to the test results, and establishment of a PFT therapeutic range for each antiplatelet drug should be considered and is discussed. © 2013 American College of Cardiology Foundation.


Harrison J.,Imperial College London
Medical Clinics of North America | Year: 2013

In this article, cognitive measures in the screening of individuals at risk for Alzheimer disease (AD) are reviewed. Use of cognitive tasks in identifying clinical cases of AD is considered, as well as methods for detecting those in the prodromal stages of the disease, including cognitive screening instruments. Traditional assessments, such as the mini-mental state examination, as well as contemporary computerized screening instruments, are examined. Areas of cognition for investigation in the detection of prodromal AD are recommended. The prospects for general cognitive screening are reviewed, and more engaging technologies to tests individuals at risk for developing AD are recommended. © 2013 Elsevier Inc.


Diaz M.B.,Imperial College London
Chaos (Woodbury, N.Y.) | Year: 2010

We present a dynamical model for rewiring and attachment in bipartite networks. Edges are placed between nodes that belong to catalogs that can either be fixed in size or growing in size. The model is motivated by an empirical study of data from the video rental service Netflix, which invites its users to give ratings to the videos available in its catalog. We find that the distribution of the number of ratings given by users and that of the number of ratings received by videos both follow a power law with an exponential cutoff. We also examine the activity patterns of Netflix users and find bursts of intense video-rating activity followed by long periods of inactivity. We derive ordinary differential equations to model the acquisition of edges by the nodes over time and obtain the corresponding time-dependent degree distributions. We then compare our results with the Netflix data and find good agreement. We conclude with a discussion of how catalog models can be used to study systems in which agents are forced to choose, rate, or prioritize their interactions from a large set of options. © 2010 American Institute of Physics.


Furlong M.J.,University of Queensland | Wright D.J.,Imperial College London | Dosdall L.M.,University of Alberta
Annual Review of Entomology | Year: 2013

Agricultural intensification and greater production of Brassica vegetable and oilseed crops over the past two decades have increased the pest status of the diamondback moth (DBM), Plutella xylostella L., and it is now estimated to cost the world economy US$4-5 billion annually. Our understanding of some fundamental aspects of DBM biology and ecology, particularly host plant relationships, tritrophic interactions, and migration, has improved considerably but knowledge of other aspects, e.g., its global distribution and relative abundance, remains surprisingly limited. Biological control still focuses almost exclusively on a few species of hymenopteran parasitoids. Although these can be remarkably effective, insecticides continue to form the basis of management; their inappropriate use disrupts parasitoids and has resulted in field resistance to all available products. Improved ecological understanding and the availability of a series of highly effective selective insecticides throughout the 1990s provided the basis for sustainable and economically viable integrated pest management (IPM) approaches. However, repeated reversion to scheduled insecticide applications has resulted in resistance to these and more recently introduced compounds and the breakdown of IPM programs. Proven technologies for the sustainable management of DBM currently exist, but overcoming the barriers to their sustained adoption remains an enormous challenge. © 2013 by Annual Reviews. All rights reserved.


Sootla A.,Imperial College London
IEEE Transactions on Automatic Control | Year: 2013

This technical note is dedicated to model order reduction of linear time-invariant systems. The main contribution of this technical note is the derivation of two scalable stability-preserving model reduction algorithms. Both algorithms constitute a development of a recently proposed model reduction method. The algorithms perform a curve fitting procedure using frequency response samples of a model and semidefinite programming methods. Computation of these samples can be done efficiently even for large scale models. Both algorithms are obtained from a reformulation of the model reduction problem. One proposes a semidefinite relaxation, while the other is an iterative semidefinite approach. The relaxation approach is similar to Hankel model reduction, which is a well-known and established method in the control literature. Due to this resemblance, the accuracy of approximation is also similar to the one of Hankel model reduction. An appealing quality of the proposed algorithms is the ability to easily perform extensions, e.g., introduce frequency-weighting, positive-real and bounded-real constraints. © 1963-2012 IEEE.


Fenwick A.,Imperial College London
Public Health | Year: 2012

The first comprehensive study on the global burden of disease and risk factors was commissioned by the World Bank in 1992. A follow-up study was performed in 2005, and another iteration was commissioned by the World Health Organization in 2010, due for publication in 2011. The author suggests that the global burden of neglected tropical diseases (NTDs) has been seriously underestimated. The way forward is the integration of control efforts, with programmes coming together to deliver a package of drugs against NTDs. Barriers to continent-wide coverage of drugs against NTDs are political will (missing in those countries with poor governance), funding (approximately half of the $1.5-2 billion is needed) and human resources. However, if the donors who give so much to malaria, tuberculosis and human immunodeficiency virus would share just 10% of the amount allocated to the big three, the most common NTDs could become diseases of the past. This could well happen within 7 years, and the targets of GET2020 (Global Elimination of Trachoma by 2020) to eliminate trachoma and GAELF (the Global Alliance to Eliminate Lymphatic Filariasis) to eliminate lymphatic filariasis by 2020 are achievable. © 2011 The Royal Society for Public Health.


Girolami D.,University of Nottingham | Tufarelli T.,Imperial College London | Adesso G.,University of Nottingham
Physical Review Letters | Year: 2013

Quantum mechanics predicts that measurements of incompatible observables carry a minimum uncertainty which is independent of technical deficiencies of the measurement apparatus or incomplete knowledge of the state of the system. Nothing yet seems to prevent a single physical quantity, such as one spin component, from being measured with arbitrary precision. Here, we show that an intrinsic quantum uncertainty on a single observable is ineludible in a number of physical situations. When revealed on local observables of a bipartite system, such uncertainty defines an entire class of bona fide measures of nonclassical correlations. For the case of 2×d systems, we find that a unique measure is defined, which we evaluate in closed form. We then discuss the role that these correlations, which are of the "discord" type, can play in the context of quantum metrology. We show in particular that the amount of discord present in a bipartite mixed probe state guarantees a minimum precision, as quantified by the quantum Fisher information, in the optimal phase estimation protocol. © 2013 American Physical Society.


Lovett M.,Imperial College London
Human Molecular Genetics | Year: 2013

We all start out as a single totipotent cell that is programmed to produce amulticellular organism. How do individual cells make those complex developmental switches? How do single cells within a tissue or organ differ, how do they coordinate their actions or go astray in a disease process? These are long-standing and fundamental questions in biology that are now becoming tractable because of advances in microfluidics, DNA amplificationandDNAsequencing. Methods for studying single-cell transcriptomes (or at least thepolyadenylatedmRNA fraction of it) are by far the furthest ahead and reveal remarkable heterogeneity between morphologically identical cells. The analysis of genomicDNAvariation is not far behind. The other 'omics' of single cells pose greater technological obstacles, but they are progressing and promise to yield highly integrated large data sets in the near future. © The Author 2013. Published by Oxford University Press. All rights reserved.


Leader E.,Imperial College London
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

There are now five angular momentum relations or sum rules in the literature: the Jaffe, Manohar relation for a longitudinally polarized nucleon, and the Bakker, Leader, Trueman result for the case of transverse polarization; the Ji relation for longitudinal polarization, and the Leader result for transverse polarization, both involving generalized parton distributions; and a new sum rule due to Ji, Xiong and Yuan dealing with the transverse component of the Pauli-Lubanski vector. I discuss these various relations and examine their precise interpretation in the light of the so-called "angular momentum controversy". In particular, I show that the claim of Ji, Xiong, Yuan that their Pauli-Lubanski relation is frame or energy independent is incorrect and that they have missed an energy dependent term in their expression. © 2013 Elsevier B.V.


Gath-Geva (GG) algorithm is one of the most popular methodologies for fuzzy c-means (FCM)-type clustering of data comprising numeric attributes; it is based on the assumption of data deriving from clusters of Gaussian form, a much more flexible construction compared to the spherical clusters assumption of the original FCM. In this paper, we introduce an extension of the GG algorithm to allow for the effective handling of data with mixed numeric and categorical attributes. Traditionally, fuzzy clustering of such data is conducted by means of the fuzzy k-prototypes algorithm, which merely consists in the execution of the original FCM algorithm using a different dissimilarity functional, suitable for attributes with mixed numeric and categorical attributes. On the contrary, in this work we provide a novel FCM-type algorithm employing a fully probabilistic dissimilarity functional for handling data with mixed-type attributes. Our approach utilizes a fuzzy objective function regularized by Kullback-Leibler (KL) divergence information, and is formulated on the basis of a set of probabilistic assumptions regarding the form of the derived clusters. We evaluate the efficacy of the proposed approach using benchmark data, and we compare it with competing fuzzy and non-fuzzy clustering algorithms. © 2011 Elsevier Ltd. All rights reserved.


Lee C.F.,Imperial College London
New Journal of Physics | Year: 2013

I study the confinement-induced aggregation phenomenon in a minimal model of self-propelled particles inside a channel. Starting from first principles, I derive a set of equations that govern the density profile of such a system at the steady-state, and calculate analytically how the aggregation at the walls varies with the physical parameters of the system. I also investigate how the gradient of the particle density varies if the inside of the channel is partitioned into two regions within which the active particles exhibit distinct levels of fluctuations in their directions of travel. © IOP Publishing and Deutsche Physikalische Gesellschaft.


Chandrawati R.,Imperial College London | Caruso F.,University of Melbourne
Langmuir | Year: 2012

Liposomes and polymersomes have attracted significant attention and have emerged as versatile materials for therapeutic delivery and in the design of artificial cells and organelles. Through the judicious choice of building blocks, these synthetic carriers can be readily engineered with tailored interfacial properties, offering new possibilities for the design of advanced assemblies with specific permeability, stability, stimuli response, and targeting capabilities. In this feature article, we highlight recent studies on biomimetic liposome- and polymersome-based multicompartmentalized assemblies en route toward the development of artificial cells, microreactors, and therapeutic delivery carriers. The strategies employed to produce these carriers are outlined, and the properties that contribute to their performance are discussed. Applications of these biomimetic assemblies are highlighted, and finally, areas that require additional investigation for the future development of these assemblies as next-generation therapeutic systems are outlined. © 2012 American Chemical Society.


Figueras P.,University of Cambridge | Wiseman T.,Imperial College London
Physical Review Letters | Year: 2013

We explore use of the harmonic Einstein equations to numerically find stationary black holes where the problem is posed on an ingoing slice that extends into the interior of the black hole. Requiring no boundary conditions at the horizon beyond smoothness of the metric, this method may be applied for horizons that are not Killing. As a nontrivial illustration we find black holes which, via AdS-CFT, describe a time-independent CFT plasma flowing through a static spacetime which asymptotes to Minkowski in the flow's past and future, with a varying spatial geometry in between. These are the first nonperturbative examples of stationary black holes which do not have Killing horizons. When the CFT spacetime slowly varies, the CFT stress tensor derived from gravity is well described by viscous hydrodynamics. For fast variation it is not, and the solutions are stationary analogs of dynamical quenches, with the plasma being suddenly driven out of equilibrium. We find evidence these flows become unstable for sufficiently strong quenches, and speculate the instability may be turbulent. © 2013 American Physical Society.


Henson J.,Imperial College London
Foundations of Physics | Year: 2013

This paper addresses arguments that "separability" is an assumption of Bell's theorem, and that abandoning this assumption in our interpretation of quantum mechanics (a position sometimes referred to as "holism") will allow us to restore a satisfying locality principle. Separability here means that all events associated to the union of some set of disjoint regions are combinations of events associated to each region taken separately. In this article, it is shown that: (a) localised events can be consistently defined without implying separability; (b) the definition of Bell's locality condition does not rely on separability in any way; (c) the proof of Bell's theorem does not use separability as an assumption. If, inspired by considerations of non-separability, the assumptions of Bell's theorem are weakened, what remains no longer embodies the locality principle. Teller's argument for "relational holism" and Howard's arguments concerning separability are criticised in the light of these results. Howard's claim that Einstein grounded his arguments on the incompleteness of QM with a separability assumption is also challenged. Instead, Einstein is better interpreted as referring merely to the existence of localised events. Finally, it is argued that Bell rejected the idea that separability is an assumption of his theorem. © 2013 Springer Science+Business Media New York.


Malijevsky A.,Institute of Chemical Technology Prague | Parry A.O.,Imperial College London
Physical Review Letters | Year: 2013

We present results of a microscopic density functional theory study of wedge filling transitions, at a right-angle wedge, in the presence of dispersionlike wall-fluid forces. Far from the corner the walls of the wedge show a first-order wetting transition at a temperature Tw which is progressively closer to the bulk critical temperature Tc as the strength of the wall forces is reduced. In addition, the meniscus formed near the corner undergoes a filling transition at a temperature Tf< Tw, the value of which is found to be in excellent agreement with macroscopic predictions. We show that the filling transition is first order if it occurs far from the critical point but is continuous if Tf is close to Tc even though the walls still show first-order wetting behavior. For this continuous transition the distance of the meniscus from the apex grows as ℓw≈(Tf-T) -βw with the critical exponent βw≈ 0.46±0.05 in good agreement with the phenomenological effective Hamiltonian prediction. Our results suggest that critical filling transitions, with accompanying large scale universal interfacial fluctuation effects, are more generic than thought previously, and are experimentally accessible. © 2013 American Physical Society.


Alastruey J.,Imperial College London
Journal of Biomechanics | Year: 2011

A local estimation of pulse wave speed c, an important predictor of cardiovascular events, can be obtained at arterial locations where simultaneous measurements of blood pressure (P) and velocity (U), arterial diameter (D) and U, flow rate (Q) and cross-sectional area (A), or P and D are available, using the PU-loop, sum-of-squares (Σ 2), lnDU-loop, QA-loop or new D 2P-loop methods. Here, these methods were applied to estimate c from numerically generated P, U, D, Q and A waveforms using a visco-elastic one-dimensional model of the 55 larger human systemic arteries in normal conditions. Theoretical c were calculated from the parameters of the model. Estimates of c given by the loop methods were closer to theoretical values and more uniform within each arterial segment than those obtained using the Σ 2. The smaller differences between estimates and theoretical values were obtained using the D 2P-loop method, with root-mean-square errors (RMSE) smaller than 0.18ms-1, followed by averaging the two c given by the PU- and lnDU-loops (RMSE <2.99ms-1). In general, the errors of the PU-, lnDU- and QA-loops decreased at locations where visco-elastic effects were small and nearby junctions were well-matched for forward-travelling waves. The Σ 2 performed better at proximal locations. © 2010 Elsevier Ltd.


Walters J.R.,Imperial College London
Nature reviews. Gastroenterology & hepatology | Year: 2014

Chronic diarrhoea induced by bile acids is common and the underlying mechanisms are linked to homeostatic regulation of hepatic bile acid synthesis by fibroblast growth factor 19 (FGF19). Increasing evidence, including that from several large case series using SeHCAT (selenium homocholic acid taurine) tests for diagnosis, indicates that bile acid diarrhoea (BAD) accounts for a sizeable proportion of patients who would otherwise be diagnosed with IBS. Studies of other approaches for diagnosis of BAD have shown increased bile acid synthesis, increased faecal levels of primary bile acids, dysbiosis and different urinary volatile organic compounds when compared with healthy controls or with other diseases. The role of the ileal hormone FGF19 in BAD has been strengthened: a prospective clinical study has confirmed low FGF19 levels in BAD, and so a test to measure these levels could be developed for diagnosis. In animal models, FGF19 depletion by antibodies produces severe diarrhoea. Bile acids affect colonic function through farnesoid X receptor (FXR) and TGR5 receptors. As well as these effects in the colon, FXR-dependent stimulation of ileal FGF19 production could be a logical mechanism to provide therapeutic benefit in BAD. Further studies of FGF19 in humans hold promise in providing novel treatments for this cause of chronic diarrhoea.


Barnes P.J.,Imperial College London
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Theophylline (dimethylxanthine) has been used to treat airway diseases for more than 80 years. It was originally used as a bronchodilator, but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled β2-agonists became more widely used. More recently it has been shown to have antiinflammatory effects in asthma and chronic obstructive pulmonary disease (COPD) at lower concentrations. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase (PDE) 3, but the antiinflammatory effect may be due to inhibition of PDE4 and histone deacetylase-2 activation, resulting in switching off of activated inflammatory genes. Through this mechanism, theophylline also reverses corticosteroid resistance, and this may be of particular value in severe asthma and COPD, wherein histone deacetylase-2 activity is reduced. Theophylline is given systemically (orally as slow-release preparations for chronic treatment and intravenously for acute exacerbations of asthma). Efficacy is related to blood concentrations, which are determined mainly by hepatic metabolism, which may be increased or decreased in several diseases and by concomitant drug therapy. Theophylline is now usually used as an add-on therapy in patients with asthma not well controlled on inhaled corticosteroids with or without long-acting β2-agonists and in patients with COPD with severe disease not controlled by bronchodilator therapy. Side effects are related to plasma concentrations and include nausea, vomiting, and headaches due to PDE inhibition and at higher concentrations to cardiac arrhythmias and seizures due to adenosine A1-receptor antagonism. In the future, low-dose theophylline may be useful in reversing corticosteroid resistance in COPD and severe asthma. Copyright © 2013 by the American Thoracic Society.


Scadding G.,Imperial College London
Current allergy and asthma reports | Year: 2014

Allergic rhinitis, particularly seasonal allergic rhinitis, is considered a classic Th2-mediated disease, with important contributions to pathology by interleukins 4, 5 and 13. As such, allergic rhinitis is an excellent model for studying allergic inflammation, with findings potentially relevant to the mechanism of lower airways inflammation seen in allergic asthma. However, recent evidence has revealed roles for additional non-Th2 cytokines in asthma, including IL-17 family cytokines and epithelial-derived cytokines. Additionally, putative roles for epithelial-derived cytokines and innate lymphoid cells have been described in chronic rhinosinusitis with nasal polyps. Here, evidence for the involvement of different cytokines and cytokine groups in allergic rhinitis is considered.


Evans A.W.,Imperial College London
Accident Analysis and Prevention | Year: 2011

This paper presents an analysis of fatal train accident rates and trends on Europe's main line railways from 1980 to 2009. The paper uses a new set of data for the European Union together with Norway and Switzerland, assembled partly under the auspices of the European Railway Agency and partly on the author's own account. The estimated overall trend in the number of fatal train collisions and derailments per train-kilometre is -6.3% per year from 1990 to 2009, with a 95% confidence interval of -8.7% to -3.9%. The estimated accident rate in 2009 is 1.35 fatal collisions or derailments per billion train-kilometres, giving an estimated mean number of fatal accidents in 2009 of 6.0. The overall number of fatalities per fatal accident in 1990-2009 is 4.10, with no apparent long term change over time, giving an estimated mean of 24.6 fatalities per year in train collisions and derailments in 2009. There are statistically significant differences in the fatal train accident rates and trends between the different European countries, although the estimates of the rates and trends for many individual countries have wide confidence limits. The distribution of broad causes of accidents appears to have remained unchanged over the long term, so that safety improvements appear to have been across the board, and not focused on any specific cause. The most frequent cause of fatal train collisions and derailments is signals passed at danger. In contrast to fatal train collisions and derailments, the rate per train-kilometre of serious accidents at level crossings remained unchanged in 1990-2009. The immediate causes of most of the serious level crossing accidents are errors or violations by road users. © 2010 Elsevier Ltd.


BACKGROUND:: Most anesthetics, particularly intravenous agents such as propofol and etomidate, enhance the actions of the neurotransmitter γ-aminobutyric acid (GABA) at the GABA type A receptor. However, there is no agreement as where anesthetics bind to the receptor. A novel approach would be to identify regions on the receptor that are state-dependent, which would account for the ability of anesthetics to affect channel opening by binding differentially to the open and closed states.METHODS:: The open and closed structures of the GABA type A receptor homologues Gloeobacter ligand–gated ion channel and glutamate-gated chloride channel were compared, and regions in the channels that move on channel opening and closing were identified. Docking calculations were performed to investigate possible binding of propofol to the GABA type A β3 homomer in this region.RESULTS:: A comparison between the open and closed states of the Gloeobacter ligand–gated ion channel and glutamate-gated chloride channel channels identified a region at the top of transmembrane domains 2 and 3 that shows maximum movement when the channels transition between the open and closed states. Docking of propofol into the GABA type A β3 homomer identified two putative binding cavities in this same region, one with a high affinity and one with a lower affinity. Both cavities were adjacent to a histidine residue that has been photolabeled by a propofol analog, and both sites would be disrupted on channel closing.CONCLUSIONS:: These calculations support the conclusion of a recent photolabeling study that propofol acts at a site at the interface between the extracellular and transmembrane domains, close to the top of transmembrane domain 2. © 2015 American Society of Anesthesiologists, Inc.


Little M.P.,Imperial College London
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2010

In this paper we review the evidence for departure from linearity for malignant and non-malignant disease and in the light of this assess likely mechanisms, and in particular the potential role for non-targeted effects.Excess cancer risks observed in the Japanese atomic bomb survivors and in many medically and occupationally exposed groups exposed at low or moderate doses are generally statistically compatible. For most cancer sites the dose-response in these groups is compatible with linearity over the range observed. The available data on biological mechanisms do not provide general support for the idea of a low dose threshold or hormesis. This large body of evidence does not suggest, indeed is not statistically compatible with, any very large threshold in dose for cancer, or with possible hormetic effects, and there is little evidence of the sorts of non-linearity in response implied by non-DNA-targeted effects.There are also excess risks of various types of non-malignant disease in the Japanese atomic bomb survivors and in other groups. In particular, elevated risks of cardiovascular disease, respiratory disease and digestive disease are observed in the A-bomb data. In contrast with cancer, there is much less consistency in the patterns of risk between the various exposed groups; for example, radiation-associated respiratory and digestive diseases have not been seen in these other (non-A-bomb) groups. Cardiovascular risks have been seen in many exposed populations, particularly in medically exposed groups, but in contrast with cancer there is much less consistency in risk between studies: risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, a cause-and-effect interpretation of the reported statistical associations for cardiovascular disease is unreliable but cannot be excluded. Inflammatory processes are the most likely mechanism by which radiation could modify the atherosclerotic disease process. If there is to be modification by low doses of ionizing radiation of cardiovascular disease through this mechanism, a role for non-DNA-targeted effects cannot be excluded. © 2010 Elsevier B.V.


Pellicori P.,Imperial College London
Current Opinion in Cardiology | Year: 2015

PURPOSE OF REVIEW: The number of patients developing heart failure is increasing dramatically, and will likely continue to do so for the next few decades. At least half of the patients with symptoms and signs of heart failure have a normal left ventricular ejection fraction on echocardiography [heart failure with preserved ejection fraction (HFPEF)]. This review updates the current management of patients with HFPEF and summarizes what is in development.RECENT FINDINGS: Many different pathophysiologies may result in HFPEF. No single imaging measure may reliably identify cardiac dysfunction, but plasma concentrations of natriuretic peptides, reflecting the final pathway of congestion, appear to. Natriuretic peptides are now an essential part of the diagnostic process and are increasingly used to select patients to be enrolled in clinical trials. No therapeutic intervention has unequivocally been shown to modify the natural history of HFPEF, although several improve symptoms and functional capacity, which are important targets in this population. The failure of many clinical trials may reflect the inclusion of patients who are at low risk of cardiovascular events or the diverse pathophysiology of HFPEF. When patients are congested (i.e. have elevated plasma concentrations of natriuretic peptides) a diagnosis of HFPEF can be made with some confidence, the patients will be at increased cardiovascular risk and treatments aimed at correcting congestion will probably be effective. Selection of treatment to target a specific underlying pathophysiology is an alternative, relatively untried approach.SUMMARY: Further clinical trials will provide new insights into the pathophysiology of this complex disease and, hopefully, identify therapies that also improve outcome. © 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins


Shanahan M.,Imperial College London
Chaos | Year: 2010

A system of symmetrically coupled identical oscillators with phase lag is presented, which is capable of generating a large repertoire of transient (metastable) "chimera" states in which synchronization and desynchronization coexist. The oscillators are organized into communities, such that each oscillator is connected to all its peers in the same community and to a subset of the oscillators in other communities. Measures are introduced for quantifying metastability, the prevalence of chimera states, and the variety of such states a system generates. By simulation, it is shown that each of these measures is maximized when the phase lag of the model is close, but not equal, to π/2. The relevance of the model to a number of fields is briefly discussed with particular emphasis on brain dynamics. © 2010 American Institute of Physics.


Umasunthar T.,Imperial College London
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology | Year: 2013

Food allergy is a common cause of anaphylaxis, but the incidence of fatal food anaphylaxis is not known. The aim of this study was to estimate the incidence of fatal food anaphylaxis for people with food allergy and relate this to other mortality risks in the general population. We undertook a systematic review and meta-analysis, using the generic inverse variance method. Two authors selected studies by consensus, independently extracted data and assessed the quality of included studies using the Newcastle-Ottawa assessment scale. We searched Medline, Embase, PsychInfo, CINAHL, Web of Science, LILACS or AMED, between January 1946 and September 2012, and recent conference abstracts. We included registries, databases or cohort studies which described the number of fatal food anaphylaxis cases in a defined population and time period and applied an assumed population prevalence rate of food allergy. We included data from 13 studies describing 240 fatal food anaphylaxis episodes over an estimated 165 million food-allergic person-years. Study quality was mixed, and there was high heterogeneity between study results, possibly due to variation in food allergy prevalence and data collection methods. In food-allergic people, fatal food anaphylaxis has an incidence rate of 1.81 per million person-years (95%CI 0.94, 3.45; range 0.63, 6.68). In sensitivity analysis with different estimated food allergy prevalence, the incidence varied from 1.35 to 2.71 per million person-years. At age 0-19, the incidence rate is 3.25 (1.73, 6.10; range 0.94, 15.75; sensitivity analysis 1.18-6.13). The incidence of fatal food anaphylaxis in food-allergic people is lower than accidental death in the general European population. Fatal food anaphylaxis for a food-allergic person is rarer than accidental death in the general population. © 2013 The Authors Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.


Habgood M.,Imperial College London
Crystal Growth and Design | Year: 2013

Cocrystals offer two novel variants on the classic salt formation method of chiral resolution. Diastereomeric cocrystal pairs are directly analogous to salts but without the requirement for proton transfer. Conversely, a coformer that cocrystallizes with one enantiomer but not the other (enantiospecific cocrystallization) has recently been shown to give high enantiomeric yield. For either variant an understanding of intermolecular interactions is vital. In this study computational crystal structure prediction (CSP) is applied to three recently reported examples: levetiracetam with mandelic acid and with tartaric acid, which display enantiospecific cocrystallization, and tartaric acid with malic acid, which forms a diastereomeric cocrystal pair. The ability of CSP techniques to predict the experimental cocrystal structures is demonstrated. The chirally selective interactions are determined using the unique capabilities of CSP, with reference to alternative structures for each cocrystal system, including the hypothetical diastereomeric twins of the levetiracetam cocrystals. In each case, chiral selectivity can be described in terms of the dominant R22(8) dimer's response to the change in enantiomer. It is concluded that when designing a coformer for chiral resolution a predilection toward a single, orientationally restrictive intermolecular motif, with minimal ability to form alternative motifs, is the best strategy. © 2013 American Chemical Society.


Strelkowa N.,Imperial College London | Lassig M.,University of Cologne
Genetics | Year: 2012

The seasonal influenza A virus undergoes rapid evolution to escape human immune response. Adaptive changes occur primarily in antigenic epitopes, the antibody-binding domains of the viral hemagglutinin. This process involves recurrent selective sweeps, in which clusters of simultaneous nucleotide fixations in the hemagglutinin coding sequence are observed about every 4 years. Here, we show that influenza A (H3N2) evolves by strong clonal interference. This mode of evolution is a red queen race between viral strains with different beneficial mutations. Clonal interference explains and quantifies the observed sweep pattern: we find an average of at least one strongly beneficial amino acid substitution per year, and a given selective sweep has three to four driving mutations on average. The inference of selection and clonal interference is based on frequency time series of single-nucleotide polymorphisms, which are obtained from a sample of influenza genome sequences over 39 years. Our results imply that mode and speed of influenza evolution are governed not only by positive selection within, but also by background selection outside antigenic epitopes: immune adaptation and conservation of other viral functions interfere with each other. Hence, adapting viral proteins are predicted to be particularly brittle. We conclude that a quantitative understanding of influenza's evolutionary and epidemiological dynamics must be based on all genomic domains and functions coupled by clonal interference. © 2012 by the Genetics Society of America.


Rosindell J.,University of Leeds | Rosindell J.,University of Idaho | Phillimore A.B.,Imperial College London
Ecology Letters | Year: 2011

Islands acquire species through immigration and speciation. Models of island biogeography should capture both processes; however quantitative island biogeography theory has either neglected speciation or treated it unrealistically. We introduce a model where the dominance of immigration on small and near islands gives way to an increasing role for speciation as island area and isolation increase. We examine the contribution of immigration and speciation to the avifauna of 35 archipelagoes and find, consistent with our model, that the zone of radiation comprises two regions: endemic species diverged from mainland sister-species at intermediate isolation and from insular sister-species at higher levels of isolation. Our model also predicts species-area curves in accord with existing research and makes new predictions about species ages and abundances. We argue that a paucity of data and theory on species abundances on isolated islands highlights the need for island biogeography to be reconnected with mainstream ecology. © 2011 Blackwell Publishing Ltd/CNRS.


Nienaber C.A.,University of Rostock | Powell J.T.,Imperial College London
European Heart Journal | Year: 2012

Acute aortic syndrome (AAS) is a modern term to describe interrelated emergency aortic conditions with similar clinical characteristics and challenges. These conditions include aortic dissection, intramural haematoma (IMH), and penetrating atherosclerotic ulcer (PAU and aortic rupture); trauma to the aorta with intimal laceration may also be considered. The common denominator of AAS is disruption of the media layer of the aorta with bleeding within IMH, along the aortic media resulting in separation of the layers of the aorta (dissection), or transmurally through the wall in the case of ruptured PAU or trauma. Population-based studies suggest that the incidence of acute dissection ranges from 2 to 3.5 cases per 100 000 person-years; hypertension and a variety of genetic disorders with altered connective tissues are the most prevalent risk conditions. Patients with AAS often present in a similar fashion, regardless of the underlying condition of dissection, IMH, PAU, or contained aortic rupture. Pain is the most commonly presenting symptom of acute aortic dissection and should prompt immediate attention including diagnostic imaging modalities (such as multislice computed tomography, transoesophageal ultrasound, or magnetic resonance imaging). Prognosis is clearly related to undelayed diagnosis and appropriate surgical repair in the case of proximal involvement of the aorta; affection of distal segments of the aorta may call for individualized therapeutic approaches favouring endovascular in the presence of malperfusion or imminent rupture, or medical management. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011.


Donos A.,Imperial College London | Hartnoll S.A.,Stanford University
Nature Physics | Year: 2013

Interaction-driven charge localization across a quantum phase transition involves a fundamental rearrangement of the low-energy degrees of freedom. This fact challenges weakly interacting quasiparticle descriptions of the physics. The canonical example of such localization is the Mott transition. Here, we present a localization mechanism distinct from 'Mottness', which employs strong interactions in an essential way. Our mechanism allows anisotropic localization: phases can arise that are insulating in some directions and metallic in others. The central observation is that localization occurs if an operator that breaks translation invariance, a 'generalized Umklapp' operator, becomes relevant in the effective low-energy theory. This does not occur at weak coupling. We realize such localization in a strongly interacting theory described by means of the holographic correspondence. Our model captures key features of metal-insulator transitions including major spectral weight transfer and bad (incoherent) metallic behaviour in the vicinity of the transition. The localized phase has a power law gap in the optical conductivity. © 2013 Macmillan Publishers Limited.


Silver M.,Imperial College London
Statistical applications in genetics and molecular biology | Year: 2012

Where causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways.We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our "pathways group lasso with adaptive weights" (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets.In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small.


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.


Barnes P.J.,Imperial College London
Trends in Pharmacological Sciences | Year: 2010

Current therapy for asthma with inhaled corticosteroids and long-acting inhaled β2-agonists is highly effective, safe and relatively inexpensive, but for many patients, their disease remains poorly controlled. Most advances in asthma therapy have occurred through improving these drug classes, and a major developmental hurdle is to improve existing drug classes. The major unmet needs include better treatment of severe asthma, and curative therapies for mild to moderate asthma. Many new treatments are specific, targeting a single mediator or receptor, and are unlikely to have a major clinical effect, although they might be effective in specific asthma phenotypes. Drugs with more widespread effects, such as kinase inhibitors, might be more effective but have a greater risk of side effects. New treatments targeting the underlying allergic/immune process would treat concomitant allergic diseases. Improved immunotherapy approaches have the prospect of disease modification, although prospects for a cure are currently remote. The most promising therapeutic developments for asthma are discussed in this review. © 2010 Elsevier Ltd.


Puri B.K.,Imperial College London
Expert Review of Neurotherapeutics | Year: 2010

Several important progressive brain changes occur in schizophrenia. Continuous progressive brain tissue decreases and lateral ventricular volume increases in chronically ill patients, up to at least 20 years after their first symptoms. The total duration of psychosis may be negatively associated with the grey matter volume change, and positively associated with the volume change of each of the lateral ventricles and the third ventricle. There are progressive frontal changes in males with adolescent-onset psychosis. Ultra high-risk patients who subsequently develop psychosis and first-episode psychosis patients develop significant grey matter reduction in the planum polare, planum temporale and caudal region; a progressive process in the superior temporal gyrus may precede the first expression of florid psychosis. The rate of decline in the sizes of the putamen and corpus callosum is greater in patients with a poor outcome compared to those with a good-outcome. In addition to describing these phenomena, their potential causes are discussed. © 2010 Expert Reviews Ltd.


Ramasamy A.,Imperial College London
The Journal of bone and joint surgery. American volume | Year: 2013

Improvements in protection and medical treatments have resulted in increasing numbers of modern-warfare casualties surviving with complex lower-extremity injuries. To our knowledge, there has been no prior analysis of foot and ankle blast injuries as a result of improvised explosive devices (IEDs). The aims of this study were to report the pattern of injury and determine which factors are associated with a poor clinical outcome. U.K. service personnel who had sustained lower leg injuries following an under-vehicle explosion from January 2006 to December 2008 were identified with the use of a prospective trauma registry. Patient demographics, injury severity, the nature of the lower leg injury, and the type of clinical management were recorded. Clinical end points were determined by (1) the need for amputation and (2) ongoing clinical symptoms. Sixty-three U.K. service personnel (eighty-nine injured limbs) with lower leg injuries from an explosion were identified. Fifty-one percent of the casualties sustained multisegmental injuries to the foot and ankle. Twenty-six legs (29%) required amputation, with six of them amputated because of chronic pain eighteen months following injury. Regression analysis revealed that hindfoot injuries, open fractures, and vascular injuries were independent predictors of amputation. At the time of final follow-up, sixty-six (74%) of the injured limbs had persisting symptoms related to the injury, and only nine (14%) of the service members were fit to return to their preinjury duties. This study demonstrates that foot and ankle injuries from IEDs are associated with a high amputation rate and frequently with a poor clinical outcome. Although not life-threatening, they remain a source of long-term morbidity in an active population.


Taylor P.C.,Imperial College London
Current Opinion in Pharmacology | Year: 2010

Tumor necrosis factor-alpha (TNF) has been unequivocally validated as a therapeutic target in a number of immune-mediated inflammatory disorders (IMIDs). There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF. But approaches to TNF inhibition differ and currently include mAbs (infliximab, adalimumab, and golimumab), either chimeric or human in sequence, a PEGylated Fab' fragment (certolizumab), and an IgG1-TNFR2 fusion protein (etanercept). It is emerging that the pharmacological properties of these three anti-TNF subtypes differ with respect to Fc function, binding of tmTNF and the possible consequences of this, as well as the ability to form complexes. The mode of administration of each agent, clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety. © 2010.


Barnes P.J.,Imperial College London
Immunological Reviews | Year: 2011

Allergic inflammation is due to a complex interplay between several inflammatory cells, including mast cells, basophils, lymphocytes, dendritic cells, eosinophils, and sometimes neutrophils. These cells produce multiple inflammatory mediators, including lipids, purines, cytokines, chemokines, and reactive oxygen species. Allergic inflammation affects target cells, such as epithelial cells, fibroblasts, vascular cells, and airway smooth muscle cells, which become an important source of inflammatory mediators. Sensory nerves are sensitized and activated during allergic inflammation and produce symptoms. Allergic inflammatory responses are orchestrated by several transcription factors, particularly NF-κB and GATA3. Inflammatory genes are also regulated by epigenetic mechanisms, including DNA methylation and histone modifications. There are several endogenous anti-inflammatory mechanisms, including anti-inflammatory lipids and cytokines, which may be defective in allergic disease, thus amplifying and perpetuating the inflammation. Better understanding of the pathophysiology of allergic inflammation has identified new therapeutic targets but developing effective novel therapies has been challenging. Corticosteroids are highly effective with a broad spectrum of anti-inflammatory effects, including epigenetic modulation of the inflammatory response and suppression of GATA3. © 2011 John Wiley & Sons A/S.


Norman P.E.,University of Western Australia | Powell J.T.,Imperial College London
Circulation Research | Year: 2014

Vitamin D plays a classical hormonal role in skeletal health by regulating calcium and phosphorus metabolism. Vitamin D metabolites also have physiological functions in nonskeletal tissues, where local synthesis influences regulatory pathways via paracrine and autocrine mechanisms. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D, binds to the vitamin D receptor that regulates numerous genes involved in fundamental processes of potential relevance to cardiovascular disease, including cell proliferation and differentiation, apoptosis, oxidative stress, membrane transport, matrix homeostasis, and cell adhesion. Vitamin D receptors have been found in all the major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the renin-angiotensin system. Clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative cardiovascular disease including vascular calcification. However, the role of vitamin D supplementation in the management of cardiovascular disease remains to be established. This review summarizes the clinical studies showing associations between vitamin D status and cardiovascular disease and the experimental studies that explore the mechanistic basis for these associations. © 2014 American Heart Association, Inc.


Fernando R.J.,Imperial College London
The Cochrane database of systematic reviews | Year: 2013

Anal sphincter injury during childbirth - obstetric anal sphincter injuries (OASIS) - are associated with significant maternal morbidity including perineal pain, dyspareunia (painful sexual intercourse) and anal incontinence, which can lead to psychological and physical sequelae. Many women do not seek medical attention because of embarrassment. The two recognised methods for the repair of damaged external anal sphincter (EAS) are end-to-end (approximation) repair and overlap repair. To compare the effectiveness of overlap repair versus end-to-end repair following OASIS in reducing subsequent anal incontinence, perineal pain, dyspareunia and improving quality of life. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013) and reference lists of retrieved studies. Randomised controlled trials comparing different techniques of immediate primary repair of EAS following OASIS. Trial quality was assessed independently by all authors. Six eligible trials, of variable quality, involving 588 women, were included. There was considerable heterogeneity in the outcome measures, time points and reported results. Meta-analyses showed that there was no statistically significant difference in perineal pain (risk ratio (RR) 0.08, 95% confidence interval (CI) 0.00 to 1.45, one trial, 52 women), dyspareunia (average RR 0.77, 95% CI 0.48 to 1.24, two trials, 151 women), flatus incontinence (average RR 1.14, 95% CI 0.58 to 2.23, three trials, 256 women) between the two repair techniques at 12 months. However, it showed a statistically significant lower incidence of faecal urgency (RR 0.12, 95% CI 0.02 to 0.86, one trial, 52 women), and lower anal incontinence score (standardised mean difference (SMD) -0.70, 95% CI -1.26 to -0.14, one trial, 52 women) in the overlap group. The overlap technique was also associated with a statistically significant lower risk of deterioration of anal incontinence symptoms over 12 months (RR 0.26, 95% CI 0.09 to 0.79, one trial, 41 women). There was no significant difference in quality of life. At 36 months follow-up, there was no difference in flatus incontinence (average RR 1.12, 95% CI 0.63 to 1.99, one trial, 68 women) or faecal incontinence (average RR 1.01, 95% CI 0.34 to 2.98, one trial, 68 women). The data available show that at one-year follow-up, immediate primary overlap repair of the external anal sphincter compared with immediate primary end-to-end repair appears to be associated with lower risks of developing faecal urgency and anal incontinence symptoms. At the end of 36 months there appears to be no difference in flatus or faecal incontinence between the two techniques. However, since this evidence is based on only two small trials, more research evidence is needed in order to confirm or refute these findings.


Brooks D.J.,Imperial College London
Movement Disorders | Year: 2010

In this review, in vivo patterns of structural, metabolic, and neurotransmitter binding changes revealed by imaging in both symptomatic Parkinson's disease (PD) and at-risk subjects are compared with those predicted at different Braak stages. It is concluded that the dysfunction revealed by imaging in PD is only partially in line with the sequential ascending topography of Lewy body pathology reported by Braak, suggesting that neurons in different brain regions are likely to be selectively vulnerable to the presence of intracellular synuclein aggregates. © 2010 Movement Disorder Society.


Ozaki R.,Imperial College London
Business Strategy and the Environment | Year: 2011

This paper investigates what encourages consumers to adopt a green electricity tariff. When people decide to adopt an innovation, such as green electricity, they consider not only functionality, usability, costs and intended outcomes, but also what the innovation means to them, for example, the way it reflects their identity, image, memberships, values and norms. The study reviews the theoretical frameworks of innovation adoption and consumption, and cognitive and normative behaviour, relevant to consumer adoption of pro-environmental innovations, and develops a research framework. Through focus group discussions, a questionnaire survey with 103 respondents and an interview with 10 people, the study finds that consumers sympathetic to environmental issues do not necessarily adopt green electricity. This is due to lack of strong social norms and personal relevance, inconvenience of switching, uncertainty about the quality of green electricity and lack of accurate information. The implications of these findings for strategy, policy and future research are explored. © 2009 John Wiley & Sons, Ltd and ERP Environment.


Marin D.,Imperial College London
Seminars in Hematology | Year: 2010

Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase. However, at 5 years more than one third of the patients have abandoned the medication on account of side effects, lack of efficacy, or progression. Here we review the current results with imatinib, the prognostic factors for response, and issues associated with long-term treatment with imatinib such as pregnancy, adherence to therapy, and complete molecular responses. © 2010 Elsevier Inc.


Muller-Wodarg I.C.F.,Imperial College London
Nature Physics | Year: 2016

Waves are ubiquitous phenomena found in oceans and atmospheres alike. From the earliest formal studies of waves in the Earth’s atmosphere to more recent studies on other planets, waves have been shown to play a key role in shaping atmospheric bulk structure, dynamics and variability. Yet, waves are difficult to characterize as they ideally require in situ measurements of atmospheric properties that are difficult to obtain away from Earth. Thus, we have incomplete knowledge of atmospheric waves on planets other than our own, and we are thereby limited in our ability to understand and predict planetary atmospheres. Here we report the first ever in situ observations of atmospheric waves in Venus’s thermosphere (130–140 km) at high latitudes (71.5°–79.0°). These measurements were made by the Venus Express Atmospheric Drag Experiment (VExADE) during aerobraking from 24 June to 11 July 2014. As the spacecraft flew through Venus’s atmosphere, deceleration by atmospheric drag was sufficient to obtain from accelerometer readings a total of 18 vertical density profiles. We infer an average temperature of T = 114 ± 23 K and find horizontal wave-like density perturbations and mean temperatures being modulated at a quasi-5-day period. © 2016 Nature Publishing Group


Peters R.,Imperial College London
Experimental Gerontology | Year: 2012

The success of the ageing global population brings with it a growth in the number of dementia sufferers. Older adults are at highest risk of dementia and are likely to manifest both vascular and Alzheimer's pathology. Blood pressure also changes with ageing and there is evidence linking high blood pressure in midlife to an increased risk of later dementia. Data from later life is sparser. A number of intervention trials have been carried out with antihypertensives and have shown mixed results with regard to cognitive and dementia outcomes (both dementia overall and of vascular and Alzheimer's types). Meta-analyses have in general not found an association between blood pressure lowering and reduced dementia incidence, although the number of cases reported in the placebo controlled trials is invariably lower in the actively treated group. Systematic reviews and meta-analyses have also been published with regard to smoking and alcohol use and incident dementia. Despite mixed reports, overall smoking was associated with an increased risk of later dementia and alcohol with a 'U' or 'J' shaped relationship. Following the systematic reviews subsequent publications tend to report similar findings. The literature in this area suffers from differing populations, lengths of follow up and assessments of both risk factor and outcome. However, at present, maintenance of cognitive function would seem to be best served by treating cardiovascular risk factors in accordance with current guidelines, controlling blood pressure, reducing smoking and if consuming alcohol doing so in moderation.This review will concentrate on the prevention of dementia and attempt to provide an overview of the evidence relating to vascular related dementia and the potential risk factors of hypertension, alcohol use and smoking behaviour. © 2012 Elsevier Inc.


Toni F.,Imperial College London
Argument and Computation | Year: 2014

We give an introductory tutorial to assumption-based argumentation (referred to as ABA)-a form of argumentation where arguments and attacks are notions derived from primitive notions of rules in a deductive system, assumptions and contraries thereof. ABA is equipped with different semantics for determining winning sets of assumptions and-interchangeably and equivalently-winning sets of arguments. It is also equipped with a catalogue of computational techniques to determine whether given conclusions can be supported by a winning set of arguments. These are in the form of disputes between (fictional) proponent and opponent players, provably correct w.r.t. the semantics. Albeit simple, ABA is powerful in that it can be used to represent and reason with a number of problems in AI and beyond: non-monotonic reasoning, preferences, decisions. While doing so, it encompasses the expressive and computational needs of these problems while affording the transparency and explanatory power of argumentation. © 2014 Taylor and Francis.


Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high-resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF. © 2014 Informa Healthcare USA, Inc. All rights reserved.


In this review, I outline the indirect evidence for the formation of singlet oxygen (1O2) obtained from experiments with the isolated PSII reaction center complex. I also review the methods we used to measure singlet oxygen directly, including luminescence at 1,270 nm, both steady state and time resolved. Other methods we used were histidine-catalyzed molecular oxygen uptake (enabling 1O2 yield measurements), and dye bleaching and difference absorption spectroscopy to identify where quenchers of 1O2 can access this toxic species. We also demonstrated the protective behavior of carotenoids bound within Chl-protein complexes which bring about a substantial amount of 1O2 quenching within the reaction center complex. Finally, I describe how these techniques have been used and expanded in research on photoinhibition and on the role of 1O2 as a signaling molecule in instigating cellular responses to various stress factors. I also discuss the current views on the role of 1O2 as a signaling molecule and the distance it might be able to travel within cells. © 2014 The Author 2014.


Walters J.R.F.,Imperial College London
Nature Reviews Gastroenterology and Hepatology | Year: 2014

Chronic diarrhoea induced by bile acids is common and the underlying mechanisms are linked to homeostatic regulation of hepatic bile acid synthesis by fibroblast growth factor 19 (FGF19). Increasing evidence, including that from several large case series using SeHCAT (selenium homocholic acid taurine) tests for diagnosis, indicates that bile acid diarrhoea (BAD) accounts for a sizeable proportion of patients who would otherwise be diagnosed with IBS. Studies of other approaches for diagnosis of BAD have shown increased bile acid synthesis, increased faecal levels of primary bile acids, dysbiosis and different urinary volatile organic compounds when compared with healthy controls or with other diseases. The role of the ileal hormone FGF19 in BAD has been strengthened: a prospective clinical study has confirmed low FGF19 levels in BAD, and so a test to measure these levels could be developed for diagnosis. In animal models, FGF19 depletion by antibodies produces severe diarrhoea. Bile acids affect colonic function through farnesoid X receptor (FXR) and TGR5 receptors. As well as these effects in the colon, FXR-dependent stimulation of ileal FGF19 production could be a logical mechanism to provide therapeutic benefit in BAD. Further studies of FGF19 in humans hold promise in providing novel treatments for this cause of chronic diarrhoea. © 2014 Macmillan Publishers Limited. All rights reserved.


Lenhard B.,Imperial College London | Lenhard B.,Clinical Science Center | Lenhard B.,University of Bergen | Sandelin A.,Copenhagen University | Carninci P.,RIKEN
Nature Reviews Genetics | Year: 2012

Promoters are crucial for gene regulation. They vary greatly in terms of associated regulatory elements, sequence motifs, the choice of transcription start sites and other features. Several technologies that harness next-generation sequencing have enabled recent advances in identifying promoters and their features, helping researchers who are investigating functional categories of promoters and their modes of regulation. Additional features of promoters that are being characterized include types of histone modifications, nucleosome positioning, RNA polymerase pausing and novel small RNAs. In this Review, we discuss recent findings relating to metazoan promoters and how these findings are leading to a revised picture of what a gene promoter is and how it works. © 2012 Macmillan Publishers Limited. All rights reserved.


Grimm S.,Imperial College London
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2012

When cellular organelles communicate bad things can happen. Recent findings uncovered that the junction between the endoplasmic reticulum (ER) and the mitochondria holds a crucial role for cell death regulation. Not only does this locale connect the two best-known organelles in apoptosis, numerous regulators of cell death are concentrated at this spot, providing a terrain for intense signal transfers. Ca 2+ is the most prominent signalling factor that is released from the ER and, at high concentration, mediates the transfer of an apoptosis signal to mitochondria as the executioner organelle for cell death. An elaborate array of checks and balances is fine-tuning this process including Bcl-2 family members. Moreover, MAMs, "mitochondria-associated membranes", are distinct membrane sections at the ER that are in close contact with mitochondria and have been found to exchange lipids and lipid-derived molecules such as ceramide for apoptosis induction. Recent work has also described a reverse transfer of apoptosis signals, from mitochondria to the ER, via cytochrome c release and prolonged IP 3R opening or through the mitochondrial fission factor Fis1 and Bap31 at the ER, which form the ARCosome, a novel caspase-activation complex. © 2011 Elsevier B.V.


Dumas M.-E.,Imperial College London
Molecular BioSystems | Year: 2012

The characterization of the metabolome has rapidly evolved over two decades, from early developments in analytical chemistry to systems biology. Metabolites and small molecules are not independent; they are organized in biochemical pathways and in a wider metabolic network, which is itself dependent on various genetic and signaling networks for its regulation. Recent advances in genomics, transcriptomics, proteomics and metabolomics have been matched by the development of publicly available repositories, which have helped shaping a new generation of integrative studies using metabolite measurements in molecular epidemiology and genetic studies. Although the environment influences metabolism, the identification of the genetic determinants of metabolic phenotypes (metabotypes) was made possible by the development of metabotype quantitative trait locus (mQTL) mapping and metabolomic genome-wide association studies (mGWAS) in a rigorous statistical genetics framework, deriving associations between metabolite concentrations and genetic polymorphisms. However, given the complexity of the biomolecular events involved in the regulation of metabolic patterns, alternative network biology approaches have also been recently introduced, such as integrated metabolome and interactome mapping (iMIM). This unprecedented convergence of metabolic biochemistry, quantitative genetics and network biology already has had a strong impact on the role of the metabolome in biomedical sciences, and this review gives a foretaste of its anticipated successes in eventually delivering personalized medicine. © 2012 The Royal Society of Chemistry.


Pollock K.M.,Imperial College London
The Journal of infectious diseases | Year: 2013

Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection. A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α). Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPDspecific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone. Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies.


Knoll R.,Imperial College London
Journal of Muscle Research and Cell Motility | Year: 2012

Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure. © 2011 The Author(s).


Edwards C.,Imperial College London
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Proinflammatory cytokines activate the hypothalamic pituitary adrenal axis in the acute phase but not with chronic inflammation; indeed, the hypothalamic pituitary adrenal axis is subtly subnormal, with apparently low ACTH and cortisol secretion. This paper reviews evidence that suggests that this is not simply an adaptation to chronic stress. These patients have increased conversion of inactive cortisone (E) to cortisol (F) by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Expression of this enzyme is markedly enhanced by TNF, an important autocrine protective mechanism at the inflammatory site. Evidence Acquisition and Synthesis: This report reviews the current understanding of the interaction between TNF and 11β-HSD1 in patients with chronic inflammatory disease. It is based on publications from PubMed and the Science Citation Index. Conclusions: The systemic effects of enhancing 11β-HSD1 activity may amplify the inflammatory response. Thus, increased conversion of cortisone to cortisol can alter the circadian rhythm of cortisol secretion (lower nadir, later rise, impaired stress response) with consequent relative nocturnal cortisol deficiency when inflammatory cytokines are highest. This could contribute to the circadian symptomatology in rheumatoid arthritis, the effectiveness of early morning (0200 h) low-dose corticosteroids, the significant correlation between total body 11β-HSD1 activity and erythrocyte sedimentation rate, and the effectiveness of 11 β-HSD inhibition in both the prevention and treatment of adjuvant arthritis in rat models of rheumatoid arthritis. It could also explain why anti-TNF therapy benefit can be predicted on the basis of the pretreatment plasma cortisol and the subsequent cortisol rise. In contrast, this mechanism is likely to be beneficial in the body's response to chronic infections such as tuberculosis and could explain why anti-TNF treatment markedly increases the risk of reactivation of the disease. Copyright © 2012 by The Endocrine Society.


Delves M.J.,Imperial College London
Future Medicinal Chemistry | Year: 2012

Malaria is a disease with a devastating impact affecting 216 million people each year and causing 655,000 deaths, most of which are children under 5 years old. Recent appreciation that malaria eradication will require novel interventions to target the parasite during transmission from the human host to the mosquito has lead to an exciting surge in activity to develop transmission-blocking drugs and the high-throughput assays to screen for them. This article presents an overview of transmission-stage cell biology and discusses its impact on assay development to provide a context for researchers to evaluate the relative merits/drawbacks of both screening data obtained from current assays and considerations for future assay design. The most recent knowledge of the transmission-blocking properties of current antimalarial classes is also summarized and, underdeveloped targets for transmission-stage drug discovery are highlighted. © 2012 Future Science Ltd.


Baxter J.,University of Sussex | Aragon L.,Imperial College London
Trends in Genetics | Year: 2012

The compaction of chromatin that occurs when cells enter mitosis is probably the most iconic process of dividing cells. Mitotic chromosomal compaction or 'condensation' is functionally linked to resolution of chromosomal intertwines, transcriptional shut-off and complete segregation of chromosomes. At present, understanding of the molecular events required to convert interphase chromatin into mitotic chromosomes is limited. Here, we review recent advances in the field, focusing on potential chromosomal compaction mechanisms and their importance to chromosome segregation. We propose a model of how metaphase chromosomes could be shaped based on the enzymatic activities of condensin and topoisomerase II in overwinding and relaxation of the DNA fiber during mitosis. We suggest that condensin overwinding is an important requirement for intertwine resolution by topoisomerase II and, together with the inhibition of transcription, contributes to cytological mitotic chromosome appearance or 'condensation'. © 2011 Elsevier Ltd.


Proton exchange membrane fuel cells (PEM FCs) offer a promising alternative to internal combustion engines in road transport. During the last decade PEM FC research, development and demonstration (RD&D) activities have been steadily increasing worldwide, and targets have been set to begin their commercialisation in road transport by 2015-2020. However, there still is considerable uncertainty on whether these targets will actually be met. The picture is complex and market and technology issues are closely interlinked; investment in RD&D projects is essential but not sufficient; the development of suitable early markets is also necessary and policy is set to play an important role. Auxiliary power units (APUs) are generally regarded as one important early market for FCs in transport. This paper analyses the possible future market for diesel PEM FC APUs onboard long-haul trucks and its implications for the development of PEM FCs in general. The analysis, part of the project HyTRAN (EC Contract no. 502577), is aided by the use of a dynamic simulation model of technology and markets developed by the author. Results suggest that an interesting window of opportunity for diesel PEM FC APUs exists but this is subject to additional research particularly targeted at the rapid development of fuel processors. © 2009 Elsevier Ltd. All rights reserved.


Crowdy D.,Imperial College London
Physics of Fluids | Year: 2011

The exact solutions due to Philip [ZAMP 23, 353 (1972)] for Stokes shear flow over a periodic array of no-shear slots embedded in a no-slip surface are generalized to account for an arbitrary pattern of no-shear slots in each period window. The slots, or grooves, in each period window run parallel to each other, and are of infinite length, but their widths and separations can be specified arbitrarily. Explicit solutions are found both for longitudinal and transverse flows over the composite grooved surface. Analytical expressions for the transverse and longitudinal slip lengths associated with the microstructured surfaces are then found as functions of the geometrical parameters characterizing the surface. The formulae are relevant to a wide class of flow geometries and are expected to provide a useful tool in the design, analysis, and optimization of the friction properties of grooved microstructured superhydrophobic surfaces. The results are used to show that introducing even a very small wetted region in a no-shear slot can have a significant influence on the effective slip length. © 2011 American Institute of Physics.


Elkington P.T.,University of Southampton | Friedland J.S.,Imperial College London
The Lancet Infectious Diseases | Year: 2015

Tuberculosis remains a global health pandemic. The current depiction of the Mycobacterium tuberculosis life cycle proposes that airborne bacilli are inhaled and phagocytosed by alveolar macrophages, resulting in the formation of a granuloma that ruptures into the airways to reinitiate the infectious cycle. However, this widely proposed model overlooks the fact, established 100 years ago, that the initial site of M tuberculosis implantation is in the lower zones of the lungs, whereas infectious cavitary pulmonary disease develops at the lung apices. The immunological events at these two pulmonary locations are different-cavitation only occurs in the apices and not in the bases. Yet the current conceptual model of tuberculosis renders the immunology of these two temporally and spatially separated events identical. One key consequence is that prevention of primary childhood tuberculosis at the lung bases is regarded as adequate immunological protection, but extensive evidence shows that greater immunity could predispose to immunopathology and transmission at the lung apex. A much greater understanding of time and place in the immunopathological mechanisms underlying human tuberculosis is needed before further pre-exposure vaccination trials can be done. © 2015 Elsevier Ltd.


Vassilicos J.C.,Imperial College London
Physics Letters, Section A: General, Atomic and Solid State Physics | Year: 2011

The von Kárman-Howarth equation implies an infinity of invariants corresponding to an infinity of different asymptotic behaviours of the double and triple velocity correlation functions at infinite separations. Given an asymptotic behaviour at infinity for which the Birkhoff-Saffman invariant is not infinite, there are either none, or only one or only two finite invariants. If there are two, one of them is the Loitsyansky invariant and the decay of large eddies cannot be self-similar. We examine the consequences of this infinity of invariants on a particular family of exact solutions of the von Kárman-Howarth equation. © 2011 Elsevier B.V.


Inositol phospholipids have emerged as important key players in a wide variety of cellular functions. Among the seven existing inositol phospholipids, phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P(2)) has attracted much attention in recent years due to its important role in numerous cellular signaling events and regulations, which in turn impact several human diseases. This particular lipid is recognized in the cell by specific lipid binding domains, such as the Pleckstrin-homology (PH) domain, which is also employed as a tool to monitor this important lipid. Here, we describe the synthesis and biological characterization of a small molecule that mimics the PH domain as judged by its ability to bind specifically to only PI(4,5)P(2) and effectively compete with the PH domain in vitro and in a cellular environment. The binding constant of this small molecule PH domain mimetic (PHDM) was determined to be 17.6 ± 10.1 μM, similar in potency to the PH domain. Using NIH 3T3 mouse fibroblast cells we demonstrated that this compound is cell-permeable and able to modulate PI(4,5)P(2)-dependent effects in a cellular environment such as the endocytosis of the transferrin receptor, loss of mitochondria, as well as stress fiber formation. This highly PI(4,5)P(2)-specific chemical mimetic of a PH domain not only is a powerful research tool but might also be a lead compound in future drug developments targeting PI(4,5)P(2)-dependent diseases such as Lowe syndrome.


Albrecht T.,Imperial College London
ACS Nano | Year: 2011

Nanopore-based single-molecule sensors have become an important class of analytical devices that have in some cases already reached the market place. Traditionally operated in a two-electrode configuration, devices with three or more electrodes have emerged recently, for example with a view on switching the transport properties of the nanopore or even tunneling-based detection of analytes with the ultimate goal of inexpensive and ultrafast DNA sequencing. How do these additional electrodes affect the current distribution in the cell and hence the sensor performance? This is significantly less clear and thus in focus here. We use impedance modeling of a prototypical three-electrode nanopore sensor and show that, depending on the conditions, standard experimental device characterization is severely affected by the presence of the third electrode. On the other hand, the simulations also provide guidelines on how to avoid such complications, identify "safe" operating conditions, and design criteria for optimized nanopore sensors. © 2011 American Chemical Society.


Tseytlin A.A.,Imperial College London
Nuclear Physics B | Year: 2013

We study 4-dimensional higher-derivative conformal higher-spin (CHS) fields generalizing Weyl graviton and conformal gravitino. They appear, in particular, as "induced" theories in the AdS/CFT context. We consider their partition function on curved Einstein-space backgrounds like (A)dS or sphere and Ricci-flat spaces. Remarkably, the bosonic (integer spin s) CHS partition function appears to be given by a product of partition functions of the standard 2nd-derivative "partially massless" spin s fields, generalizing the previously known expression for the 1-loop Weyl graviton (s=2) partition function. We compute the corresponding spin s Weyl anomaly coefficients as and cs. Our result for as reproduces the expression found recently in arXiv:1306.5242 by an indirect method implied by AdS/CFT (which relates the partition function of a CHS field on S4 to a ratio of known partition functions of massless higher-spin field in AdS5 with alternate boundary conditions). We also obtain similar results for the fermionic CHS fields. In the half-integer s case the CHS partition function on (A)dS background is given by the product of squares of "partially massless" spin s partition functions and one extra factor corresponding to a special massive conformally invariant spin s field. It was noticed in arXiv:1306.5242 that the sum of the bosonic as coefficients over all s is zero when computed using the ζ-function regularization, and we observe that the same property is true also in the fermionic case. © 2013 Elsevier B.V.


Pusey M.F.,Imperial College London
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

The violation of a Bell inequality certifies the presence of entanglement even if neither party trusts their measurement devices. Recently Moroder showed how to make this statement quantitative, using semidefinite programming to calculate how much entanglement is certified by a given violation. Here I adapt their techniques to the case in which Bob's measurement devices are in fact trusted, the setting for Einstein-Podolsky-Rosen steering inequalities. Interestingly, all of the steering inequalities studied turn out to require negativity for their violations. This supports a significant strengthening of Peres's conjecture that negativity is required to violate a bipartite Bell inequality. © 2013 American Physical Society.


Barnes P.J.,Imperial College London
Pharmacological Reviews | Year: 2016

Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation, and proliferation. For this reason there has been great interest in the development of kinase inhibitors as anti-inflammatory therapies, particular where corticosteroids are less effective, as in severe asthma and COPD. However, it has proven difficult to develop selective kinase inhibitors that are both effective and safe after oral administration and this has led to a search for inhaled kinase inhibitors, which would reduce systemic exposure. Although many kinases have been implicated in inflammation and remodeling of airway disease, very few classes of drug have reached the stage of clinical studies in these diseases. The most promisingdrugs arep38MAPkinases, isoenzyme-selective PI3-kinases, Janus-activated kinases, and Syk-kinases, and inhaled formulations of these drugs are now in development. There has also been interest in developing inhibitors that block more than one kinase, because these drugs may be more effective and with less risk of losing efficacy with time. No kinase inhibitors are yet on the market for the treatment of airway diseases, but as kinase inhibitors are improved from other therapeutic areas there is hope that these drugs may eventually prove useful in treating refractory asthma and COPD. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.


Chung K.F.,Imperial College London
Pulmonary Pharmacology and Therapeutics | Year: 2011

Chronic cough remains a challenge to many clinicians because there is often no diagnostic link to causation, and because indirect antitussives are largely ineffective. Chronic cough can also be a predominant symptom associated with many chronic respiratory diseases such as COPD, asthma and pulmonary fibrosis. Chronic cough itself does impair the quality of life and is associated with psychological impairment. The symptoms associated with chronic cough include persistent tickling or irritating sensation in the chest or throat, hoarse voice, dysphonia or vocal cord dysfunction. Currently, the clinical diagnosis of cough is associated with chronic cough caused by airway eosinophilic conditions such as asthma, gastrooesophageal reflux disease or post-nasal drip (or upper airway syndrome), which implies cause and effect, or with chronic cough associated with other diseases such as COPD, cancer or heart failure, that does not necessarily imply cause and effect. A recently-recognised category is idiopathic cough, with no associated or causative diagnosis. We suggest that there is a better label needed for chronic cough, that includes the common association with a hypersensitive cough response to tussive stimuli such as capsaicin or citric acid. This would invoke a hypersensitive syndrome, and there are good reasons to use a new label that would encompass the problem of chronic cough: the chronic 'cough hypersensitivity syndrome'. This would focus the problem on the cough symptomatology and lead to greater focus on understanding the mechanisms of cough sensitisation, with the ultimate aim of obtaining more effective antitussives. © 2011 Elsevier Ltd.


Postma D.S.,University of Groningen | Bush A.,Imperial College London | Van Den Berge M.,University of Groningen
The Lancet | Year: 2015

Summary Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent around the age of 40-50 years, its origins can begin very early in life. Different risk factors in very early life - ie, in utero and during early childhood - drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life. © 2015 Elsevier Ltd.


Forbes S.J.,University of Edinburgh | Rosenthal N.,Imperial College London | Rosenthal N.,Monash University
Nature Medicine | Year: 2014

Chronic diseases confer tissue and organ damage that reduce quality of life and are largely refractory to therapy. Although stem cells hold promise for treating degenerative diseases by 'seeding' injured tissues, the regenerative capacity of stem cells is influenced by regulatory networks orchestrated by local immune responses to tissue damage, with macrophages being a central component of the injury response and coordinator of tissue repair. Recent research has turned to how cellular and signaling components of the local stromal microenvironment (the 'soil' to the stem cells' seed), such as local inflammatory reactions, contribute to successful tissue regeneration. This Review discusses the basic principles of tissue regeneration and the central role locally acting components may play in the process. Application of seed-and-soil concepts to regenerative medicine strengthens prospects for developing cell-based therapies or for promotion of endogenous repair. © 2014 Nature America, Inc.


Diez-Gonzalez S.,Imperial College London
Current Organic Chemistry | Year: 2011

The last decade has witnessed a tremendous increase of the studies concerning [3+2] cycloaddition reactions of azides and alkynes. The recent discovery of copper(I) species as efficient catalysts for this transformation is at the origin of this true explosion. In contrast with classical thermal reactions, copper catalysis leads to the regioselective formation of 1,4-disubstituted 1,2,3-triazoles in high yields and under simple reaction conditions. This transformation has indeed become the most prominent example of the principles of Click chemistry, postulated in 2001 by Sharpless and co-workers. Despite the ever-increasing interest in this process, the use of ligands in this context remains minor when compared to ligandless systems. Nevertheless, besides overcoming the inherent limitations of ligandless systems, the use of ligands in this context has been shown to increase and, more importantly, modulate the catalytic activity of the metal center. Herein, the catalytic activities of ligated copper systems are reviewed in a way intended inspirational for future developments in this field. © 2011 Bentham Science Publishers Ltd.


Cargill P.J.,Imperial College London | Cargill P.J.,University of St. Andrews
Astrophysical Journal | Year: 2014

The temperature dependence of the emission measure (EM) in the core of active regions coronal loops is an important diagnostic of heating processes. Observations indicate that EM(T) ∼ Ta below approximately 4 MK, with 2 < a < 5. Zero-dimensional hydrodynamic simulations of nanoflare trains are used to demonstrate the dependence of a on the time between individual nanoflares (TN) and the distribution of nanoflare energies. If TN is greater than a few thousand seconds, a < 3. For smaller values, trains of equally spaced nanoflares cannot account for the observed range of a if the distribution of nanoflare energies is either constant, randomly distributed, or a power law. Power law distributions where there is a delay between consecutive nanoflares proportional to the energy of the second nanoflare do lead to the observed range of a. However, TN must then be of the order of hundreds to no more than a few thousand seconds. If a nanoflare leads to the relaxation of a stressed coronal field to a near-potential state, the time taken to build up the required magnetic energy is thus too long to account for the EM measurements. Instead, it is suggested that a nanoflare involves the relaxation from one stressed coronal state to another, dissipating only a small fraction of the available magnetic energy. A consequence is that nanoflare energies may be smaller than previously envisioned. © 2014. The American Astronomical Society. All rights reserved.


Marcano Belisario J.S.,Imperial College London
The Cochrane database of systematic reviews | Year: 2013

Asthma is one of the most common long-term conditions worldwide, which places considerable pressure on patients, communities and health systems. The major international clinical guidelines now recommend the inclusion of self management programmes in the routine management of did not conduct a meta-analysis of the data extracted due to the considerable degree of heterogeneity between these studies. Instead we adopted a narrative synthesis approach. Overall, the results were inconclusive and we judged the evidence to have a GRADE rating of low quality because further evidence is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. In addition, there was not enough information in one of the included studies to assess the risk of bias for the majority of the domains. Although the other included study was methodologically rigorous, it was not possible to blind participants or personnel in the study. Moreover, there are concerns in both studies in relation to attrition bias and other sources of bias.One study showed that the use of a smartphone app for the delivery of an asthma self management programme had no statistically significant effect on asthma symptom scores (mean difference (MD) 0.01, 95% confidence interval (CI) -0.23 to 0.25), asthma-related quality of life (MD of mean scores 0.02, 95% CI -0.35 to 0.39), unscheduled visits to the emergency department (OR 7.20, 95% CI 0.37 to 140.76) or frequency of hospital admissions (odds ratio (OR) 3.07, 95% CI 0.32 to 29.83). The other included study found that the use of a smartphone app resulted in higher asthma-related quality of life scores at six-month follow-up (MD 5.50, 95% CI 1.48 to 9.52 for the physical component score of the SF-12 questionnaire; MD 6.00, 95% CI 2.51 to 9.49 for the mental component score of the SF-12 questionnaire), improved lung function (PEFR) at four (MD 27.80, 95% CI 4.51 to 51.09), five (MD 31.40, 95% CI 8.51 to 54.29) and six months (MD 39.20, 95% CI 16.58 to 61.82), and reduced visits to the emergency department due to asthma-related complications (OR 0.20, 95% CI 0.04 to 0.99). Both studies failed to find any statistical differences in terms of adherence to the intervention and occurrence of other asthma-related complications. The current evidence base is not sufficient to advise clinical practitioners, policy-makers and the general public with regards to the use of smartphone and tablet computer apps for the delivery of asthma self management programmes. In order to understand the efficacy of apps as standalone interventions, future research should attempt to minimise the differential clinical management of patients between control and intervention groups. Those studies evaluating apps as part of complex, multicomponent interventions, should attempt to tease out the relative contribution of each intervention component. Consideration of the theoretical constructs used to inform the development of the intervention would help to achieve this goal. Finally, researchers should also take into account: the role of ancillary components in moderating the observed effects, the seasonal nature of asthma and long-term adherence to self management practices.


Boasso A.,Imperial College London
Current Medicinal Chemistry | Year: 2011

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme which plays a key role in maintaining the physiologic immune balance between the efficient responses to insulting pathogens and the control of harmful autoimmune reactions. During HIV infection, multiple mechanisms involving both viral and cellular components, contribute to enhance IDO expression and activity in an uncontrolled manner. The downstream effects of IDO overactivation collectively contribute to the immune alterations which characterize HIV disease. This review explores the cellular and molecular pathways which result in IDO upregulation during HIV infection and considers the consequences of IDO hyperactivity on the immune system, their relevance in the context of HIV immunopathogenesis and the potential for specific therapeutic intervention. © 2011 Bentham Science Publishers Ltd.


Markus M.B.,Imperial College London
Parasitology Research | Year: 2011

In 1978, the nature of the hypnozoite was discussed in an article that appeared in a relatively obscure journal, which is also where the term was adopted for Plasmodium (a little-known fact). As a result, that commentary on the use of the word "hypnozoite" has been almost completely overlooked. Although the publication is now more than three decades old, the analysis remains valid today. It is explained in the present paper that like "merozoite" and "sporozoite", the name " hypnozoite" is applicable not only to a latent stage in the life cycle of Plasmodium but to some apparently dormant forms of other kinds of apicomplexan parasites as well. Merozoites of different genera of parasitic protozoa are not necessarily the same biologically and/or otherwise. Similarly, although the hypnozoite concept relates primarily to pre-merozoite stages, some atypical post-divisional apicomplexan forms might also be hypnozoites. Examples are likewise given of latent organisms that, in contrast, are clearly not hypnozoites, such as dormant merozoites in malaria infections. Lastly, the plasmodial hypnozoite is placed in context in relation to the relatively unfamiliar (nomenclaturally) malarial bradysporozoite, chronozoite, dormozoite, merophore, merosome and x body. This paper is based on a presentation by the author, as a Life Member of the American Society of Tropical Medicine and Hygiene, to its 59th Annual Meeting in Atlanta, Georgia, USA, 3-7 November 2010. © 2010 Springer-Verlag.


Sugand K.,Imperial College London
Anatomical sciences education | Year: 2010

Anatomy has historically been a cornerstone in medical education regardless of nation or specialty. Until recently, dissection and didactic lectures were its sole pedagogy. Teaching methodology has been revolutionized with more reliance on models, imaging, simulation, and the Internet to further consolidate and enhance the learning experience. Moreover, modern medical curricula are giving less importance to anatomy education and to the acknowledged value of dissection. Universities have even abandoned dissection completely in favor of user-friendly multimedia, alternative teaching approaches, and newly defined priorities in clinical practice. Anatomy curriculum is undergoing international reformation but the current framework lacks uniformity among institutions. Optimal learning content can be categorized into the following modalities: (1) dissection/prosection, (2) interactive multimedia, (3) procedural anatomy, (4) surface and clinical anatomy, and (5) imaging. The importance of multimodal teaching, with examples suggested in this article, has been widely recognized and assessed. Nevertheless, there are still ongoing limitations in anatomy teaching. Substantial problems consist of diminished allotted dissection time and the number of qualified anatomy instructors, which will eventually deteriorate the quality of education. Alternative resources and strategies are discussed in an attempt to tackle these genuine concerns. The challenges are to reinstate more effective teaching and learning tools while maintaining the beneficial values of orthodox dissection. The UK has a reputable medical education but its quality could be improved by observing international frameworks. The heavy penalty of not concentrating on sufficient anatomy education will inevitably lead to incompetent anatomists and healthcare professionals, leaving patients to face dire repercussions. Copyright 2010 American Association of Anatomists.


Barraclough T.G.,Imperial College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Current approaches to studying the evolution of biodiversity differ in their treatment of species and higher level diversity patterns. Species are regarded as the fundamental evolutionarily significant units of biodiversity, both in theory and in practice, and extensive theory explains how they originate and evolve. However, most species are still delimited using qualitative methods that only relate indirectly to the underlying theory. In contrast, higher level patterns of diversity have been subjected to rigorous quantitative study (using phylogenetics), but theory that adequately explains the observed patterns has been lacking. Most evolutionary analyses of higher level diversity patterns have considered non-equilibrium explanations based on rates of diversification (i.e. exponentially growing clades), rather than equilibrium explanations normally used at the species level and below (i.e. constant population sizes). This paper argues that species level and higher level patterns of diversity can be considered within a common framework, based on equilibrium explanations. It shows how forces normally considered in the context of speciation, namely divergent selection and geographical isolation, can generate evolutionarily significant units of diversity above the level of reproductively isolated species. Prospects for the framework to answer some unresolved questions about higher level diversity patterns are discussed. ©2010 The Royal Society.


Chevin L.-M.,Imperial College London
Biology Letters | Year: 2011

Distributions of mutation fitness effects from evolution experiments are available in an increasing number of species, opening the way for a vast array of applications in evolutionary biology. However, comparison of estimated distributions among studies is hampered by inconsistencies in the definitions of fitness effects and selection coefficients. In particular, the use of ratios of Malthusian growth rates as 'relative fitnesses' leads to wrong inference of the strength of selection. Scaling Malthusian fitness by the generation time may help overcome this shortcoming, and allow accurate comparison of selection coefficients across species. For species reproducing by binary fission (neglecting cellular death), In2 can be used as a correction factor, but in general, the growth rate and generation time of the wild-type should be provided in studies reporting distribution of mutation fitness effects. I also discuss how density and frequency dependence of population growth affect selection and its measurement in evolution experiments. © 2011 The Royal Society.


Gilestro G.F.,Imperial College London
Nature protocols | Year: 2012

In the past decade, Drosophila has emerged as an ideal model organism for studying the genetic components of sleep as well as its regulation and functions. In fruit flies, sleep can be conveniently estimated by measuring the locomotor activity of the flies using techniques and instruments adapted from the field of circadian behavior. However, proper analysis of sleep requires degrees of spatial and temporal resolution higher than is needed by circadian scientists, as well as different algorithms and software for data analysis. Here I describe how to perform sleep experiments in flies using techniques and software (pySolo and pySolo-Video) previously developed in my laboratory. I focus on computer-assisted video tracking to monitor fly activity. I explain how to plan a sleep analysis experiment that covers the basic aspects of sleep, how to prepare the necessary equipment and how to analyze the data. By using this protocol, a typical sleep analysis experiment can be completed in 5-7 d.


Ashton-Rickardt P.G.,Imperial College London
Immunological Reviews | Year: 2010

Serine proteases control a wide variety of physiological and pathological processes in multi-cellular organisms, including blood clotting, cancer, cell death, osmoregulation, tissue remodeling, and immunity to infection. Cytotoxic T lymphocytes (CTLs) are required for adaptive cell-mediated immunity to intracellular pathogens by killing infected cells and through the development of memory T cells. Serine proteases not only allow a CTL to kill but also impose homeostatic control on CTL number. Serine protease inhibitors (serpins) are the physiological regulators of serine proteases' activity. In this review, I discuss the role of serpins in controlling the recognition of antigen, effector function, and homeostatic control of CTLs through the inhibition of physiological serine protease targets. An emerging view of serpins is that they are important promoters of cellular viability through their inhibition of executioner proteases. This view is discussed in the context of the T-lymphocyte survival during effector responses and the development and persistence of long-lived memory T cells. Given the important role serpins play in CTL immunity, I discuss the potential for developing new immunotherapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets. © 2010 John Wiley & Sons A/S.


Gavins F.N.E.,Imperial College London
Trends in Pharmacological Sciences | Year: 2010

Ischaemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as stroke and myocardial infarction. The damaged tissue displays cardinal signs of inflammation and microvascular injury that, unless resolved, lead to long-term tissue damage with associated dysfunction. Current therapies are limited and are often associated with many side effects. Increasing evidence suggests that members of the formyl peptide receptor (FPR) family, in particular human FPR2/ALX, might have an important role in the pathophysiology of I/R injury. It was recently demonstrated that several peptides and non-peptidyl small-molecule compounds have anti-inflammatory and pro-resolving properties via their action on members of the FPR family. Here I review this evidence and suggest that FPR ligands, particularly in the brain, could be novel and exciting anti-inflammatory therapeutics for the treatment of a variety of clinical conditions, including stroke. © 2010 Elsevier Ltd.


Wang Y.,Imperial College London
Geophysical Journal International | Year: 2013

This paper presents a novel system for computing seismic slowness paths and the traveltime field simultaneously in anisotropic media, in which the ray path concept is replaced with the concept of slowness paths. Like ray paths in isotropic media, slowness paths are orthogonal to the wave fronts in anisotropic media. The novelty of the proposed system relies on the explicit normal constraint that slowness vectors are perpendicular to wave fronts. While the system finds the positions of sequential wave fronts with a constant time interval, samples of consecutive wave fronts represent slowness paths which are normal to wave fronts and follow phase velocities in anisotropic media. The simultaneous calculation can remove any shadow zones where paths might fail to emerge by path-tracing and meanwhile avoid the instability problem in conventional eikonal-equation solution for traveltimes. While any differential discontinuity (such as cusps in a wave front) causes numerical instability, it is dealt with by a least-squares smoothing strategy along the wave front. The feasibility is demonstrated using numerical examples from simple to realistic anisotropic models. © The Authors 2013. Published by Oxford University Press on behalf of The Royal Astronomical Society.


OBJECTIVES: B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity.METHODS: B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system.RESULTS: Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls.CONCLUSION: In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


Arulkumaran N.,Imperial College London
Rheumatology (Oxford, England) | Year: 2011

ANCA-associated vasculitis and interstitial lung disease (ILD) are uncommon conditions. The occurrence of both diseases in the same patient is increasingly recognized. Our aim was to ascertain the characteristics and outcomes of patients with ILD and ANCA-associated vasculitis. A retrospective observational cohort study was performed. Patients who presented to the Hammersmith Hospital, London, with ANCA-associated vasculitis [granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis (MPA) or Churg-Strauss syndrome] who also had ILD were included. Following hospital discharge, all patients were followed up in a multi-disciplinary vasculitis clinic. We recorded patient demographics, diagnostic tests, treatment, complications and mortality. ILD was observed in 2.7% (n = 14) of our patients with ANCA-associated vasculitis (n = 510); all had MPO-ANCA and a clinical diagnosis of MPA, giving a prevalence of 7.2% in patients with MPA (n = 194). There was no significant difference in survival between patients with MPA and ILD and those with MPA alone. It is important that physicians are aware of this clinical association and the presence of ILD should be considered in all patients with ANCA-associated vasculitis, especially those with MPO-ANCA. The possibility that patients with ILD may subsequently develop features of systemic vasculitis should also be remembered.


Rezvani K.,Imperial College London
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

Allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) remains a curative treatment for hematological malignancies resistant to other treatment approaches through the unique GVL effect. However, relapse remains a major cause of treatment failure after allogeneic HSCT for patients with high-risk hematological malignancies. Further improvements in exploiting the GVL effect to prevent relapse in high-risk leukemias while minimizing toxicity have focused on the use of targeted antileukemic immunotherapy. These strategies include methods to boost the GVL effect with leukemia vaccines or the adoptive transfer of leukemia-specific lymphocytes. Vaccines can be classified as those against defined antigens such as minor histocompatibility antigens (mHags) or leukemia-associated antigens (PR1, WT1, and BCR-ABL) and those that have broad "antileukemic" activity such as engineered irradiated leukemia cells or leukemia-derived dendritic cells (DCs). The unique posttransplantation milieu, which is characterized by lymphopenia, regulatory T-cell depletion, and the release of growth factors, provides a unique opportunity for effective antitumor immunotherapy and augmenting specific GVL responses. This review focuses on approaches to enhancimg the GVL response by combining allogeneic HSCT with vaccination.


Barnes P.J.,Imperial College London
Journal of Allergy and Clinical Immunology | Year: 2013

Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. © 2013 American Academy of Allergy, Asthma & Immunology.


Whittaker A.C.,Imperial College London
Lithosphere | Year: 2012

The Earth's surface is shaped by tectonics and climate. This simple statement implies that we should, in principle, be able to use the landscape as an archive of both tectonic rates and of changes to climate regime. To solve this inverse problem, and decipher the geomorphic record effectively, we need a sound understanding of how landscapes respond and erode in response to changes in tectonic or climatic boundary conditions. Rivers have been a major focus of research in this fi eld because they are patently sensitive to tectonic and climatic forcing via their channel gradient and discharge. Theoretical, fi eld, and numerical modeling techniques in the last few years have produced a wealth of insight into the behavior of fl uvial landscapes, while the increasing availability of high-resolution topographic models have provided the data sets necessary to address this research challenge across the globe. New work by Miller et al. (2012) in Papua New Guinea highlights the progress we have made in extracting tectonics from topography due to these developments, but also illustrates the problems that still remain. This paper reviews our current knowledge of how fl uvial landscapes record tectonics at topographic steady-state and under "transient" conditions, assesses why the climate signal has proven so challenging to interpret, and maps out where we need to go in the future. © 2012 Geological Society of America.


Sephton M.A.,Imperial College London
Geochimica et Cosmochimica Acta | Year: 2013

Ancient meteorites contain several percent of organic matter that represents a chronicle of chemical evolution in the early solar system. Aromatic hydrocarbon units make up the majority of meteorite organic matter but reading their record of organic evolution is not straightforward and their formation mechanisms have remained elusive. Most aromatic units reside in a macromolecular material and new perceptions of its structure have been provided by a novel on-line hydrogenation approach. When applied to the Orgueil (CI1) and Murchison (CM2) meteorites the technique releases a range of aromatic hydrocarbons along with some oxygen, sulphur and nitrogen-containing aromatic units. When on-line hydrogenation is compared to conventional pyrolysis, more high molecular weight units and a wider range of liberated entities are evident. Comparisons of results from Orgueil and Murchison reveal variations that are most likely related to differing levels of parent body alteration. The enhancement of straight-chain hydrocarbons (n-alkanes) in the hydrogenation products imply a source of these common contaminants from straight-chain carboxylic acid (n-alkanoic acid) precursors, perhaps from bacterial contributions on Earth. The on-line hydrogenation data also highlight a long-standing but unexplained observation related to the relative preference for specific isomers in methyl-substituted benzenes (meta-, ortho- and para-xylenes). The new hydrogenation approach appears to release and transform macromolecular material meta-structures (benzenes with substituents separated by single carbon atoms) into their free hydrocarbon counterparts. Their release characteristics suggest that the meta-structures are bound by oxygen-linkages. The meta-structures may be molecular probes of specific ancient cosmic environments. Parent body processing may have performed a similar function as hydrogenation to produce the most common meta configuration for free substituted benzenes. Notably, this isomeric preference for substituted benzenes is relatively distinctive for meteorites and can help in the discrimination of meteorite-derived and fossil biology-derived organic matter on Earth and on Mars. © 2013 Elsevier Ltd.


Prospective studies have consistently reported lower colorectal cancer risks associated with higher intakes of total dairy products, total milk and dietary calcium. However, less is known about whether the inverse associations vary for individual dairy products with differing fat contents. In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between intakes of total milk and milk subtypes (whole-fat, semi-skimmed and skimmed), yoghurt, cheese, and dietary calcium with colorectal cancer risk amongst 477,122 men and women. Dietary questionnaires were administered at baseline. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for relevant confounding variables. During the mean 11 years of follow-up, 4,513 incident cases of colorectal cancer occurred. After multivariable adjustments, total milk consumption was inversely associated with colorectal cancer risk (HR per 200 g/day 0.93, 95% CI: 0.89-0.98). Similar inverse associations were observed for whole-fat (HR per 200 g/day 0.90, 95% CI: 0.82-0.99) and skimmed milk (HR per 200 g/day 0.90, 95% CI: 0.79-1.02) in the multivariable models. Inverse associations were observed for cheese and yoghurt in the categorical models; although in the linear models, these associations were non-significant. Dietary calcium was inversely associated with colorectal cancer risk (HR per 200 mg/day 0.95, 95% CI: 0.91-0.99); this association was limited to dairy sources of calcium only (HR per 200 mg/day 0.95, 95% CI: 0.91-0.99), with no association observed for non-dairy calcium sources (HR per 200 mg/day 1.00, 95% CI: 0.81-1.24). Our results strengthen the evidence for a possible protective role of dairy products on colorectal cancer risk. The inverse associations we observed did not differ by the fat content of the dairy products considered.


Soto D.,Imperial College London | Silvanto J.,University of Westminster | Silvanto J.,Aalto University
Trends in Cognitive Sciences | Year: 2014

Classically, the operation of working memory (WM) has been strongly coupled with conscious states; it is thought that WM operates on conscious input and that we are conscious of the contents and operations of WM. Here, we re-evaluate the relationship between WM and conscious awareness in light of current data and question the views that awareness is mandatory for the operation of WM and that WM contents are necessarily linked to experiential states that are consciously accessible for perceptual report. We propose a novel framework for the relationship between WM and conscious awareness. © 2014 Elsevier Ltd.


Grimm S.,Imperial College London
Biochimica et Biophysica Acta - Bioenergetics | Year: 2013

I review here the evidence that complex II of the respiratory chain (RC) constitutes a general sensor for apoptosis induction. This concept emerged from work on neurodegenerative diseases and from recent data on metabolic alterations in cancer cells affecting the RC and in particular on mutations of complex II subunits. It is also supported by experiments with many anticancer compounds that compared the apoptosis sensitivities of complex II-deficient versus WT cells. These results are explained by the mechanistic understanding of how complex II mediates the diverse range of apoptosis signals. This protein aggregate is specifically activated for apoptosis by pH change as a common and early feature of dying cells. This leads to the dissociation of its SDHA and SDHB subunits from the remaining membrane-anchored subunits and the consequent block of it enzymatic SQR activity, while its SDH activity, which is contained in the SDHA/SDHB subcomplex, remains intact. The uncontrolled SDH activity then generates excessive amounts of reactive oxygen species for the demise of the cell. Future studies on these mitochondrial processes will help refine this model, unravel the contribution of mutations in complex II subunits as the cause of degenerative neurological diseases and tumorigenesis, and aid in discovering novel interference options. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease. © 2012 Elsevier B.V.


Barnes P.J.,Imperial College London
Medical Principles and Practice | Year: 2010

Chronic obstructive pulmonary disease (COPD) is a major global health problem which is increasing throughout the world and a major cause of death. However, current therapies fail to prevent disease progression or mortality. The mainstay of current drug therapy are long-acting bronchodilators; several longer-acting inhaled β2-agonists and muscarinic antagonists (and combinations) are now in development. No treatments have so far been shown to suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new targets have been identified. Several mediator antagonists tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, NF-κB kinase and phosphoinositide 3 kinase-γ and -δ, but side effects will be a major limitation so that inhaled delivery may be necessary. Perhaps the most promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by theophylline-like drugs, phosphoinositide 3 kinase-δ inhibitors, more effective antioxidants and non-antibiotic macrolides. © 2010 S. Karger AG.


Poulter N.R.,Imperial College London | Prabhakaran D.,Center for Chronic Disease Control | Caulfield M.,Queen Mary, University of London
The Lancet | Year: 2015

Raised blood pressure is the biggest single contributor to the global burden of disease and to global mortality. The numbers of people affected and the prevalence of high blood pressure worldwide are expected to increase over the next decade. Preventive strategies are therefore urgently needed, especially in less developed countries, and management of hypertension must be optimised. Genetic advances in some rare causes of hypertension have been made lately, but the aggregate effect on blood pressure of all the genetic loci identified to date is small. Hence, intervention on key environmental determinants and effective implementation of trial-based therapies are needed. Three-drug combinations can control hypertension in about 90% of patients but only if resources allow identification of patients and drug delivery is affordable. Furthermore, assessment of optimal drug therapy for each ethnic group is needed. © 2015 Elsevier Ltd.


McNab F.,Glaxosmithkline | McNab F.,UK National Institute for Medical Research | Mayer-Barber K.,National Institute of Allergy and Infectious Diseases | Sher A.,National Institute of Allergy and Infectious Diseases | And 3 more authors.
Nature Reviews Immunology | Year: 2015

Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis. Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host. © 2015 Macmillan Publishers Limited. All rights reserved.


Elkeles R.S.,Imperial College London
Atherosclerosis | Year: 2010

Measurement of coronary artery calcium score (CACS) by electron beam tomography has been shown to a powerful predictor of coronary heart disease events in asymptomatic non-diabetic subjects. In type 2 diabetes, measurement of CACS was found to be a powerful predictor of cardiovascular events which could enhance prediction provided by established risk models. 23% of type 2 diabetic subjects with low CACS were found to be at low risk for cardiovascular events. Moreover mortality was similar for type 2 diabetic and non-diabetic subjects with undetectable coronary artery calcification. Conversely type 2 diabetic subjects with high CACS were identified who were at high cardiovascular risk. Thus not all those with type 2 diabetes are at similar cardiovascular risk. Measurement of CACS enables cardiovascular risk in type 2 diabetes to be stratified so that the level of preventive therapy could be reduced in some and intensified in others. Although prospective data for the power of CACS to predict CHD events in type 1 diabetes are lacking, measurement of CACS could help in deciding on preventive therapy in type 1 diabetes. © 2009 Elsevier Ireland Ltd.


Hoskins B.,Imperial College London | Hoskins B.,University of Reading
Quarterly Journal of the Royal Meteorological Society | Year: 2013

Predictability is considered in the context of the seamless weather-climate prediction problem, and the notion is developed that there can be predictive power on all timescales. On all scales there are phenomena that occur as well as longer time-scales and external conditions that should combine to give some predictability. To what extent this theoretical predictability may actually be realised and, further, to what extent it may be useful is not clear. However the potential should provide a stimulus to, and high profile for, our science and its application for many years. © 2012 Royal Meteorological Society.


Graefe E.-M.,Imperial College London
Journal of Physics A: Mathematical and Theoretical | Year: 2012

The understanding of nonlinear PT symmetric quantum systems, arising for example in the theory of Bose-Einstein condensates in PT symmetric potentials, is widely based on numerical investigations, and little is known about generic features induced by the interplay of PT symmetry and nonlinearity. To gain deeper insights it is important to have analytically solvable toy models at hand. In the present paper the stationary states of a simple toy model of a PT symmetric system previously introduced in [1, 2] are investigated. The model can be interpreted as a simple description of a Bose-Einstein condensate in a PT symmetric double well trap in a two-mode approximation. The eigenvalues and eigenstates of the system can be explicitly calculated in a straightforward manner; the resulting structures resemble those that have recently been found numerically for a more realistic PT symmetric double delta potential. In addition, a continuation of the system is introduced that allows an interpretation in terms of a simple linear matrix model. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to Quantum physics with non-Hermitian operators. © 2012 IOP Publishing Ltd.


Young A.H.,Imperial College London
Journal of psychopharmacology (Oxford, England) | Year: 2013

Bipolar disorder is a chronic mental illness associated with high levels of somatic morbidity, comorbidity and mortality. Treatment guidelines for bipolar mania generally recommend initiating first-line therapy with a second-generation antipsychotic or mood stabiliser, either alone or in combination. Asenapine is a second-generation antipsychotic with a unique receptor binding profile, licensed for the treatment of manic episodes in adults with bipolar I disorder. 'Real-world' data are needed to complement evidence from clinical trials, in order to provide clinicians with pragmatic information regarding the likely risks and benefits of using a new agent in clinical practice. Evidence from real-world case reports demonstrates that - as in clinical trials - asenapine is effective in treating mania and mixed episodes associated with bipolar I disorder, whether used as monotherapy or in combination with a mood stabiliser. It has a rapid onset of antimanic effect and an early improvement is associated with treatment outcome. Asenapine also shows promise in controlling depressive symptoms and clinically challenging mixed states. Asenapine has a favourable tolerability profile, compared with other first-line agents, having a minimal impact on weight and metabolic parameters. Asenapine should be considered a first-line treatment option for adults with bipolar I disorder.


The Irish and British governments have recently mandated the replacement of domestic gas and electricity meters with smart meters. Their deployment strategies differ based on the extent to which deregulation of the gas and electricity market has been successful. A broad debate has been held on the various assumptions justifying the cost-benefit analyses and the permutations of these assumptions. What has been paid less attention is to what end is a smart meter being employed towards. A corollary research question is whether the deployment plan is targeting the correct sector.If the purpose is to introduce automated meter reading across the housing sector then a better strategy would be to legislate for accurate monthly bills, as in Sweden. Allowing suppliers to have greater flexibility will likely reward rather than stifle the design of competition. If the purpose is to manage demand then it may be that it's working with complex tariffs and not the meter per se that counts. The high consuming end-use categories and profile classes would be better placed for that exercise. Innovation theory also supports the targeting of new innovations to larger consumers, allowing metering innovations to proceed along historical trajectories. © 2013 Elsevier Ltd.


Jawad M.,Imperial College London
Nicotine and Tobacco Research | Year: 2014

Introduction: Waterpipe tobacco smoking (WTS) is prevalent worldwide and is legislatively enforceable under many countries' existing tobacco laws. Globally, however, the waterpipe tobacco industry anecdotally appears poorly controlled. This study aimed to gather intelligence from local government (known as local authority [LA]) staff in London, United Kingdom, about their WTS enforcement experiences. Methods: In-depth telephone interviews were conducted among 26 LA staff from 14 London boroughs, exploring industry characteristics and tobacco legislation compliance. Recurrent themes were analyzed and derived deductively. Results: Approximately 400 waterpipe premises operate across London, benefiting from high profit margins. LA staff are resource strained, limiting their surveillance of waterpipe premises, some of which are associated with an "underground" culture. Noise and nuisance are key features of waterpipe premises. Most waterpipe premises were generally noncompliant with most aspects of existing tobacco legislation, mainly due to disproportionately low fines and unclear legislation enforcement guidance. Successful methods for enforcing legislation included a synchronized, multiagency approach; however, this was inconsistently implemented across boroughs. Many LA staff believe licensing waterpipe premises will improve surveillance and control the industry's proliferation. Conclusions: The waterpipe tobacco industry is unregulated and places a significant burden on many LAs in London, mainly due to lack of resources. These problems may also occur in other large cities worldwide. Existing tobacco legislation should be amended to accommodate WTS, including consideration of licensing the industry. More research is needed to gain a full understanding of the waterpipe tobacco industry and its impact on other global cities. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.


Masters A.,Imperial College London
Journal of Geophysical Research A: Space Physics | Year: 2015

What we know about the magnetosphere of the outermost planet, Neptune, is primarily based on data taken during the Voyager 2 flyby in 1989. Establishing how Neptune's magnetosphere interacts with the solar wind is crucial for understanding the dynamics of the system. Here we assess how magnetic reconnection couples the solar wind to Neptune's magnetosphere, using analytical modeling that was recently applied to the case of Uranus. The modeling suggests that typical near-Neptune solar wind parameters make conditions at Neptune's magnetopause less favorable for magnetic reconnection than at the magnetopause boundary of any other solar system magnetosphere. The location of reconnection sites on Neptune's magnetopause is expected to be highly sensitive to planetary longitude and season, as well as interplanetary magnetic field (IMF) orientation, which is similar to the situation at Uranus. Also similar to past Uranus results, the present Neptune modeling indicates a seasonal effect, where one of the two dominant (Parker spiral) IMF orientations produces more favorable conditions for magnetopause reconnection than the other near equinox. We estimate the upper limit of the reconnection voltage applied to Neptune's magnetosphere as 35 kV (the typical voltage is expected to be considerably lower). Further progress in understanding the solar wind-magnetosphere interaction at Neptune requires other coupling mechanisms to be considered, as well as how reconnection operates at high plasma β. ©2014. American Geophysical Union. All Rights Reserved.


Milner-Gulland E.J.,Imperial College London
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

Natural resource management is littered with cases of overexploitation and ineffectual management, leading to loss of both biodiversity and human welfare. Disciplinary boundaries stifle the search for solutions to these issues. Here, I combine the approach of management strategy evaluation, widely applied in fisheries, with household utility models from the conservation and development literature, to produce an integrated framework for evaluating the effectiveness of competing management strategies for harvested resources against a range of performance metrics. I demonstrate the strengths of this approach with a simple model, and use it to examine the effect of manager ignorance of household decisions on resource management effectiveness, and an allocation tradeoff between monitoring resource stocks to reduce observation uncertainty and monitoring users to improve compliance. I show that this integrated framework enables management assessments to consider household utility as a direct metric for system performance, and that although utility and resource stock conservation metrics are well aligned, harvest yield is a poor proxy for both, because it is a product of household allocation decisions between alternate livelihood options, rather than an end in itself. This approach has potential far beyond single-species harvesting in situations where managers are in full control; I show that the integrated approach enables a range of management intervention options to be evaluated within the same framework.


Auner H.W.,Imperial College London | Cenci S.,Vita-Salute San Raffaele University
British Journal of Haematology | Year: 2015

Multiple myeloma is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage specialized in producing large amounts of immunoglobulins. The uniquely well-developed secretory apparatus that equips normal and transformed plasma cells with the capacity for high-level protein secretion constitutes a distinctive therapeutic target. In this review we discuss how fundamental cellular processes, such as the unfolded protein response (UPR), endoplasmic reticulum (ER)-associated degradation and autophagy, maintain intracellular protein homeostasis (proteostasis) and regulate plasma cell ontogeny and malignancy. We summarize our current understanding of the cellular effects of proteasome inhibitors and the molecular bases of resistance to them. Furthermore, we discuss how improvements in our understanding of the secretory apparatus and of the complex interactions between intracellular protein synthesis and degradation pathways can disclose novel drug targets for multiple myeloma, defining a paradigm of general interest for cancer biology and disorders of altered proteostasis. © 2014 John Wiley & Sons Ltd.


Shaik S.,Hebrew University of Jerusalem | Rzepa H.S.,Imperial College London | Hoffmann R.,Cornell University
Angewandte Chemie - International Edition | Year: 2013

What could be simpler than C2, a diatomic molecule that has the second strongest homonuclear bond? This molecule turns out to be a microcosm of the bonding issues that bother chemists, as is shown in this trialogue. Join the three authors in their lively debate, light a candle, as Faraday did, and see the excited states of C2! Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Rutter G.A.,Imperial College London | Chimienti F.,Astrazeneca
Diabetologia | Year: 2015

SLC30A8 encodes the secretory granule-resident and largely endocrine pancreas-restricted zinc transporter ZnT8. Interest in this gene product was sparked amongst diabetologists in 2007 when the first genome-wide association study for type 2 diabetes identified polymorphisms in SLC30A8 as affecting disease risk. Thus, the common polymorphism rs13266634 was associated with lowered beta cell function and a 14% increase in diabetes abundance per risk (C) allele. This non-synonymous variant encodes a tryptophan-to-arginine switch at position 325 in the protein’s intracellular carboxy-terminal domain, resulting in reduced zinc transport activity and, consequently, decreased intragranular zinc levels. Whereas insulin secretion from isolated islets is most often increased in mice inactivated for Slc30a8, null animals usually show impaired glucose tolerance and lowered circulating insulin. Since Slc30a8 null animals display little, if any, zinc secretion from islets, the lower plasma insulin levels could be explained by increased hepatic clearance as a result of lowered local zinc levels, or less efficient insulin action on target tissues. Despite the emerging consensus on the role of ZnT8 in glucose homeostasis, a recent genetic study in humans has unexpectedly identified loss-of-function SLC30A8 mutants that are associated with protection from diabetes. Here, we attempt to reconcile these apparently contradictory findings, implicating (1) differing degrees of inhibition of ZnT8 activity in carriers of common variants vs rare loss-of-function forms, (2) effects dependent on age or hypoxic beta cell stress. We propose that these variables conspire to affect both the size and the direction of the effect of SLC30A8 risk alleles in man. © 2014, Springer-Verlag Berlin Heidelberg.


Brusamento S.,Imperial College London
Cochrane database of systematic reviews (Online) | Year: 2012

Despite efforts to increase the uptake of prevention of mother to child transmission of HIV (PMTCT) services, coverage is still lower than desired in developing countries. A lack of male partner involvement in PMTCT services is a major barrier for women to access these services. To evaluate the impact of interventions which aim to enhance male involvement to increase women's uptake of PMTCT interventions in developing countries. We searched the following databases from the year 2000 to November 2011: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, the WHO Global Health Library, ClinicalTrials.gov, Current Controlled Trials, AEGIS, CROI, IAS, IAC web sites. We included randomised controlled trials (RCTs), cluster-randomised controlled trials, quasi-randomised controlled trials, controlled before and after studies and interrupted time series studies assessing interventions to increase male involvement for improvement of uptake PMTCT services in low- and middle-income countries.. Two reviewers independently searched, screened, assessed study quality and extracted data. A third reviewer resolved any disagreement. Only one study met the inclusion criteria, an RCT conducted in Tanzania between May 2003 and October 2004. Women in the intervention group (n=760) received a letter for their male partners, which invited them to return together to receive Couple Voluntary Counselling and Testing (CVCT) for HIV. Women in the control group (n=761) received individual HIV VCT during their first ANC visit and then usual care. The percentages of women who received HIV VCT and collected their results were 48%, 45% and 39% in the intervention group and 93%, 78% and 71% in the control group (p <0,001). Only 33% of women in the intervention group returned with their male partners and only 47% of them went through the whole CVCT process. The proportion of women who received HIV prophylaxis at delivery was not different between the two arms (27% in the intervention and 22% in the control group). The study had a high risk of bias.   We found only one eligible study that assessed the effectiveness of male involvement in improving women's uptake of PMTCT services, which only focused on one part of the perinatal PMTCT cascade. We urgently need more rigorously designed studies assessing the impact of male engagement interventions on women's uptake of PMTCT services to know if this intervention can contribute to improve uptake of PMTCT services and reduce vertical transmission of HIV in children.   


Arias A.C.,Palo Alto Research Center PARC | MacKenzie J.D.,Green Hills | McCulloch I.,Imperial College London | Rivnay J.,Stanford University | Salleo A.,Stanford University
Chemical Reviews | Year: 2010

The synthesis, processing, and device performance of polymeric semiconductors has been reported. The polysilicon TFT technology is used for active matrix organic light-emitting diode (AMOLED) as the higher carrier mobilities of polysilicon as compared to a-Si, and increased stability of polysilicon-based devices under bias stress, are more effective in AMOLED. The radio frequency (RF) wireless applications are required in large area, self-powered, or maximized range device is partially driven by the fundamental physics of the frequency regimes in which they operate. Large area, high throughput manufacturing of organic electronic roducts is most efficiently enabled by solution based, additive printing techniques. Regioregular (RR) poly(3-hexylthiophene) (P3HT) is an exemplary semiconducting polymer due to its ready availability, ease of processing from solution, and its promising electrical properties arising from a highly crystalline microstructure.


Jones H.F.,Imperial College London
Journal of Physics A: Mathematical and Theoretical | Year: 2012

Propagation of light through a medium with a complex refractive index in which gain and loss are engineered to be PT symmetric has many remarkable features. In particular the usual unitarity relations are not satisfied, so that the reflection coefficients can be greater than 1, and in general are not the same for left or right incidence. Within the class of optical potentials of the form v(x) = v 1cos(2βx) + iv 2sin(2βx) the case v 2 = v 1 is of particular interest, as it lies on the boundary of PT-symmetry breaking. It has been shown in a recent paper by Lin et al that in this case one has the property of unidirectional invisibility, while for propagation in the other direction there is a greatly enhanced reflection coefficient proportional to L 2, where L is the length of the medium in the direction of propagation. For this potential we show how analytic expressions can be obtained for the various transmission and reflection coefficients, which are expressed in a very succinct form in terms of modified Bessel functions. While our numerical results agree very well with those of Lin et al we find that the invisibility is not quite exact, in amplitude or phase. As a test of our formulas we show that they identically satisfy a modified version of unitarity appropriate for PT-symmetric potentials. We also examine how the enhanced transmission comes about for a wave packet, as opposed to a plane wave, finding that the enhancement now arises through an increase, of O(L), in the pulse length, rather than the amplitude. © 2012 IOP Publishing Ltd.


Chatzis S.P.,Imperial College London
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2010

Hidden Markov models (HMMs) are a popular approach for modeling sequential data comprising continuous attributes. In such applications, the observation emission densities of the HMM hidden states are typically modeled by means of elliptically contoured distributions, usually multivariate Gaussian or Student's-t densities. However, elliptically contoured distributions cannot sufficiently model heavy-tailed or skewed populations which are typical in many fields, such as the financial and the communication signal processing domain. Employing finite mixtures of such elliptically contoured distributions to model the HMM state densities is a common approach for the amelioration of these issues. Nevertheless, the nature of the modeled data often requires postulation of a large number of mixture components for each HMM state, which might have a negative effect on both model efficiency and the training data set's size required to avoid overfitting. To resolve these issues, in this paper, we advocate for the utilization of a nonelliptically contoured distribution, the multivariate normal inverse Gaussian (MNIG) distribution, for modeling the observation densities of HMMs. As we experimentally demonstrate, our selection allows for more effective modeling of skewed and heavy-tailed populations in a simple and computationally efficient manner. © 2010 IEEE.


Anie K.A.,Imperial College London
Cochrane database of systematic reviews (Online) | Year: 2012

Sickle cell disease comprises a group of genetic blood disorders. It occurs when the sickle haemoglobin gene is inherited from both parents. The effects of the condition are: varying degrees of anaemia which, if severe, can reduce mobility; a tendency for small blood capillaries to become blocked causing pain in muscle and bone commonly known as 'crises'; damage to major organs such as the spleen, liver, kidneys, and lungs; and increased vulnerability to severe infections. There are both medical and non-medical complications, and treatment is usually symptomatic and palliative in nature. Psychological interventions for individuals with sickle cell disease might complement current medical treatment, and studies of their efficacy have yielded encouraging results. To examine the evidence that psychological interventions improve the ability of people with sickle cell disease to cope with their condition. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and the Internet, handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 28 July 2011. All randomised or quasi-randomised controlled trials comparing psychological interventions with no (psychological) intervention in people with sickle cell disease. Both authors independently extracted data and assessed the risk of bias of the included studies. Eleven studies were identified in the searches and six of these were eligible for inclusion in the review. Four studies, involving 223 participants, provided data for analysis. One study showed that cognitive behaviour therapy significantly reduced the affective component of pain, mean difference -3.00 (95% confidence interval -4.63 to -1.37), but not the sensory component, mean difference 0.00 (95% confidence interval -9.39 to 9.39). One study of family psycho-education was not associated with a reduction in depression. Another study evaluating cognitive behavioural therapy had inconclusive results for the assessment of coping strategies, and showed no difference between groups assessed on health service utilisation. Evidence for the efficacy of psychological therapies in sickle cell disease is currently limited. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions in sickle cell disease.


Zaki T.A.,Imperial College London
Flow, Turbulence and Combustion | Year: 2013

".an eerie type of chaos can lurk just behind a facade of order, and yet deep inside the chaos lurks an even eerier type of order." Douglas Hofstadter Bypass transition to turbulence in boundary layers is examined using linear theory and direct numerical simulations (DNS). First, the penetration of low-frequency free-stream disturbances into the boundary layer is explained using a model problem with two time scales, namely the shear and wall-normal diffusion. The simple model provides a physical understanding of the phenomenon of shear sheltering. The second stage in bypass transition is the amplification of streaks. Streak detection and tracking algorithms were applied to examine the characteristics of the streak population inside the boundary layer, beneath free-stream turbulence. It is demonstrated that simple statistical averaging masks the wealth of streak amplitudes in transitional flows, and in particular the high-amplitude, relatively rare events that precede the onset of turbulence. The third stage of the transition process, namely the secondary instability of streaks, is examined using secondary instability analysis. It is demonstrated that two types of instability are possible: An outer instability arises near the edge of the boundary layer on the lifted, low-speed streaks. An inner instability also exists, and has the appearance of a near-wall wavepacket. The stability theory is robust, and can predict the particular streaks which are likely to undergo secondary instability and break down in transitional boundary layers beneath free-stream turbulence. Beyond the secondary instability, turbulent spots are tracked in DNS in order to examine their characteristics in the subsequent non-linear stages of transition. At every stage, we compare the findings from linear theory to the empirical observations from direct solutions of the Navier-Stokes equations. The complementarity between the theoretical predictions and the computational experiments is highlighted, and it leads to a detailed view of the mechanics of transition. © 2013 Springer Science+Business Media Dordrecht.


Rudenko G.,Imperial College London
Essays in Biochemistry | Year: 2010

The African trypanosome Trypanosoma brucei is a unicellular parasite which causes African sleeping sickness. Transcription in African trypanosomes displays some unusual features, as most of the trypanosome genome is transcribed as extensive polycistronic RNA Pol II (polymerase II) transcription units that are not transcriptionally regulated. In addition, RNA Pol I is used for transcription of a small subset of protein coding genes in addition to the rDNA (ribosomal DNA). These Pol I-transcribed protein coding genes include the VSG (variant surface glycoprotein) genes. Although a single trypanosome has many hundreds of VSG genes, the active VSG is transcribed in a strictly monoalleleic fashion from one of approx. 15 telomeric VSG ESs (expression sites). Originally, it was thought that chromatin was not involved in the transcriptional control of ESs; however, this view is now being re-evaluated. It has since been shown that the active ES is depleted of nucleosomes compared with silent ESs. In addition, a number of proteins involved in chromatin remodelling or histone modification and which play a role in ES silencing {including TbISWI [T. brucei ISWI (imitation-switch protein)] and DOT1B} have recently been identified. Lastly, the telomere-binding protein TbRAP1 (T. brucei RAP1) has been shown to establish a repressive gradient extending from the ES telomere end up to the ES promoter. We still need to determine which epigenetic factors are involved in 'marking' the active ES as part of the counting mechanism of monoallelic exclusion. The challenge will come in determining how these multiple regulatory layers contribute to ES control. © 2010 Biochemical Society.


Khullar V.,Imperial College London
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2012

Overactive bladder (OAB) is highly prevalent and associated with considerable impact on patient health-related quality of life (HRQoL). Assessment of HRQoL can reveal the burden of disease and post-intervention improvement. This review aims to highlight the importance of HRQoL assessment and outline the tools available for use in clinical trials and real-world clinical practice. A number of validated measures of HRQoL specific to OAB have been developed, offering greater sensitivity and responsiveness over generic instruments. These condition-specific, multi-dimensional and single-item global questionnaires are particularly useful for the multiple and varied symptoms of OAB, as they reflect the patient's needs, concerns and values. Measurements for lower urinary tract symptoms, e. g. bladder diaries, are being compared with HRQoL instruments to provide greater understanding of the disease and treatment from the patient's perspective. Therapeutic interventions to improve OAB symptoms should also be evaluated for their effect on the patient's HRQoL. © The International Urogynecological Association 2011.


Tyrer P.,Imperial College London
Personality and Mental Health | Year: 2015

Objective: The objective of this study is to examine the evidence for a new hypothesis explaining the relationship between personality and mental state disorders. Design: At present, the attribution of personality disorder as a primary diagnosis only applies to patients who are antisocial, and particularly regarded as psychopathic, as in these patients, the mental state disorder that are associated are regarded in many respects as atypical and not representative of other mental disorders. The case is made in this paper that personality dysfunction lies behind the persistence of all non-cognitive mental disorders and that our failure to recognise this follows from our collective refusal to assess personality status early in life. Method: Narrative review of relevant literature, which is limited as personality status is not often assessed early in life. Results: Support is adduced that personality dysfunction lies behind the persistence of all non-cognitive mental disorders (i.e. those that are not specifically neurodevelopmental and linked to cognitive impairment). The potential importance of this hypothesis is presented with regard to treatment and management strategy, emphasising that without specific intervention for personality dysfunction, many patients are destined for persistent morbidity. © 2014 John Wiley & Sons, Ltd.


Wimalasundera R.C.,Imperial College London
Seminars in Fetal and Neonatal Medicine | Year: 2010

The substantial increase in high order multiple pregnancies in the last two decades as a result of assisted reproductive techniques has necessitated the development of multifetal pregnancy reduction as a management tool to decrease fetal number and improve perinatal survival. The evidence in favour of reduction in pregnancies with more than four fetuses to twins is undisputed. Despite the recent improvements in expectant management of triplets with reasonable perinatal outcomes, the evidence suggests that reduction to twins significantly reduces the risk of preterm delivery without an increase in miscarriage rates. Recent advances in vascular-occlusive techniques have allowed the possibility of selective termination in monochorionic pregnancies in the presence of discordant anomalies or indeed multifetal reduction in non-trichorionic triplets, with radiofrequency ablation and cord occlusion appearing to be the most successful. However, the techniques vary in complexity and complication rates, which increase with gestation. Hence the need to refer these pregnancies early to specialist centres. © 2010 Elsevier Ltd.


Rankin S.M.,Imperial College London
Immunology Letters | Year: 2012

The adult bone contains a number of distinct populations of stem cells, including haematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells and fibrocytes. While haematopoietic stem cells are required to provide a lifelong supply of blood cells it is thought that the other populations of stem cells play a role in tissue regeneration and potentially disease. The chemokine CXCL12 is produced constitutively in the bone marrow and, acting . via CXCR4, is critical in maintaining HSPCs in a quiescent state and retaining all subsets of stem and progenitor cells in the bone marrow environment. The cytokine G-CSF, used clinically to mobilize haematopoietic stem cells for bone marrow transplants, activates the sympathetic nervous system and bone marrow macrophages to reduce the expression of CXCL12 by bone marrow stromal cells, thereby promoting the exit of haematopoietic stem cells from the bone marrow. Understanding the molecular mechanisms underlying G-CSF stimulated mobilization has led to development of CXCR4 antagonists as fast acting mobilizing agents for haematopoietic stem cells. Evidence now suggests that CXCR4 antagonists can similarly mobilize distinct subsets of progenitor cells, namely the endothelial progenitor cells and mesenchymal stem cells, but this requires conditioning of the bone marrow with VEGF rather than G-CSF. © 2012 Elsevier B.V..


Barnes P.,Imperial College London
Seminars in Respiratory and Critical Care Medicine | Year: 2012

Current therapy for asthma with inhaled corticosteroids and long-acting inhaled β2-agonists is highly effective, safe, and relatively inexpensive, but many patients remain poorly controlled. Most advances have been through improving these drug classes and a major developmental hurdle is to improve existing drug classes. Major unmet needs include better treatment of severe asthma (which has some similarity to chronic obstructive pulmonary disease), as well as curative therapies for mild to moderate asthma that do not result in the return of symptoms when the treatment is stopped. Several new treatments are in development, but many are specific, targeting a single mediator or receptor, and are unlikely to have a major clinical impact, although they may be effective in specific asthma phenotypes (endotypes). Drugs with more widespread effects, such as kinase inhibitors, may be more effective but have a greater risk of side effects so inhaled delivery may be needed. Several new treatments target the underlying allergic/immune process and would treat concomitant allergic diseases. Improved immunotherapy approaches have the potential for disease modification, although prospects for a cure are currently remote. © Georg Thieme Verlag Stuttgart ·New York.


Apperley J.F.,Imperial College London
The Lancet | Year: 2015

In less than 10 years, the prognosis of chronic myeloid leukaemia has changed from that of a fatal disease to a disorder amenable simply to lifelong oral medication and compatible with a normal lifespan. This change has been made possible by a deep understanding of the molecular pathogenesis and a determination to develop targeted and selective drugs. This Seminar summarises the presentation, pathophysiology, diagnosis and monitoring technology, treatment options, side-effects, and outcomes of chronic myeloid leukaemia, and discusses the possibility of cure - ie, stable undetectable or low level disease in the absence of medication. Chronic myeloid leukaemia continues to instruct us in the mechanisms of leukaemogenesis and provides hope not only for similar developments in management of other malignancies, but also for the remarkable speed with which these can move from bench to bedside.


Barnes P.J.,Imperial College London
Journal of Allergy and Clinical Immunology | Year: 2012

Effective treatment of severe asthma is a major unmet need because patients' symptoms are not controlled on maximum treatment with inhaled therapy. Asthma symptoms can be poorly controlled because of poor adherence to controller therapy, and this might be addressed by using combination inhalers that contain a corticosteroid and long-acting β 2-agonist as reliever therapy in addition to maintenance treatment. New bronchodilators with a longer duration of action are in development, and recent studies have demonstrated the benefit of a long-acting anticholinergic bronchodilator in addition to β 2-agonists in patients with severe asthma. Anti-IgE therapy is beneficial in selected patients with severe asthma. Several new blockers of specific mediators, including prostaglandin D 2, IL-5, IL-9, and IL-13, are also in clinical trials and might benefit patients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilic inflammation are in clinical development for the treatment of severe asthma, but adverse effects after oral administration might necessitate inhaled delivery. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma. Corticosteroid resistance is a major problem in patients with severe asthma, and several molecular mechanisms have been described that might lead to novel therapeutic approaches, including drugs that could reverse this resistance, such as theophylline and nortriptyline. In selected patients with severe asthma, bronchial thermoplasty might be beneficial, but thus far, clinical studies have not been encouraging. Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy. © 2011 American Academy of Allergy, Asthma & Immunology.


Usmani O.S.,Imperial College London
Allergy, Asthma and Immunology Research | Year: 2014

The small airways have been neglected for many years, but interest in the topic has been rekindled with recent advances in measurement techniques to assess this region and also the ability to deliver therapeutics to the distal airways. Current levels of disease control in asthmatic patients remain poor and there are several contributory factors including; poor treatment compliance, heterogeneity of asthma phenotypes and associated comorbidities. However, the proposition that we may not be targeting all the inflammation that is present throughout the whole respiratory tree may also be an important factor. Indeed decades ago, pathologists and physiologists clearly identified the importance of small airways dysfunction in asthmatic patients. With improved inhaler technology to deliver drug to target the whole respiratory tree and more sensitive measures to assess the distal airways, we should certainly give greater consideration to treating the small airway region when seeing our asthmatic patients in clinic. The aim of this review is to address the relevance of small airways dysfunction in the daily clinical management of patients with asthma. In particular the role of small particle aerosols in the management of patients with asthma will be explored. © 2014 The Korean Academy of Asthma, Allergy and Clinical Immunology. The Korean Academy of Pediatric Allergy and Respiratory Disease.


Koppelaar R.H.E.M.,Imperial College London | Weikard H.P.,Wageningen University
Global Environmental Change | Year: 2013

We analyze global elemental phosphorus flows in 2009 for (1) mining to products, (2) animal and human manure flows, (3) crop harvests and animal production, (4) food production, (5) soil erosion, (6) and crop uptake. Informed by the flow assessment the potential and cost of phosphorus usage reduction and recycling measures are quantified, and fed into a constructed phosphorus supply-demand model with reserve assessment to assess the impact of these measures on phosphate rock resource availability. According to our results in 2009 globally 21.4. Mt elemental phosphorus from rock phosphate was consumed in products of which 17.6. Mt used as fertilizers, fully able to cover erosion losses and outputs in agriculture in aggregate, but insufficient from the perspective of bio-available phosphorus in soils. We find substantial scope for phosphorus use reduction, at potentially 6.9. Mt phosphorus, or 32% of 2009 phosphate rock supply. Another 6.1. Mt, or 28% can technologically be recycled from waterways and wastewater, but at a cost substantially above any foreseeable phosphate rock fertilizer price. The model results suggests phosphate rock reserves are sufficient to meet demand into the 22nd century, and can be extended well into the 23rd century with assessed use reduction and recycling measures. © 2013 Elsevier Ltd.


Marin D.,Imperial College London
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Imatinib has been the preferred initial therapy for newly diagnosed chronic myeloid leukemia patients for the past 10 years. Recently, other, possibly better, tyrosine kinase inhibitors have been licensed for first-line use based on the early results of 2 large, randomized clinical trials. The pros and cons of the various alternatives to imatinib are analyzed herein, and I try to answer the question of are we ready to abandon imatinib and, if yes, then what treatment should a patient diagnosed today receive.


Wang Y.,Imperial College London
Geophysical Journal International | Year: 2011

Seismic anisotropy is evidenced in the inner core, upper mantle and the lower crust in large scale, and the evidence is generally provided by shear wave splitting analysis. Here this paper searches for the evidence of anisotropy in the uppermost crust, by using P-wave arrival times from crosshole seismic measurement to directly estimate velocity anisotropy associated with the fine-layering effect of multiple sedimentary beds. Conceptually fine layering causes the so-called VTI (vertical transverse isotropy) anisotropy with a vertical symmetry and the effect is parametrized by the horizontal and vertical velocity ratio. It is found however that the VTI anisotropic parameter does not have a simple vertical symmetry but is also azimuth dependent. This azimuthal anisotropy may reflect the fracture orientation due to large-scale tectonic movements, and is very important in the production of oil reservoirs, as the seismically fast directions can indicate preferred directions of fluid flow. This paper presents innovative methods for anisotropy analysis in both vertical and horizontal plane. Integrated seismic anisotropy interpretation clearly indicates distinguished strain orientations forming fractures in Oligocenic, Miocenic and Pliocenic sediment, in the edge of the extensional basin immediately next to Tan-Lu Fault, an active continental strike-slip fault zone. © 2011 The Author Geophysical Journal International © 2011 RAS.


Three-dimensional seismic reflection data are used to investigate the geometry, scale, and distribution of structures within large clasts (megaclasts) contained within a Tertiary mass transport deposit, Santos Basin, offshore Brazil. Normal faults and folds are observed within the megaclasts; the folds are typically best developed toward either the frontal or lateral margins of the clasts. The highly variable map-view orientation of these structures, their relative ages, and their relationship to the geometry of the basal shear surface indicate that the structures developed during both the motion and arrest of the parent flow. This study indicates that megaclasts may be deformed despite the associated flow being cohesive and lacking turbulence. Deformation is related to local differential shear within the viscous body of the flow and mechanical interaction of megaclasts with the basal shear surface. © 2011 Geological Society of America.


Martins Z.,Imperial College London
Elements | Year: 2011

The early Solar System contained a wide range of abiotic organic compounds. As the Solar System evolved, these organic molecules were incorporated into planetesimals and eventually planetary bodies, such as the parent bodies of meteorites. One particular class of meteorites, the carbonaceous meteorites, contains a large variety of extraterrestrial organic compounds. These compounds represent a record of the chemical reactions and conditions in the early Solar System. Different formation mechanisms and sources (interstellar, nebular or parent body) contributed to the inventory of meteoritic organic molecules. Their subsequent delivery to the early Earth may have contributed the first prebiotic building blocks of life.


Pendry J.B.,Imperial College London
New Journal of Physics | Year: 2010

Two parallel dielectric plates separated by vacuum interact through zero-point charge fluctuations and experience friction when the plates are in relative motion and the vacuum is sheared. Even at the absolute zero of temperature, residual quantum fluctuations remain because the zero-point energy gives rise to 'quantum friction'. In a recent paper, the reality of these fluctuations is questioned and the existence of quantum friction is called into question. Here we refute this assertion. © IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.


Crowdy D.,Imperial College London
Physics of Fluids | Year: 2010

An analytical formula for the frictional slip length associated with transverse shear flow over a bubble mattress comprising a dilute periodic array of parallel circular-arc grooves protruding into the fluid has recently been presented by Davis and Lauga [Phys. Fluids21, 011701 (2009)]. This letter derives an analytical formula for the slip length associated with longitudinal shear flow over the same surface. The formula is in excellent agreement with a phenomenological result based on finite element simulations given by Teo and Khoo [Microfluid. Nanofluid.9, 499 (2010)]. © 2010 American Institute of Physics.


Amis A.A.,Imperial College London
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2012

This paper reviews the functional anatomy of the anterior cruciate ligament (ACL), which has a parallel array of collagen fascicles that have usually been divided into two 'fibre bundles': anteromedial (AM) and posterolateral (PL), according to their tibial attachment sites. The PL bundle has shorter fibres, and so it is subjected to greater tensile strains than the AM bundle when the whole ACL is stretched; its oblique orientation in the coronal plane imbues it with greater ability to resist tibial rotation than the more vertical AM fibre bundle. Most studies have found that the AM bundle is close to isometric when the knee flexes, while the PL bundle slackens approximately 6 mm. There is little evidence of significant fibre bundle elongation in response to tibial rotation. Selective bundle cutting studies have been performed, allowing both the bundle tensions and their contributions to resisting tibial anterior translation and tibial rotation to be calculated. These show that the function of the PL bundle was dominant near knee extension in some studies, particularly when resisting anterior drawer and that its contribution reduced rapidly with knee flexion through 30 degrees. There has been little study of the contributions of the fibre bundles in control of tibial internal-external rotation or the pivot shift: one study found that the AM bundle had larger tensions than the PL bundle during a simulated pivot shift, but another study found that cutting the PL bundle allowed a larger increase in coupled tibial anterior translation than cutting the AM bundle. It was concluded that the AM bundle is most important for resisting tibial anterior drawer-the primary function of the ACL-while the PL bundle is tight near knee extension, when it has a role in control of tibial rotational laxity. There is a clear need for further study of dynamic knee instability, to gain better understanding of how best to reconstruct the ACL and associated tissues. © 2012 Springer-Verlag.


Buchbinder E.I.,Imperial College London
Journal of High Energy Physics | Year: 2010

We study the relation between vertex operators in AdS 5 × S 5 and classical spinning string solutions. In the limit of large quantum numbers the treatment of vertex operators becomes semiclassical. In this regime, a given vertex operator carrying a certain set of quantum numbers defines a singular solution. We show in a number of examples that this solution coincides with the classical string solution with the same quantum numbers but written in a different two-dimensional coordinate system. The marginality condition imposed on an operator yields a relation between the energy and the other quantum numbers which is shown to coincide with that of the corresponding classical string solution. We also argue that in some cases vertex operators in AdS 5×S 5 cannot be given by expressions similar to the ones in flat space and a more involved consideration is required. © SISSA 2010.


Taylor G.P.,Imperial College London
HIV medicine | Year: 2012

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.


Salhiyyah K.,Imperial College London
Cochrane database of systematic reviews (Online) | Year: 2012

Intermittent claudication (IC) is a symptom of peripheral arterial occlusive disease (PAD). It is associated with high morbidity and mortality. Pentoxifylline is one of many drugs used to treat IC. Pentoxifylline decreases blood viscosity, improves erythrocyte flexibility, and increases microcirculatory flow and tissue oxygen concentration.Many studies have evaluated the efficacy of pentoxifylline in treating PAD but the results of these studies are very variable. To determine the efficacy of pentoxifylline in improving the walking capacity (that is pain-free walking distance and the total (absolute, maximum) walking distance) of patients with stable intermittent claudication, Fontaine stage II. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched January 2011) and CENTRAL (2011, Issue 1). In addition, we searched MEDLINE (Week 2 January 2011) and EMBASE (2011 Week 03). ClinicalTrials.gov and Current Controlled Trials were searched for ongoing or unpublished trials. All double blind, randomised controlled trials (RCTs) comparing pentoxifylline to placebo or any other pharmacological intervention in patients with IC Fontaine stage II. Included studies were assessed separately by two review authors. Data were matched and disagreements resolved by discussion. The quality of the studies was assessed using the Jadad score and the Cochrane risk of bias tool. Results relating to pain-free walking distance (PFWD) and total walking distance (TWD) were collected. Studies were compared based on the duration and dose of pentoxifylline. Twenty-three studies with 2816 participants were included in this review. There was considerable heterogeneity between the included studies with regards to multiple variables including duration of treatment, dose of pentoxifylline, baseline walking distance and patient characteristics, and therefore pooled analysis was not possible. The quality of the included studies was generally low. There was very large variability in the reported findings between the individual studies. In a total of 17 studies which compared pentoxifylline with placebo, of which 14 reported TWD and 11 reported PFWD, the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and for PFWD the difference ranged from -33.8% to 73.9%. Testing for statistical significance of these results was generally not possible due to the lack of data. There was no statistically significant difference in ankle brachial pressure index (ABI) between the pentoxifylline and placebo groups. Pentoxifylline was generally well tolerated. Given the generally poor quality of the published studies and the large degree of heterogeneity in the interventions and the results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline is generally well tolerated.  Based on the totality of the available evidence, it is possible that pentoxifylline could have a place in the treatment of IC as a means of improving walking distance and as a complimentary treatment assuming all other essential measures such as lifestyle change, exercise and treatment for secondary prevention have been taken into account. However, the response to pentoxifylline should be assessed on an individual basis.


Car J.,Imperial College London
Cochrane database of systematic reviews (Online) | Year: 2012

Missed appointments are a major cause of inefficiency in healthcare delivery, with substantial monetary costs for the health system, leading to delays in diagnosis and appropriate treatment. Patients' forgetfulness is one of the main reasons for missed appointments, and reminders may help alleviate this problem. Modes of communicating reminders for appointments to patients include face-to-face communication, postal messages, calls to landlines or mobile phones, and mobile phone messaging. Mobile phone messaging applications such as Short Message Service (SMS) and Multimedia Message Service (MMS) could provide an important, inexpensive delivery medium for reminders for healthcare appointments. To assess the effects of mobile phone messaging reminders for attendance at healthcare appointments. Secondary objectives include assessment of patients' and healthcare providers' evaluation of the intervention; costs; and possible risks and harms associated with the intervention. We searched the Cochrane Central Register of Controlled Trials (CENTRAL,The Cochrane Library 2009, Issue 2), MEDLINE (OvidSP) (January 1993 to June 2009), EMBASE (OvidSP) (January 1993 to June 2009), PsycINFO (OvidSP) (January 1993 to June 2009), CINAHL (EbscoHOST) (January 1993 to June 2009), LILACS (January 1993 to June 2009) and African Health Anthology (January 1993 to June 2009). We also reviewed grey literature (including trial registers) and reference lists of articles. We included randomised controlled trials (RCTs), quasi-randomised controlled trials (QRCTs), controlled before-after (CBA) studies, or interrupted time series (ITS) studies with at least three time points before and after the intervention. We included studies assessing mobile phone messaging as reminders for healthcare appointments. We only included studies in which it was possible to assess effects of mobile phone messaging independent of other technologies or interventions.   Two review authors independently assessed all studies against the inclusion criteria, with any disagreements resolved by a third review author. Study design features, characteristics of target populations, interventions and controls, and results data were extracted by two review authors and confirmed by a third author. Primary outcomes of interest were rate of attendance at healthcare appointments. We also considered health outcomes as a result of the intervention, patients' and providers' evaluation of the intervention, perceptions of safety, costs, and potential harms or adverse effects. As the intervention characteristics and outcome measures were similar across included studies, we conducted a meta-analysis to estimate an overall effect size. We included four randomised controlled trials involving 3547 participants. Three studies with moderate quality evidence showed that mobile text message reminders improved the rate of attendance at healthcare appointments compared to no reminders (risk ratio (RR) 1.10 (95% confidence interval (CI) 1.03 to 1.17)). One low quality study reported that mobile text message reminders with postal reminders, compared to postal reminders, improved rate of attendance at healthcare appointments (RR 1.10 (95% CI 1.02 to 1.19)). However, two studies with moderate quality of evidence showed that mobile phone text message reminders and phone call reminders had a similar impact on healthcare attendance (RR 0.99 (95% CI 0.95 to 1.03). The costs per attendance of mobile phone text message reminders were shown to be lower compared to phone call reminders. None of the included studies reported outcomes related to harms or adverse effects of the intervention, nor health outcomes or user perception of safety related to the intervention. There is moderate quality evidence that mobile phone text message reminders are more effective than no reminders, and low quality evidence that text message reminders with postal reminders are more effective than postal reminders alone. Further, according to the moderate quality evidence we found, mobile phone text message reminders are as effective as phone call reminders. Overall, there is limited evidence on the effects of mobile phone text message reminders for appointment attendance, and further high-quality research is required to draw more robust conclusions.


Shah R.R.,Rashmi Shah Consultancy Ltd | Smith R.L.,Imperial College London
Drug Metabolism and Disposition | Year: 2015

Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infectioninduced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Cantilever arrays have been used to monitor biochemical interactions and their associated stress. However, it is often necessary to passivate the underside of the cantilever to prevent unwanted ligand adsorption, and this process requires tedious optimization. Here, we show a way to immobilize membrane receptors on nanomechanical cantilevers so that they can function without passivating the underlying surface. Using equilibrium theory, we quantitatively describe the mechanical responses of vancomycin, human immunodeficiency virus type 1 antigens and coagulation factor VIII captured on the cantilever in the presence of competing stresses from the top and bottom cantilever surfaces. We show that the area per receptor molecule on the cantilever surface influences ligand–receptor binding and plays an important role on stress. Our results offer a new way to sense biomolecules and will aid in the creation of ultrasensitive biosensors. © 2015 Nature Publishing Group


Bearman P.W.,Imperial College London
Journal of Fluids and Structures | Year: 2011

This paper presents a selective review of recent research on vortex-induced vibrations of isolated circular cylinders and the flow and vibration of circular cylinders in a tandem arrangement; a common thread being that the topics raised are of particular interest to the author. The influence of Reynolds number on the response of isolated cylinders is presented and recent developments using forced vibration are discussed. The response of a cylinder free to respond in the in-line and transverse directions is contrasted with that of a cylinder responding in only one direction. The interference between two circular cylinders is discussed and prominence given to the case of cylinders in a tandem arrangement. The origin of the time-mean lift force on the downstream cylinder is considered together with the cause of the large amplitude transverse vibration experienced by the cylinder above vortex resonance. This wake-induced vibration is shown to be a form of vortex-induced vibration. © 2011 Elsevier Ltd.


Cardona G.A.,Livestock Laboratory | Carmena D.,Imperial College London
Veterinary Parasitology | Year: 2013

Cystic echinococcosis (CE) is an important and widespread zoonotic infection caused by the larval stages of taeniid cestodes of the genus Echinococcus. The disease represents a serious animal health concern in many rural areas of the world, causing important economic losses derived from decreased productivity and viscera condemnation in livestock species. In this review we aim to provide a comprehensive overview on recent research progress in the epidemiology of CE in production animals from a global perspective. Particular attention has been paid to the discussion of the extent and significance of recent molecular epidemiologic data. The financial burden associated to CE on the livestock industry has also been addressed. Data presented are expected to improve our current understanding of the parasite's geographical distribution, transmission, host range, immunogenicity, pathogenesis, and genotype frequencies. This information should be also valuable for the design and implementation of more efficient control strategies against CE. © 2012 Elsevier B.V.


Leader E.,Imperial College London | Lorce C.,University Paris - Sud | Lorce C.,University of Liege
Physics Reports | Year: 2014

The general question, crucial to an understanding of the internal structure of the nucleon, of how to split the total angular momentum of a photon or gluon into spin and orbital contributions is one of the most important and interesting challenges faced by gauge theories like Quantum Electrodynamics and Quantum Chromodynamics. This is particularly challenging since all QED textbooks state that such a splitting cannot be done for a photon (and a fortiori for a gluon) in a gauge-invariant way, yet experimentalists around the world are engaged in measuring what they believe is the gluon spin! This question has been a subject of intense debate and controversy, ever since, in 2008, it was claimed that such a gauge-invariant split was, in fact, possible. We explain in what sense this claim is true and how it turns out that one of the main problems is that such a decomposition is not unique and therefore raises the question of what is the most natural or physical choice. The essential requirement of measurability does not solve the ambiguities and leads us to the conclusion that the choice of a particular decomposition is essentially a matter of taste and convenience. In this review, we provide a pedagogical introduction to the question of angular momentum decomposition in a gauge theory, present the main relevant decompositions and discuss in detail several aspects of the controversies regarding the question of gauge invariance, frame dependence, uniqueness and measurability. We stress the physical implications of the recent developments and collect into a separate section all the sum rules and relations which we think experimentally relevant. We hope that such a review will make the matter amenable to a broader community and will help to clarify the present situation. © 2014 Elsevier B.V.


Brazeau M.D.,Imperial College London | Friedman M.,University of Oxford
Nature | Year: 2015

Fossils of early gnathostomes (or jawed vertebrates) have been the focus of study for nearly two centuries. They yield key clues about the evolutionary assembly of the group's common body plan, as well the divergence of the two living gnathostome lineages: the cartilaginous and bony vertebrates. A series of remarkable new palaeontological discoveries, analytical advances and innovative reinterpretations of existing fossil archives have fundamentally altered a decades-old consensus on the relationships of extinct gnathostomes, delivering a new evolutionary framework for exploring major questions that remain unanswered, including the origin of jaws. © 2015 Macmillan Publishers Limited. All rights reserved.


Bowcock A.M.,Imperial College London
Thorax | Year: 2014

Lung cancer usually presents as advanced stage disease and there is a need for early diagnosis so that appropriate treatments can be provided prior to tumour progression. Copy number variation is frequently detected in tumours and can contribute to tumour progression. This is because regions harbouring DNA imbalance can contain genes encoding critical proteins whose altered dosage contributes to the neoplastic process. Three copy number variations (CNVs) from chromosomes 3p26-p11.1 (loss), 3q26.2-29 (gain) and 6q25.3-24.3 (loss) have previously been described in individuals presenting with endobronchial squamous metaplasia. These CNVs were predictors of cancer diagnosed within 44 months with 97% accuracy. An evaluation of this CNV-based classifier with an independent set of 12 samples (10 men and 2 women), each with a carcinoma in situ or invasive carcinoma at the same site at follow-up demonstrated 92% prediction accuracy. The negative predictive value of this classifier was 89%. The gain at 3q26.2-q29 contributed the most to the classification, being present in virtually all lesions. This region harbours the PIK3CA gene and evaluation of the number of copies of this gene gave very similar results to those from array comparative genomic hybridisation. This type of test can be performed on sputum or bronchial brushings. Larger cohorts now need to be examined to confirm this finding and to possibly refine the regions of CNV. This type of approach paves the way for future molecular analyses to assist in selecting subjects with endobronchial squamous metaplastic or dysplastic lesions who might benefit from more aggressive therapeutic intervention or surveillance.


Muxworthy A.R.,Imperial College London
Physics of the Earth and Planetary Interiors | Year: 2010

The use of a domain-state independent method (the Wilson method) of acquiring absolute palaeointensities is tested using three sets of historical lavas from Mexico, Italy and Iceland. The Wilson method works by plotting continuous thermal demagnetisation curve data for the original natural remanent magnetisation against those for a laboratory-induced thermoremanence. By comparing the predicted intensities with the known fields, a new empirically derived rejection criterion is proposed that accounts for chemical alteration and improves the accuracy of the palaeointensity estimates. The Wilson palaeointensity estimates are compared with palaeointensity determinations made on sister samples using standard Thellier-type heating. Generally, the Wilson palaeointensity estimates compare favourably for samples that yielded technically correct Thellier-type determinations. However, at one locality the Wilson method did not yield any estimates due to severe chemical alteration, in contrast it was still possible to determine palaeointensity estimates from the lower temperature Thellier data. To assess the Wilson palaeointensity protocol's ability to return a correct estimate for a true multidomain system, a synthetic multidomain magnetite sample was imparted with a thermoremanent magnetisation. The Wilson protocol returned the correct palaeointensity within error, in contrast the Thellier-type protocol failed. As the Wilson method is significantly faster than Thellier-type methods, it is suggested that the Wilson method should be tried as a 'first-approach' in palaeointensity studies, or for samples dominated by multidomain material. © 2010 Elsevier B.V. All rights reserved.


Muller E.A.,Imperial College London | Mejia A.,University of Concepcion
Journal of Physical Chemistry Letters | Year: 2014

Literature values regarding the pressure dependence of the interfacial tension of the system of carbon dioxide (CO2) + water (H 2O) show an unexplained divergence and scatter at the transition between low-pressure gas-liquid equilibrium and the high-pressure liquid-liquid equilibrium. We employ the Statistical Associating Fluid Theory (SAFT) and canonical molecular dynamics simulations based on the corresponding coarse grained force field to map out the phase diagram of the mixture and the interfacial tension for this system. We showcase how at ambient temperatures a triple point (gas-liquid-liquid) is expected and detail the implications that the appearance of the third phase has on the interfacial tensions of the system. © 2014 American Chemical Society.


Three-dimensional seismic-reflection data are used to characterize the seismic expression and investigate the origin of two mass transport complexes (sensu Moscardelli and Wood, 2007) that are contained in two saltrelated minibasins on the São Paulo Plateau, offshore SE Brazil. The mass transport complexes contain numerous slide blocks, which are expressed on seismic data as broadly tabular packages of weakly deformed reflections. Individual slide blocks are up to 50 m thick and up to 1 km2 in plan view. The slide blocks are flanked by laterally continuous reflections, which are interpreted as the seismic expression of either a thin mudstonedominated debrite deposit or a thin interval of hemi pelagic mudstones. The surface that bounds the base of the two mass transport complexes is planar, and this suggests that the associated gravity-flow event caused only limited erosion of the seafloor. The upper surfaces of the mass transport complexes are very rugose and onlapped by overlying strata, indi cating that the slide blocks formed seabed relief of up to 20 m. The complexes occur at the base of a unit that thins toward the margins of the studied minibasins, and the slide blocks in the mass transport complexes decrease in size and density away from the saltcored structural high that separates the two minibasins. Based on its seismic stratigraphic context and the spatial distribution of the slide blocks that they contain, the mass transport complexes are interpreted to have been derived from the failure of the margins of the salt-cored high in response to a period of relatively rapid minibasin sub sidence. The results of this study indicate that large volumes of sedimentary material may be derived from the margins of salt-related minibasins in relatively distal submarine settings. From a geohazard perspective, this observa tion is important because the risk asso ciated with submarine slope failure, and the transport and emplacement of large blocks, is typically thought to be low in relatively distal, deepwater environments. © 2012 Geological Society of America.


Selley R.C.,Imperial College London
Marine and Petroleum Geology | Year: 2012

The UK's first well to encounter shale gas was drilled into the Upper Jurassic Kimmeridge Clay in 1875, but its significance was not realised at the time. 25 years ago research at Imperial College applied the US shale gas paradigm to evaluate the UK's shale gas potential. Shale sequences with potential for gas production were identified in Carboniferous strata in the Midlands, and in Jurassic strata, particularly in the Weald. Without encouragement from Her Majesty's Government no exploration resulted from this initial research. Publication of the results of the project was rejected by many UK journals. It was finally published in the USA in 1987. Subsequent evaluations of UK petroleum resources by the Department of Energy and its descendants published in 2001 and 2003 omitted any mention of shale gas resources. Recent timely re-evaluations of the UK's shale gas potential have been carried out by the British Geological Survey and the Department for Energy & Climate Change. In 2008 the 13th Round of Onshore Licensing resulted in the award of several blocks for shale gas exploration, though bids were often based on a quest for both shale gas and conventional prospects. Cuadrilla Resource's Preese Hall No. 1 well drilled in 2010 was the first well drilled to specifically test for UK shale gas. The same drilling and fracturing techniques that led to the shale gas renaissance in the USA are now being applied to extracting oil from organic-rich shales that are currently in the oil window. It is interesting to speculate that oil may be produced by such techniques from the thermally mature Jurassic shales in the Wessex and Weald basins in the southern UK. © 2011 Elsevier Ltd.


Tachibana Y.,RMIT University | Tachibana Y.,Japan Science and Technology Agency | Tachibana Y.,Osaka University | Vayssieres L.,Xian Jiaotong University | Durrant J.R.,Imperial College London
Nature Photonics | Year: 2012

Hydrogen generated from solar-driven water-splitting has the potential to be a clean, sustainable and abundant energy source. Inspired by natural photosynthesis, artificial solar water-splitting devices are now being designed and tested. Recent developments based on molecular and/or nanostructure designs have led to advances in our understanding of light-induced charge separation and subsequent catalytic water oxidation and reduction reactions. Here we review some of the recent progress towards developing artificial photosynthetic devices, together with their analogies to biological photosynthesis, including technologies that focus on the development of visible-light active hetero-nanostructures and require an understanding of the underlying interfacial carrier dynamics. Finally, we propose a vision for a future sustainable hydrogen fuel community based on artificial photosynthesis. © 2012 Macmillan Publishers Limited. All rights reserved.


Modi N.,Imperial College London
Neonatology | Year: 2014

Evidence-based medicine has been embraced wholeheartedly, and rightly so, as the best approach for reducing clinical uncertainty and ensuring that patients receive treatment and care that are efficacious (i.e. they work) and effective (i.e. they work in real life). High-quality evidence comes from high-quality clinical research. It would hence be reasonable to assume that these two would form a closely integrated partnership. Alas, this is not yet the case. So many uncertainties in medical care relate to treatments and practices already widely in use. In neonatal medicine, for example, some of us use protein-carbohydrate fortification of human milk and some of us do not, some of us stop enteral feeds during blood transfusions whereas some of us do not, some of us reach for dopamine when blood pressure falls while some of us use dobutamine. For our patients, these uncertainties represent a lottery, the throw of the dice that determines whether they receive the treatment advocated by Dr. A or Dr. B. They deserve better than this. Randomization is considered the gold standard approach to eliminating the clinician bias that very often dominates the choice of treatments. Randomization reduces the influence on outcomes of confounding by unknown factors, and ensures that every patient has a fair and equal chance of receiving the best possible treatment when this is, in fact, not known. In an ideal world, every medical uncertainty would be addressed in this way. The evaluation of treatments that are in accepted use has been termed 'comparative effectiveness research', i.e. the comparison of existing healthcare interventions to determine which works best, for whom and under which circumstances. Recently a long-standing uncertainty, the optimum saturation target for preterm babies receiving oxygen was put to the test of randomization. The accepted standard-of-care saturation range of 85-95% has been used for a considerable time and its use is intended to avoid both levels of oxygen that are too low or too high. Investigators in the UK, Australia, New Zealand and the USA designed randomized controlled trials to provide more precise guidance, by determining whether targeting the lower end of the accepted range (85-89%) resulted in reduced retinopathy of prematurity when compared with the upper end of the accepted range (91-95%). Between 2004 and 2009, the US SUPPORT trial (Surfactant, Positive Pressure and Oxygenation Randomized Trial) recruited approximately 1,300 infants and showed that babies at the higher end of the recommended oxygen saturation range had a greater incidence of retinopathy of prematurity, but that, unexpectedly, babies at the lower end had a higher risk of death [1]. The data monitoring committees of the BOOST II (Oxygen Saturation and Outcomes in Preterm Infants) trials in the UK, Australia and New Zealand reviewed their interim data, confirmed the higher risk of death in babies randomized to the lower saturation range, and halted further recruitment [2]. Without the trials, the lower saturation target would have continued to be applied to many babies, and many would have died as a result. Though many uncertainties remain, the trials facilitated advances in care. However, in March 2013, the lead investigators for the SUPPORT trial were informed by the US 'Office for Human Research Protections' that they were 'in violation of the regulatory requirements for informed consent, stemming from the failure to describe the reasonably foreseeable risks of blindness, neurological damage and death' [3]. This extraordinary conclusion indicates that the US regulators considered the researchers to be at fault for failing to foresee an unexpected trial result, and for randomizing babies to receive oxygen within the accepted standard-of-care limits. The ruling further implies that the regulators consider that clinicians are acting ethically when they deliver an accepted but non-evidence-based treatment based upon their personal bias, but are acting unethically when they make the selection by randomization. Clearly, there is a gulf between the view of the medical profession and that of the regulators regarding the ethical and scientific validity of randomization as a means to select treatments in comparative effectiveness research aimed at reducing uncertainties in care. What are the ways forward? I suggest that, in order for medicine to advance, a paradigm shift is necessary, involving a deeper public (and regulator) understanding of randomization as the fairest approach to allocating treatments that are in wide and accepted use, but where the evidence base is actually uncertain, so that the chance of receiving the as yet unknown best treatment is unaffected by clinician bias, and where care is delivered along a clearly designed, closely monitored pathway. In practice, peer review, regulatory approval, patient involvement and the delivery of explanation and information would be the same as for research involving experimental treatments. The key difference would be that randomization would be the recommended default and patients would be offered the opportunity to opt out, rather than be invited to opt in. For neonatal medicine, this would reduce the risk of 'injurious misconception', where trial entry is inappropriately rejected by parents because of an exaggerated and disproportionate perception of risk [4] that is brought on or magnified by the burden of making decisions at this difficult and stressful time. Randomization to treatments that fall within accepted practice and are considered standard-of-care involves no research-related risks to participants, and as trial data can increasingly be extracted from electronic clinical records [5], the costs and burden of data collection placed upon clinical teams will be minimized and, ultimately, the resolution of uncertainties about treatment can be hastened. It should also be noted that this approach fulfils the four cardinal principles of research ethics, namely: autonomy, justice, beneficence and nonmaleficence as well as upholding the responsibility of all doctors to strive to reduce uncertainty in the care they provide to their patients [6].


Nelson J.,Imperial College London | Nelson J.,Albert Ludwigs University of Freiburg
Materials Today | Year: 2011

The efficiency of solar cells made from a conjugated polymer blended with a fullerene derivative has risen from around 1 to over 9 in the last ten years, making organic photovoltaic technology a viable contender for commercialization. The efficiency increases have resulted from the development of new materials with lower optical gaps, new polymer:fullerene combinations with higher charge separated state energies, and new approaches to control the blend microstructure, all driven by a qualitative understanding of the principles governing organic solar cell operation. In parallel, a device physics framework has been developed that enables the rational design of device structures and materials for improved organic photovoltaic devices. We review developments in both materials science and device physics for organic photovoltaics. © 2011 Elsevier Ltd.


Bedingham D.J.,Imperial College London
Foundations of Physics | Year: 2011

A mechanism describing state reduction dynamics in relativistic quantum field theory is outlined. The mechanism involves nonlinear stochastic modifications to the standard description of unitary state evolution and the introduction of a relativistic field in which a quantized degree of freedom is associated to each point in spacetime. The purpose of this field is to mediate in the interaction between classical stochastic influences and conventional quantum fields. The equations of motion are Lorentz covariant, frame independent, and do not result in divergent behavior. It is shown that the mathematical framework permits the specification of unambiguous local properties providing a connection between the model and evidence of real world phenomena. The collapse process is demonstrated for an idealized example. © 2010 Springer Science+Business Media, LLC.


Joffe M.,Imperial College London
Preventive Medicine | Year: 2011

The concept of causation in epidemiology can be illuminated by situating the discussion within a more general concept of causation in biology: "a causal relationship is one that has a mechanism that by its operation makes a difference". Mechanism and difference-making are complementary, and discovery can proceed from either direction; each type of evidence can be qualitative or quantitative. An explanation becomes fully convincing only when supported by both. In biology, causation is typically stochastic and/or multiple. Multiple causation can be analysed statistically/epidemiologically, even though it is not truly (ontologically) stochastic. This requires some degree of regularity in the outcome variable, plus sufficient variation in the exposure(s). The analysis then demonstrates co-variations between exposure(s) and outcome that regularly occur. Rose's important distinction of "causes of incidence" and "causes of cases" should be reconceptualised in terms of epidemiological visibility, raising the possibility of epidemiological "dark matter". © 2011 Elsevier Inc.


The forkhead transcription factor FOXM1 has a key role in DNA damage response, and its deregulated overexpression is associated with genotoxic drug resistance in breast cancer. However, little is known about the posttranslational mechanisms by which FOXM1 expression is regulated by genotoxic agents and how they are deregulated in resistant cells. Initial co-immunoprecipitation studies verified previous proteomic analysis finding that the OTUB1 is a novel FOXM1-interacting protein. Western blot analysis showed that both OTUB1 and FOXM1 expression reduced upon genotoxic agent treatment in MCF-7 cells, but remained relatively constant in resistant cells. FOXM1 expression reduced upon OTUB1 depletion by siRNA and increased with OTUB1 overexpression in MCF-7 cells, arguing that OTUB1 positively regulates FOXM1 expression. In agreement, co-immunoprecipitation experiments demonstrated that FOXM1 expression is associated with OTUB1 binding but inversely correlates with conjugation to the protein degradation-associated Lys-48-linked ubiquitin-chains. Overexpression of wild-type (WT) OTUB1, but not the OTUB1(C91S) mutant, disrupted the formation of Lys48-linked ubiquitin-conjugates on FOXM1. Importantly, knockdown of OTUB1 by siRNA resulted in an increase in turnover of FOXM1 in MCF-7 cells treated with the protein synthesis inhibitor cycloheximide, whereas overexpression of WT OTUB1, but not the OTUB1(C91S) mutant, significantly enhances the half-life of FOXM1. In addition, proliferative and clonogenic assays also show that OTUB1 can enhance the proliferative rate and epirubicin resistance through targeting FOXM1, as OTUB1 has little effect on FOXM1-deficient cells. The physiological relevance of the regulation of FOXM1 by OTUB1 is further underscored by the significant correlations between FOXM1 and OTUB1 expression in breast cancer patient samples. Cox-regression survival analysis indicates that OTUB1 overexpression is linked to poorer outcome in particular in patients treated with chemotherapy. Collectively, these data suggest that OTUB1 limits the ubiquitination and degradation of FOXM1 in breast cancer and has a key role in genotoxic agent resistance.Oncogene advance online publication, 6 July 2015; doi:10.1038/onc.2015.208. © 2015 Macmillan Publishers Limited


Alizon S.,IRD Montpellier | Fraser C.,Imperial College London
Retrovirology | Year: 2013

Background: HIV evolves rapidly at the epidemiological level but also at the within-host level. The virus' within-host evolutionary rates have been argued to be much higher than its between-host evolutionary rates. However, this conclusion relies on analyses of a short portion of the virus envelope gene. Here, we study in detail these evolutionary rates across the HIV genome.Results: We build phylogenies using a relaxed molecular clock assumption to estimate evolutionary rates in different regions of the HIV genome. We find that these rates vary strongly across the genome, with higher rates in the envelope gene (env). Within-host evolutionary rates are consistently higher than between-host rates throughout the HIV genome. This difference is significantly more pronounced in env. Finally, we find weak differences between overlapping and non-overlapping regions.Conclusions: We provide a genome-wide overview of the differences in the HIV rates of molecular evolution at the within- and between-host levels. Contrary to hepatitis C virus, where differences are only located in the envelope gene, within-host evolutionary rates are higher than between-host evolutionary rates across the whole HIV genome. This supports the hypothesis that HIV strains that are less adapted to the host have an advantage during transmission. The most likely mechanism for this is storage and then preferential transmission of viruses in latent T-cells. These results shed a new light on the role of the transmission bottleneck in the evolutionary dynamics of HIV. © 2013 Alizon and Fraser; licensee BioMed Central Ltd.


Sutton R.,Imperial College London
Progress in Cardiovascular Diseases | Year: 2013

Syncope is a presenting symptom, and in itself is not a diagnosis. An etiology or a mechanism must be sought in all cases. Currently, most clinicians classify syncope on clinical grounds by attempting to ascertain its etiology. They then use this classification to guide further management. Using this approach, reflex syncope is the most common form of syncope, occurring in approximately 60% of syncope presentations. Orthostatic hypotension presents in around 15% with arrhythmic syncope in 10% and structural heart disease as the cause of syncope in 5%; in 10% of patients no diagnosis is made. An alternative classification system uses the mechanism of syncope derived from an implanted ECG loop recorder (ILR). While this approach may be of value for optimizing therapy, it cannot be considered as the primary classification since ILRs are not typically implanted early in the evaluation process of most patients. ILRs are usually placed after "risk stratification" in those deemed not to be at high risk but remain in the uncertain etiology category. Furthermore, there exists, in current ILR technology, lack of ambulatory blood pressure monitoring capability. Thus, vasodilation leading to hypotension, the main trigger of cerebral hypoperfusion other than bradycardia, cannot be detected and is currently unavailable for use in a mechanistic-based classification. Thus, the etiological classification remains the basis for both risk stratification and subsequent clinical management. © 2013 Elsevier Inc.


Wulff L.,Imperial College London
Journal of High Energy Physics | Year: 2015

Abstract: In the absence of NSNS three-form flux the bosonic string on a symmetric space is described by a symmetric space coset sigma-model. Such models are known to be classically integrable. We show that the integrability extends also to cases with non-zero NSNS flux (respecting the isometries) provided that the flux satisfies a condition of the form HabcHcde ∼ Rabde. We then turn our attention to the type II Green-Schwarz superstring on a symmetric space. We prove that if the space preserves some supersymmetry there exists a truncation of the full superspace to a supercoset space and derive the general form of the superisometry algebra. In the case of vanishing NSNS flux the corresponding supercoset sigma-model for the string is known to be integrable. We prove that the integrability extends to the full string by augmenting the supercoset Lax connection with terms involving the fermions which are not captured by the supercoset model. The construction is carried out to quadratic order in these fermions. This proves the integrability of strings on symmetric spaces supported by RR flux which preserve any non-zero amount of supersymmetry. Finally we also construct Lax connections for some supercoset models with non-zero NSNS flux describing strings in AdS2,3 × S2,3 × S2,3 × T2,3,4 backgrounds preserving eight supersymmetries. © 2015, The Author(s).


Sever P.S.,Imperial College London | Messerli F.H.,Columbia University
European Heart Journal | Year: 2011

Raised levels of blood pressure result from the complex interplay of environmental and genetic factors. The complexity of blood pressure control mechanisms has major implications for individual responsiveness to antihypertensive drugs. The underlying haemodynamic disorder in the majority of cases is a rise in peripheral vascular resistance. This observation led to the discovery and development of increasingly sophisticated and targeted vasodilators, although many of the earlier antihypertensive drugs, by virtue of their actions blocking the sympathetic nervous system, had a vasodilator component to their mode of action. A recent meta-analysis of placebo controlled trials of monotherapy in unselected hypertensives, reports average (placebo-corrected) blood pressure responses to single agents of 9.1 mmHg systolic and 5.5 mmHg diastolic pressure. These average values disguise the extremely wide ranging responses in individuals across a fall of 2030 mmHg systolic at one extreme, to no effect at all, or even a small rise in blood pressure at the other. The second factor determining individual responses to monotherapy is the extent to which initial falls in pressure are opposed by reflex responses in counter regulatory mechanisms that are activated following the blood pressure reduction. Thus, a satisfactory blood pressure response is rarely reached with monotherapy alone. What then is the next step if blood pressure is not a goal after the patient has been treated with monotherapy for a few weeks? Should you uptitrate, substitute or combine? © 2011 The Author.


Hopkins T.G.,Imperial College London | Wood N.,Royal Preston Hospital
Vaccine | Year: 2013

Human papillomavirus (HPV) is the causative agent in cervical cancer and has been implicated in a range of other malignancies. Preventative vaccines are now internationally available and provide high levels of protection from common viral strains. The introduction of a comprehensive vaccination programme (except 'program' in computers) could prevent over 60% of current cervical cancer cases, but this is dependent on such programmes achieving a high level of coverage. In this review, we summarise the current trends in female HPV vaccination coverage throughout the world, and place it in the context of available research on attitudes towards vaccination amongst the public and health professionals.Where countries have the resources for mass vaccination programmes, uptake has varied. School-based opt-out programmes consistently achieve highest coverage, whilst countries and regions without systematic vaccination schemes have low coverage. In all countries, the success of vaccination programmes is dependent on the support of the public and healthcare professionals. Whilst public acceptance is dependent on multiple factors, it has repeatedly been shown that recommendation by a health professional, particularly clinicians, is key to vaccine uptake. Worryingly, it appears that a proportion of clinicians still have significant reservations about promoting vaccination, particularly for younger age groups. A commitment now, to fully educating both the public and clinicians, has the potential to make a dramatic future impact. © 2013 Elsevier Ltd.


Tarbutt M.R.,Imperial College London
New Journal of Physics | Year: 2015

Laser cooling and magneto-optical trapping of molecules typically involves multiple transitions driven by several laser frequencies. We analyze how magneto-optical trapping forces depend on the angular momenta, Fl and Fu, and the g-factors, gl and gu, of the lower and upper states. When the polarizations must be reversed relative to cases where Fu ≥ Fl. The correct choice of circular polarization depends on the sign of gu but not on the sign of gl. If gu is zero there is no trapping force, and the trapping force is very weak whenever gu is small compared to gl, which it usually is when the cooling transition is the 2σ to 2π1/2 transition of a molecule. For some molecules, mixing of the excited 2π1/2 state with a nearby 2σ excited state can greatly increase gu, leading to stronger trapping forces. A strong trapping force can also be produced by rapidly and synchronously reversing both the magnetic field and the laser polarizations. We simulate a recent experiment on magneto-optical trapping of SrF molecules, and suggest that an alternative choice of laser beam polarizations will strengthen the trapping force. © 2015 IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.


Donos A.,University of Cambridge | Gauntlett J.P.,Imperial College London
Journal of High Energy Physics | Year: 2014

Abstract: An analytic expression for the DC electrical conductivity in terms of black hole horizon data was recently obtained for a class of holographic black holes exhibiting momentum dissipation. We generalise this result to obtain analogous expressions for the DC thermoelectric and thermal conductivities. We illustrate our results using some holographic Q-lattice black holes as well as for some black holes with linear massless axions, in both D = 4 and D = 5 bulk spacetime dimensions, which include both spatially isotropic and anisotropic examples. We show that some recently constructed ground states of holographic Q-lattices, which can be either electrically insulating or metallic, are all thermal insulators. © 2014, The Author(s).


Barber T.M.,University of Warwick | Franks S.,Imperial College London
Molecular and Cellular Endocrinology | Year: 2013

Polycystic Ovary Syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including insulin resistance. There is a clear association between obesity, the development of PCOS and the severity of its phenotypic, biochemical and metabolic features. Evidence to support this link includes data from epidemiological, pathophysiological and genetic studies. Given the importance of obesity in the development and manifestation of PCOS, ongoing research into the many facets of adipocyte biology in women with the condition is important and should continue to be a priority. In this review article, we discuss the existing literature on fat distribution, adipokines, adipocyte hypertrophy and adipocyte steroid metabolism in women with PCOS. © 2012 Elsevier Ireland Ltd.


Donos A.,University of Cambridge | Gauntlett J.P.,Imperial College London
Journal of High Energy Physics | Year: 2014

Using simple holographic models in D = 4 spacetime dimensions we construct black hole solutions dual to d = 3 CFTs at finite charge density with a Q-lattice deformation. At zero temperature we find new ground state solutions, associated with broken translation invariance in either one or both spatial directions, which exhibit insulating or metallic behaviour depending on the parameters of the holographic theory. For low temperatures and small frequencies, the real part of the optical conductivity exhibits a power-law behaviour. We also obtain an expression for the the DC conductivity at finite temperature in terms of horizon data of the black hole solutions. © 2014 The Author(s).


Wulff L.,Imperial College London
Journal of High Energy Physics | Year: 2014

For type II supergravity backgrounds with superisometries the corresponding transformations and conserved currents for the superstring are constructed up to fourth order in Θ. It is then shown how, for certain backgrounds related to near horizon geometries of intersecting branes, the components of the superisometry current can be used to construct a Lax connection demonstrating the classical integrability of the string in these backgrounds. This includes examples of AdS 2 and AdS 3 backgrounds with a D(2, 1; α) isometry group which have not previously been studied from an integrability point of view. The construction of the Lax connection is carried out up to second order in Θ. © 2014 The Author(s).


Hull C.M.,Imperial College London
Journal of High Energy Physics | Year: 2015

Abstract: Recently proposed forms for gauge transformations with finite parameters in double field theory are discussed and problematic issues are identified. A new form for finite gauge transformations is derived that reveals the underlying gerbe structure and the close relationship with generalised geometry. The nature of generalised tensors is elucidated, and in particular it is seen that the presence of a constant metric with split signature does not restrict the doubled geometry, provided it is a generalised tensor rather than a conventional tensor. © 2015, The Author(s).


Smallegange I.M.,Imperial College London
Evolutionary Ecology | Year: 2010

Understanding the evolution and maintenance of within-sex reproductive morphs, or alternative reproductive phenotypes (ARPs), requires in depth understanding of the proximate mechanisms that determine ARP expression. Most species express ARPs in complex ecological environments, yet little is know about how different environmental variables collectively affect ARP expression. Here, I investigated the influence of maternal and developmental nutrition and sire phenotype on ARP expression in bulb mites (Rhizoglyphus robini), where males are either fighters, able to kill other mites, or benign scramblers. In a factorial experiment, females were raised on a rich or a poor diet, and after maturation they were paired to a fighter or a scrambler. Their offspring were put on the rich or poor diet. Females on the rich diet increased investment into eggs when mated to a fighter, but suffered reduced longevity. Females indirectly affected offspring ARP expression as larger eggs developed into larger final instars, which were more likely to develop into a fighter. Final instar size, which also strongly depended on offspring nutrition, was the main cue for morph development: a switch point, or size threshold, existed where development switched from one phenotype to the other. Sire phenotype affected offspring phenotype, but only if offspring were on the poor diet, indicating a gene by environment interaction. Overall, the results revealed that complex environmental effects can underlie ARP expression, with differential maternal investment potentially amplifying genetic effects on offspring morphology. These effects can therefore play an important role in understanding how selection affects ARP expression and, like quantitative genetics models for continuous traits, should be incorporated into models of threshold traits. © Springer Science+Business Media B.V. 2010.


Dazzi F.,Imperial College London
Blood | Year: 2013

In this issue of Blood, Zhang and colleagues report the identification of a novel subset of circulating myeloid cells with immunosuppressive activity in pediatric patients with metastatic sarcomas. © 2013 by The American Society of Hematology.


Leitinger B.,Imperial College London
International Review of Cell and Molecular Biology | Year: 2014

The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors that are members of the receptor tyrosine kinase family. Both DDRs bind a number of different collagen types and play important roles in embryo development. Dysregulated DDR function is associated with progression of various human diseases, including fibrosis, arthritis, and cancer. By interacting with key components of the extracellular matrix and displaying distinct activation kinetics, the DDRs form a unique subfamily of receptor tyrosine kinases. DDR-facilitated cellular functions include cell migration, cell survival, proliferation, and differentiation, as well as remodeling of extracellular matrices. This review summarizes the current knowledge of DDR-ligand interactions, DDR-initiated signal pathways and the molecular mechanisms that regulate receptor function. Also discussed are the roles of DDRs in development and disease progression. © 2014 Elsevier Inc.


Dorsett D.,Saint Louis University | Merkenschlager M.,Imperial College London
Current Opinion in Cell Biology | Year: 2013

Cohesin is an evolutionarily ancient multisubunit protein complex with a deeply conserved function: it provides cohesion between sister chromatids from the time of DNA replication in S-phase until mitosis. This cohesion facilitates repair of damage that occurs during DNA replication, and, crucially, enforces faithful segregation of chromosomes upon cell division. Cohesin also influences gene expression, and relative to sister chromatid cohesion, gene expression is exquisitely sensitive to moderate changes in cohesin activity. Early studies revealed differences in cohesin's roles in gene expression between various organisms. In all organisms examined, however, cohesin marks a subset of active genes. This review focuses on the roles of cohesin at active genes, and to what extent these roles are conserved between organisms. © 2013 Elsevier Ltd.


Ferrai C.,Imperial College London
Cold Spring Harbor perspectives in biology | Year: 2010

Eukaryotic gene expression is an intricate multistep process, regulated within the cell nucleus through the activation or repression of RNA synthesis, processing, cytoplasmic export, and translation into protein. The major regulators of gene expression are chromatin remodeling and transcription machineries that are locally recruited to genes. However, enzymatic activities that act on genes are not ubiquitously distributed throughout the nucleoplasm, but limited to specific and spatially defined foci that promote preferred higher-order chromatin arrangements. The positioning of genes within the nuclear landscape relative to specific functional landmarks plays an important role in gene regulation and disease.


Donos A.,University of Cambridge | Gauntlett J.P.,Imperial College London
Journal of High Energy Physics | Year: 2015

Abstract: We consider inhomogeneous, periodic, holographic lattices of D = 4 Einstein-Maxwell theory. We show that the DC thermoelectric conductivity matrix can be expressed analytically in terms of the horizon data of the corresponding black hole solution. We numerically construct such black hole solutions for lattices consisting of one, two and ten wave-numbers. We numerically determine the AC electric conductivity which reveals Drude physics as well as resonances associated with sound modes. No evidence for an intermediate frequency scaling regime is found. All of the monochromatic lattice black holes that we have constructed exhibit scaling behaviour at low temperatures which is consistent with the appearance of AdS2 ×2 in the far IR at T = 0. © 2015, The Author(s).


Lucy L.B.,Imperial College London
Astronomy and Astrophysics | Year: 2014

The problem of estimating the total mass of a visual binary when its orbit is incomplete is treated with Bayesian methods. The posterior mean of a mass estimator is approximated by a triple integral over orbital period, orbital eccentricity and time of periastron. This reduction to 3D from the 7D space defined by the conventional Campbell parameters is achieved by adopting the Thiele-Innes elements and exploiting the linearity with respect to the four Thiele-Innes constants. The formalism is tested on synthetic observational data covering a variable fraction of a model binary's orbit. The posterior mean of the mass estimator is numerically found to be unbiased when the data cover ≳40% of the orbit. © ESO, 2014.


Armstrong-James D.,Imperial College London | Harrison T.S.,St Georges, University of London
Current Opinion in Microbiology | Year: 2012

Invasive fungal infections have become a major cause of mortality in immunocompromised individuals. Despite the current availability of number of highly active antifungal agents, overall mortality remains around 40%. Importantly, it is clear that a failure to restore host immunity leads to worse outcomes. These observations provide clear rationale for the development of novel immunotherapies to improve outcomes in immunocompromised individuals with invasive fungal infections. In this article we summarise the key advances that have been made in the field of immunotherapy for fungal infections in recent years, with a particular focus on clinical studies of interferon-γ therapy, adoptive T cell therapy, and gene therapy for chronic granulomatous disorder. In addition a number of pre-clinical approaches are reviewed. © 2012.


Bazant M.Z.,Massachusetts Institute of Technology | Storey B.D.,Franklin W. Olin College Of Engineering | Kornyshev A.A.,Imperial College London
Physical Review Letters | Year: 2011

We develop a simple Landau-Ginzburg-type continuum theory of solvent-free ionic liquids and use it to predict the structure of the electrical double layer. The model captures overscreening from short-range correlations, dominant at small voltages, and steric constraints of finite ion sizes, which prevail at large voltages. Increasing the voltage gradually suppresses overscreening in favor of the crowding of counterions in a condensed inner layer near the electrode. This prediction, the ion profiles, and the capacitance-voltage dependence are consistent with recent computer simulations and experiments on room-temperature ionic liquids, using a correlation length of order the ion size. © 2011 American Physical Society.


These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated. © 2011 The Author(s).


Mason R.M.,Imperial College London
International Journal of Experimental Pathology | Year: 2013

Connective tissue growth factor (CTGF, CCN2) is a member of the CCN family of matricellular proteins. It interacts with many other proteins, including plasma membrane proteins, modulating cell function. It is expressed at low levels in normal adult kidney cells but is increased in kidney diseases, playing important roles in inflammation and in the development of glomerular and interstitial fibrosis in chronic disease. This review reports the evidence for its expression in human and animal models of chronic kidney disease and summarizes data showing that anti-CTGF therapy can successfully attenuate fibrotic changes in several such models, suggesting that therapies targeting CTGF and events downstream of it in renal cells may be useful for the treatment of human kidney fibrosis. Connective tissue growth factor stimulates the development of fibrosis in the kidney in many ways including activating cells to increase extracellular matrix synthesis, inducing cell cycle arrest and hypertrophy, and prolonging survival of activated cells. The relationship between CTGF and the pro-fibrotic factor TGFβ is examined and mechanisms by which CTGF promotes signalling by the latter are discussed. No specific cellular receptors for CTGF have been discovered but it interacts with and activates several plasma membrane proteins including low-density lipoprotein receptor-related protein (LRP)-1, LRP-6, tropomyosin-related kinase A, integrins and heparan sulphate proteoglycans. Intracellular signalling and downstream events triggered by such interactions are reviewed. Finally, the relationships between CTGF and several anti-fibrotic factors, such as bone morphogenetic factor-4 (BMP4), BMP7, hepatocyte growth factor, CCN3 and Oncostatin M, are discussed. These may determine whether injured tissue heals or progresses to fibrosis. © 2012 International Journal of Experimental Pathology.


Lemaitre B.,Ecole Polytechnique Federale de Lausanne | Miguel-Aliaga I.,Imperial College London
Annual Review of Genetics | Year: 2013

The digestive tract plays a central role in the digestion and absorption of nutrients. Far from being a passive tube, it provides the first line of defense against pathogens and maintains energy homeostasis by exchanging neuronal and endocrine signals with other organs. Historically neglected, the gut of the fruit fly Drosophila melanogaster has recently come to the forefront of Drosophila research. Areas as diverse as stem cell biology, neurobiology, metabolism, and immunity are benefitting from the ability to study the genetics of development, growth regulation, and physiology in the same organ. In this review, we summarize our knowledge of the Drosophila digestive tract, with an emphasis on the adult midgut and its functional underpinnings. © 2013 by Annual Reviews. All rights reserved.


Donos A.,Durham University | Gauntlett J.P.,Imperial College London
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

Within the context of the AdS/CFT correspondence, we show that the DC thermoelectric conductivity can be obtained by solving the linearized, time-independent, and forced Navier-Stokes equations on the black hole horizon for an incompressible and charged fluid. © 2015 American Physical Society.


Figueras P.,University of Cambridge | Wiseman T.,Imperial College London
Physical Review Letters | Year: 2011

We show how to construct low energy solutions to the Randall-Sundrum II (RSII) model by using an associated five-dimensional anti-de Sitter space (AdS 5) and/or four-dimensional conformal field theory (CFT 4) problem. The RSII solution is given as a perturbation of the AdS 5-CFT 4 solution, with the perturbation parameter being the radius of curvature of the brane metric compared to the AdS length ℓ. The brane metric is then a specific perturbation of the AdS 5-CFT 4 boundary metric. For low curvatures the RSII solution reproduces 4D general relativity on the brane. Recently, AdS 5-CFT 4 solutions with a 4D Schwarzschild boundary metric were numerically constructed. We modify the boundary conditions to numerically construct large RSII static black holes with radius up to ∼20ℓ. For a large radius, the RSII solutions are indeed close to the associated AdS 5-CFT 4 solution. © 2011 American Physical Society.


Howes O.D.,Imperial College London | Howes O.D.,Kings College London | Murray R.M.,Kings College London
The Lancet | Year: 2014

Schizophrenia remains a major burden on patients and society. The dopamine hypothesis attempts to explain the pathogenic mechanisms of the disorder, and the neurodevelopmental hypothesis the origins. In the past 10 years an alternative, the cognitive model, has gained popularity. However, the first two theories have not been satisfactorily integrated, and the most influential iteration of the cognitive model makes no mention of dopamine, neurodevelopment, or indeed the brain. In this Review we show that developmental alterations secondary to variant genes, early hazards to the brain, and childhood adversity sensitise the dopamine system, and result in excessive presynaptic dopamine synthesis and release. Social adversity biases the cognitive schema that the individual uses to interpret experiences towards paranoid interpretations. Subsequent stress results in dysregulated dopamine release, causing the misattribution of salience to stimuli, which are then misinterpreted by the biased cognitive processes. The resulting paranoia and hallucinations in turn cause further stress, and eventually repeated dopamine dysregulation hardwires the psychotic beliefs. Finally, we consider the implications of this model for understanding and treatment of schizophrenia.


Hawkes A.D.,Imperial College London
Applied Energy | Year: 2014

Estimates of the magnitude of CO2 emissions reduction brought about by an intervention in the energy system are important because they signal which interventions are the most potent in terms of climate change mitigation. Yet quantifying emissions changes is not trivial because interventions act on the margin of the energy system, rather than acting on all components of the whole energy system equally. Therefore, in order to accurately attribute outcomes to interventions, the specific energy system changes precipitated by the intervention should be estimated, along with the corresponding change in emissions. This paper builds on previous research in this regard estimating short-run marginal emissions factors in national electricity systems. It presents the concept of the long-run marginal emissions factor (LR-MEF), and builds and applies a new electricity system model to study the problem. For the British electricity system it is found that the average LR-MEF is approximately 0.26-0.53kgCO2/kWh for the coming decade, but this reduces to approximately zero by 2035 and onwards as the system decarbonises. Furthermore, it is found that the LR-MEF can diverge very significantly from the short-run. This highlights the state of flux of the British electricity system and the importance of taking structural changes in the electricity system into account when attributing emissions reduction to interventions. © 2014 The Author.


Turnbull C.,Imperial College London
Journal of Experimental Botany | Year: 2011

One of the great mysteries of plant science appears to have been resolved with the discovery that the protein FT can act as a phloem-mobile florigen hormone. The collective evidence from several laboratories, many from studies on photoperiod response, indicates that FT and its homologues are universal signalling molecules for flowering plants. Duplication and divergence of FT-like proteins reveals an increased complexity of function in certain taxonomic groups including grasses and legumes. There are additional components of long-distance flowering time control, such as a role for gibberellins in some species but probably not others. Cytokinins and sugars are further putative signals. Vernalization processes and responses are generally considered to occur in shoot meristems, but systemic responses to cold have been reported several times. Finally, there is increasing evidence that FT does not act purely to switch on flowering, but in addition, has broader roles in seasonal developmental switches such as bud dormancy and tuberization, and in the regulation of meristem determinacy and compound leaf development. This review seeks to highlight recent progress in systemic floral signalling, and to indicate areas in need of further research. © 2011 The Author(s).


O'Brien A.G.,Imperial College London
Tetrahedron | Year: 2011

Recent developments in models for acyclic stereocontrol have been discussed in the context of three important classes of organic reaction and some recent organometallic reactions. For additions of nucleophiles to carbonyls with an adjacent stereocentre, both computational and experimental evidence have challenged the predominance of the FelkineAnh and Cram models for predicting stereoselectivity. Various models for describing electrophilic and nucleophilic addition to double bonds have been proposed that account for variations in selectivity. However, these are often very specific to each particular reaction. In some cases, the major product arises from a seemingly highenergy transition state, e.g., in examples of the inside-methyl effect. Above all, 1,3-allylic strain appears to be the most important control element in reactions of C]C double bonds adjacent to a stereocentre. Many of the same models have been extended to explain acyclic stereocontrol in pericyclic reactions. In these cases, both stereoelectronic effects, again 1,3-allylic strain in particular, and electrostatic effects must be taken into account. Stereoselective reactions of unsaturated functional groups adjacent to organometallic complexes are also emerging as useful tools for establishing acyclic stereocontrol. Taking into account the above examples, some general conclusions can be drawn. There is no unified theory that explains all modes of acyclic stereocontrol. Rather, it appears that models are very specific to the individual reaction mechanism, and the nature of the incoming electrophile or nucleophile must be considered. Additional complexity is encountered when stereoselectivity is a function of both acyclic and cyclic stereocontrol (double diastereoselection). These cannot be considered in isolation and models must take into account interactions between cyclic and acyclic transition states. Developments in computational methods have contributed to our ability to predict the sense of acyclic stereocontrol,although exceptions to these predictions are often encountered in experiments. Development of models and methods for establishing acyclic stereocontrol remains a highly active area of interest in synthetic chemistry. © 2011 Elsevier Ltd. All rights reserved.


Gawer A.,Imperial College London
Research Policy | Year: 2014

An integrative framework is proposed to advance management research on technological platforms, bridging two theoretical perspectives: economics, which sees platforms as double-sided markets, and engineering design, which sees platforms as technological architectures. While the economic perspective informs our understanding of platform competition, the engineering design perspective informs our view of platform innovation. The article argues that platforms can be usefully conceptualized as evolving organizations or meta-organizations that: (1) federate and coordinate constitutive agents who can innovate and compete; (2) create value by generating and harnessing economies of scope in supply or/and in demand; and (3) entail a modular technological architecture composed of a core and a periphery. In support of this conceptualization, a classification system is presented, indicating that technological platforms appear in a variety of organizational forms: within firms, across supply chains, and across industry innovation ecosystems. As an illustration, the framework is then applied to derive a simple model highlighting patterns of interaction between platform innovation and competition, yielding hypotheses that could be tested empirically by future scholars. © 2014 The Authors.


Morgan T.J.,University of Hawaii at Manoa | Kandiyoti R.,Imperial College London
Chemical Reviews | Year: 2014

A survey of experimental data and analytical tools that have served to formulate a conceptual model of thermal breakdown processes taking place during pyrolysis of middle-rank coals and lignocellulosic biomass is studied. When solid fuels are heated beyond their characteristic threshold thermal breakdown temperatures, irreversible chemical and physical changes are initiated. These processes constitute the first stage of all solid fuel utilization processes, including combustion, coking, liquefaction, and gasification. The thermal breakdown phenomena are intimately related to processing routes for making synthetic liquids from diverse starting materials that include biomass to liquids (BTL), natural gas to liquids (GTL), coal to liquids (CTL), and wastes to liquids (WTL), collectively referred to as feed to liquids (XTL). The size distribution of polynuclear aromatic ring systems is a key parameter that would be useful to evaluate at successive stages of thermal breakdown processes.


Dalakas M.C.,Imperial College London
Current Opinion in Pharmacology | Year: 2010

Based on unique clinicopathological criteria, the most common immune inflammatory muscle disorders include Dermatomyositis (DM), Polymyositis (PM), Necrotizing Myositis (NM), and sporadic Inclusion Body Myositis (sIBM). DM is an undeniably a complement-mediated microangiopathy with destruction of capillaries, hypoperfusion, and inflammatory cell stress on the perifascicular regions. Necrotizing Myopathy is a poorly studied subacute myopathy triggered by toxic, viral, or autoimmune factors with macrophages as the final effector cells. In PM and IBM cytotoxic CD8-positive T-cells clonally expand in situ and invade MHC-I-expressing muscle fibers. In sIBM, in addition to autoimmune inflammation, there are degenerative features characterized by vacuolization and accumulation of stressor and amyloid-related molecules. Advances in the immunobiology of these disorders are discussed including the interaction between pro-inflammatory and β-amyloid or stressor proteins. A critical review regarding tissue biomarkers and strategies for more effective treatments are presented. © 2010 Elsevier Ltd.


The availability of in vitro assembly systems to produce recombinant archaeal RNA polymerases (RNAPs) offers one of the most powerful experimental tools for investigating the still relatively poorly understood molecular mechanisms underlying RNAP function. Over the last few years, we pioneered new robot-based high-throughput mutagenesis approaches to study structure/function relationships within various domains surrounding the catalytic center. The Bridge Helix domain, which appears in numerous X-ray structures as a 35-amino-acid-long alpha helix, coordinates the concerted movement of several other domains during catalysis through kinking of two discrete molecular hinges. Mutations affecting these kinking mechanisms have a direct effect on the specific catalytic activity of RNAP and can in some instances more than double it. Molecular dynamics simulations have established themselves as exceptionally useful for providing additional insights and detailed models to explain the underlying structural motions. Copyright © 2011 Robert O. J. Weinzierl.


Kornyshev A.A.,Imperial College London | Qiao R.,Virginia Polytechnic Institute and State University
Journal of Physical Chemistry C | Year: 2014

Electrical double layers are ubiquitous; they will inevitably emerge, given mobile charge carriers and an interface. They play a decisive role in well-known problems such as electrochemical reactions, electrokinetics, and colloidal stability and thus have been studied extensively since the very concept of the double layer was postulated by Helmholtz. Furthermore, the transition between different lateral arrangements of counter and co-ions during electrification of narrow pores has been observed in simulations and shown to greatly affect both the capacitance and dynamics of the double layers. These relatively new issues and developments all point to new challenges in understanding the three-dimensional (3D) structures of the double layers controlled by the electrification of surfaces. The new feature of the double layer in ionic liquids is that structural transitions can take place in the adjacent layer to the electrode, even when its ions may not be specifically adsorbed on the electrode.


Mayne D.Q.,Imperial College London
Automatica | Year: 2014

This paper recalls a few past achievements in Model Predictive Control, gives an overview of some current developments and suggests a few avenues for future research. © 2014 Elsevier Ltd. All rights reserved.


Zangwill A.,Georgia Institute of Technology | Vvedensky D.D.,Imperial College London
Nano Letters | Year: 2011

Graphene, a hexagonal sheet of sp 2-bonded carbon atoms, has extraordinary properties which hold immense promise for nanoelectronic applications. Unfortunately, the popular preparation methods of micromechanical cleavage and chemical exfoliation of graphite do not easily scale up for application purposes. Epitaxial graphene provides an attractive alternative, though there are many challenges, not least of which is the absence of any understanding of the complex atomistic assembly kinetics of graphene layers. Here, we present a simple rate theory of epitaxial graphene growth on close-packed metal surfaces. On the basis of recent low-energy electron-diffraction microscopy experiments, our theory supposes that graphene islands grow predominantly by the attachment of five-atom clusters. With optimized kinetic parameters, our theory produces a quantitative account of the measured time-dependent carbon adatom density. The temperature dependence of this density at the onset of nucleation leads us to predict that the smallest stable precursor to graphene growth is an immobile island composed of six five-atom clusters. This conclusion is supported by a recent study based on temperature-programmed growth of epitaxial graphene, which provides direct evidence of nanoclusters whose coarsening leads to the formation of graphene layers. Our findings should motivate additional high-resolution imaging experiments and more detailed simulations which will yield important input to developing strategies for the large-scale production of epitaxial graphene. © 2011 American Chemical Society.


Hallett T.B.,Imperial College London
Current Opinion in HIV and AIDS | Year: 2011

Purpose of review: To describe the needs for information on the rate of new HIV infections (incidence) in epidemics and review developments in various methods for its estimation. Recent findings: Epidemiological methods for estimating incidence with models using prevalence data have been useful, but the expansion of antiretroviral treatment programmes could now challenge their reliability. Laboratory-based HIV incidence assays that can be used to measure HIV incidence using a cross-sectional survey, provide a promising concept, but current technologies have not been sufficiently accurate. New statistical methods have been developed that show that if the properties of the assay are properly measured then unbiased estimates of incidence can be derived, and that assays meeting certain criteria can produce estimates of acceptable accuracy and precision. Encouragingly, some new assays and algorithms show signs of potentially meeting those criteria. Among the next challenges will be the systematic evaluation of assay performance in many different types of specimen and the validation of those methods through comparison with other measurements of incidence. Summary: Recent developments in epidemiological and incidence assay-based methods of measuring incidence have been substantial and are likely to eventually lead to a revolution in the way that worldwide HIV epidemics are routinely tracked. © 2011 Lippincott Williams & Wilkins, Inc.


Merkenschlager M.,Imperial College London | Odom D.T.,University of Cambridge
Cell | Year: 2013

Current epigenomics approaches have facilitated the genome-wide identification of regulatory elements based on chromatin features and transcriptional regulator binding and have begun to map long-range interactions between regulatory elements and their targets. Here, we focus on the emerging roles of CTCF and the cohesin in coordinating long-range interactions between regulatory elements. We discuss how species-specific transposable elements may influence such interactions by remodeling the CTCF binding repertoire and suggest that cohesin's association with enhancers, promoters, and sites defined by CTCF binding has the potential to form developmentally regulated networks of long-range interactions that reflect and promote cell-type-specific transcriptional programs. © 2013 Elsevier Inc.


Gelenbe E.,Imperial College London
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2010

N searchers are sent out by a source in order to locate a fixed object which is at a finite distance D, but the search space is infinite and D would be in general unknown. Each of the searchers has a finite random lifetime, and may be subject to destruction or failures, and it moves independently of other searchers, and at intermediate locations some partial random information may be available about which way to go. When a searcher is destroyed or disabled, or when it "dies naturally," after some time the source becomes aware of this and it sends out another searcher, which proceeds similarly to the one that it replaces. The search ends when one of the searchers finds the object being sought. We use N coupled Brownian motions to derive a closed form expression for the average search time as a function of D which will depend on the parameters of the problem: the number of searchers, the average lifetime of searchers, the routing uncertainty, and the failure or destruction rate of searchers. We also examine the cost in terms of the total energy that is expended in the search. © 2010 The American Physical Society.


Boyle R.J.,Imperial College London
Cochrane database of systematic reviews (Online) | Year: 2012

Venom immunotherapy (VIT) is commonly used for preventing further allergic reactions to insect stings in people who have had a sting reaction. The efficacy and safety of this treatment has not previously been assessed by a high-quality systematic review. To assess the effects of immunotherapy using extracted insect venom for preventing further allergic reactions to insect stings in people who have had an allergic reaction to a sting. We searched the following databases up to February 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), AMED (from 1985), LILACS (from 1982), the Armed Forces Pest Management Board Literature Retrieval System, and OpenGrey. There were no language or publication status restrictions to our searches. We searched trials databases, abstracts from recent European and North American allergy meetings, and the references of identified review articles in order to identify further relevant trials. Randomised controlled trials of venom immunotherapy using standardised venom extract in insect sting allergy. Two authors independently undertook study selection, data extraction, and assessment of risk of bias. We identified adverse events from included controlled trials and from a separate analysis of observational studies identified as part of a National Institute for Health and Clinical Excellence Health Technology Assessment. We identified 6 randomised controlled trials and 1 quasi-randomised controlled trial for inclusion in the review; the total number of participants was 392. The trials had some risk of bias because five of the trials did not blind outcome assessors to treatment allocation. The interventions included ant, bee, and wasp immunotherapy in children or adults with previous systemic or large local reactions to a sting, using sublingual (one trial) or subcutaneous (six trials) VIT. We found that VIT is effective for preventing systemic allergic reaction to an insect sting, which was our primary outcome measure. This applies whether the sting occurs accidentally or is given intentionally as part of a trial procedure.In the trials, 3/113 (2.7%) participants treated with VIT had a subsequent systemic allergic reaction to a sting, compared with 37/93 (39.8%) untreated participants (risk ratio [RR] 0.10, 95% confidence interval [CI] 0.03 to 0.28). The efficacy of VIT was similar across studies; we were unable to identify a patient group or mode of treatment with different efficacy, although these analyses were limited by small numbers. We were unable to confirm whether VIT prevents fatal reactions to insect stings, because of the rarity of this outcome.Venom immunotherapy was also effective for preventing large local reactions to a sting (5 studies; 112 follow-up stings; RR 0.41, 95% CI 0.24 to 0.69) and for improving quality of life (mean difference [MD] in favour of VIT 1.21 points on a 7-point scale, 95% CI 0.75 to 1.67).We found a significant risk of systemic adverse reaction to VIT treatment: 6 trials reported this outcome, in which 14 of 150 (9.3%) participants treated with VIT and 1 of 135 (0.7%) participants treated with placebo or no treatment suffered a systemic reaction to treatment (RR 8.16, 95% CI 1.53 to 43.46; 2 studies contributed to the effect estimate). Our analysis of 11 observational studies found systemic adverse reactions occurred in 131/921 (14.2%) participants treated with bee venom VIT and 8/289 (2.8%) treated with wasp venom VIT. We found venom immunotherapy using extracted insect venom to be an effective therapy for preventing further allergic reactions to insect stings, which can improve quality of life. The treatment carries a small but significant risk of systemic adverse reaction.


We performed a systematic review to assess the effect of integrated perinatal prevention of mother-to-child transmission of HIV interventions compared to non- or partially integrated services on the uptake in low- and middle-income countries. We searched for experimental, quasi-experimental and controlled observational studies in any language from 21 databases and grey literature sources. Out of 28 654 citations retrieved, five studies met our inclusion criteria. A cluster randomized controlled trial reported higher probability of nevirapine uptake at the labor wards implementing HIV testing and structured nevirapine adherence assessment (RRR 1.37, bootstrapped 95% CI, 1.04-1.77). A stepped wedge design study showed marked improvement in antiretroviral therapy (ART) enrolment (44.4% versus 25.3%, p<0.001) and initiation (32.9% versus 14.4%, p<0.001) in integrated care, but the median gestational age of ART initiation (27.1 versus 27.7 weeks, p = 0.4), ART duration (10.8 versus 10.0 weeks, p = 0.3) or 90 days ART retention (87.8% versus 91.3%, p = 0.3) did not differ significantly. A cohort study reported no significant difference either in the ART coverage (55% versus 48% versus 47%, p = 0.29) or eight weeks of ART duration before the delivery (50% versus 42% versus 52%; p = 0.96) between integrated, proximal and distal partially integrated care. Two before and after studies assessed the impact of integration on HIV testing uptake in antenatal care. The first study reported that significantly more women received information on PMTCT (92% versus 77%, p<0.001), were tested (76% versus 62%, p<0.001) and learned their HIV status (66% versus 55%, p<0.001) after integration. The second study also reported significant increase in HIV testing uptake after integration (98.8% versus 52.6%, p<0.001). Limited, non-generalizable evidence supports the effectiveness of integrated PMTCT programs. More research measuring coverage and other relevant outcomes is urgently needed to inform the design of services delivering PMTCT programs.


Albrecht T.,Imperial College London
Nature Communications | Year: 2012

The quantum-mechanical tunnelling effect allows charge transport across nanometre-scale gaps between conducting electrodes. Application of a voltage between these electrodes leads to a measurable tunnelling current, which is highly sensitive to the gap size, the voltage applied and the medium in the gap. Applied to liquid environments, this offers interesting prospects of using tunnelling currents as a sensitive tool to study fundamental interfacial processes, to probe chemical reactions at the single-molecule level and to analyse the composition of biopolymers such as DNA, RNA or proteins. This offers the possibility of a new class of sensor devices with unique capabilities. © 2012 Macmillan Publishers Limited. All rights reserved.


Rosen S.D.,Imperial College London
Canadian Journal of Cardiology | Year: 2012

Angina pectoris is important because of its association with heart disease and risk of death. Historically after Heberden's account of angina in 1772, the association of pain with coronary artery disease quickly followed. Within a few years, Burns suggested an etiological role for ischemia. Subsequently, theories of differential myocardial stretch dominated thinking until Lewis' chemical hypothesis in 1932, in which the local release of chemical substances during ischemia was seen as the cause of pain. This review considers how ischemia at the tissue level triggers activation of afferent nociceptive pain fibres. The afferent projections of sympathetic and vagal afferent fibres are described, with a number of methodologies cited (eg, injection of pseudorabies virus into the heart with mapping of the retrograde viral transport pathways; and elevation of neuronal c-fos synthesis in brain regions activated by capsaicin application to the heart). Our own functional neuroimaging studies of angina are also reviewed. There are 2 intriguing features of angina. The first is the poor correlation between symptoms and extent of coronary disease. The spectrum ranges from entirely silent myocardial ischemia to that of a functional pain syndrome-the 'sensitive heart'-of cardiac syndrome X. An even more difficult aspect is the wide variability in symptoms experienced by an individual patient. A new paradigm is presented which, besides considering myocardial oxygen supply/demand imbalance, also draws insights from the broader field of pain research. Neuromodulation applies at multiple levels of the neuraxis-peripheral nerves, spinal cord, and brain-and it invites exploitation, whether pharmacological or electrical, for the benefit of the cardiac patient in pain. © 2012 Canadian Cardiovascular Society.


Bull J.A.,Imperial College London
Angewandte Chemie - International Edition | Year: 2012

With or without you: Chiral secondary alkylboronates can now be accessed by highly enantioselective catalytic methods including conjugate addition under metal-free conditions with an NHC catalyst, and also iridium-catalyzed hydrogenation. These methods reinforce the potential of secondary alkylboronates as ideal and universal chiral building blocks for bond formation to sp 3 carbon atoms. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Scheschkewitz D.,Imperial College London
Angewandte Chemie - International Edition | Year: 2011

Two major breakthroughs in the chemistry of silicon compounds with double bonds have been reported recently: the reaction of a zwitterionic silylene with arsane yields the blue donor-stabilized arsasilene with an Asi=Si bond (see left picture). Secondly, the extremely bulky and rigid hydrindacenyl substituent Eind allows for the preparation of emissive disilenes that are stable in the solid state towards air and moisture (right picture). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Rzepa H.S.,Imperial College London
Chemical Communications | Year: 2011

The calculated free energy barrier at 175 K between 1,3- dimethylcyclobutadiene and carbon dioxide inside a calixarene host (ωB97XD/6-311G(d,p)+polarizable continuum solvent model) has the low value of ∼8-10.5 kcal mol -1. This value casts doubt on the recently claimed isolation and X-ray structure determination at 175 K of 1,3-dimethylcyclobutadiene and carbon dioxide as separate species inside such a cavity. © 2011 The Royal Society of Chemistry.


Spanu P.D.,Imperial College London
Annual Review of Phytopathology | Year: 2012

Biotrophy is a pervasive trait that evolved independently in plant pathogenic fungi and oomycetes. Comparative genomics of the first sequenced biotrophic pathogens highlight remarkable convergences, including gene losses in the metabolism of inorganic nitrogen, inorganic sulfur, and thiamine, and genes encoding carbohydrate active enzymes and secondary metabolism enzymes. Some biotrophs, but not all, display marked increases in overall genome size because of a proliferation of retrotransposons. I argue here that the release of constraints on transposon activity is driven by the advantages conferred by the genetic variability that results from transposition, in particular by the creation and diversification of broad palettes of effector genes. Increases in genome size and gene losses are the consequences of this trade-off. Genes that are not necessary for growth on a plant disappeared, but we still do not know what lost functions make some of these pathogens obligate. © 2012 by Annual Reviews. All rights reserved.


Park J.,Electronics and Telecommunications Research Institute | Clerckx B.,Imperial College London
IEEE Transactions on Wireless Communications | Year: 2013

This paper investigates joint wireless information and energy transfer in a two-user MIMO interference channel, in which each receiver either decodes the incoming information data (information decoding, ID) or harvests the RF energy (energy harvesting, EH) to operate with a potentially perpetual energy supply. In the two-user interference channel, we have four different scenarios according to the receiver mode - (ID-1, ID-2), (EH-1, EH-2), (EH-1, ID-2), and (ID-1, EH-2). While the maximum information bit rate is unknown and finding the optimal transmission strategy is still open for (ID-1, ID-2), we have derived the optimal transmission strategy achieving the maximum harvested energy for (EH-1, EH-2). For (EH-1, ID-2), and (ID-1, EH-2), we find a necessary condition of the optimal transmission strategy and, accordingly, identify the achievable rate-energy (R-E) tradeoff region for two transmission strategies that satisfy the necessary condition - maximum energy beamforming (MEB) and minimum leakage beamforming (MLB). Furthermore, a new transmission strategy satisfying the necessary condition - signal-to-leakage-and-energy ratio (SLER) maximization beamforming - is proposed and shown to exhibit a better R-E region than the MEB and the MLB strategies. Finally, we propose a mode scheduling method to switch between (EH-1, ID-2) and (ID-1, EH-2) based on the SLER. © 2002-2012 IEEE.


Bedingham D.J.,Imperial College London
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

Energy diffusion due to spontaneous localization (SL) for a relativistically fast moving particle is examined. Spontaneous localization is an alternative to standard quantum theory in which quantum state reduction is treated as a random physical process which is incorporated into the Schrödinger equation in an observer-independent way. These models make predictions in conflict with standard quantum theory one of which is nonconservation of energy. On the basis of proposed relativistic extensions of SL it is argued that for a single localized particle, nonrelativistic SL should remain valid in the rest frame of the particle. The implication is that relativistic calculations can be performed by transforming nonrelativistic results from the particle rest frame to the frame of an inertial observer. This is demonstrated by considering a relativistic stream of noninteracting particles of cosmological origin and showing how their energy distribution evolves as a result of SL as they traverse the Universe. A solution is presented and the potential for astrophysical observations is discussed. © 2013 American Physical Society.


Eichhorn A.,Imperial College London
Journal of High Energy Physics | Year: 2015

Abstract: Unimodular gravity is classically equivalent to General Relativity. This equivalence extends to actions which are functions of the curvature scalar. At the quantum level, the dynamics could differ. Most importantly, the cosmological constant is not a coupling in the unimodular action, providing a new vantage point from which to address the cosmological constant fine-tuning problem. Here, a quantum theory based on the asymptotic safety scenario is studied, and evidence for an interacting fixed point in unimodular f (R) gravity is found. We study the fixed point and its properties, and also discuss the compatibility of unimodular asymptotic safety with dynamical matter, finding evidence for its compatibility with the matter degrees of freedom of the Standard Model. © 2015, The Author(s).


Shamonina E.,Imperial College London
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

A theory is presented combining effective-medium theory with that of magnetoinductive (MI) waves propagating by virtue of coupling between the resonant elements. The resulting circuit equations for the split-ring resonator (SRR) loaded transmission line are shown to be analogous to those describing a continuous anisotropic magnetic plasma exhibiting spatial dispersion due to interelement coupling. Interelement coupling is also shown to govern the properties of both bulk and surface magnetoinductive polaritons (hybrid polaritonic modes of electromagnetic waves and of slow waves of coupling between resonators). Implications of our method in the design of structures with controllable effective material parameters and with required functionality are demonstrated. We are able to design SRR-based near field manipulating devices for transverse electric (TE) polarization, including a realization of Pendry's near-perfect lens. Considering that surface waves of various kinds have found a wide range of applications in the past, it is envisaged that surface magnetoinductive polaritons will open up fresh possibilities. © 2012 American Physical Society.


Joffe M.,Imperial College London
Human Reproduction | Year: 2010

Semen quality appears to have declined in recent decades in some populations, e.g. north-western Europe. At the same time, couple fertility may have increased. Hypotheses are suggested for this apparent inconsistency. Alongside the deterioration of spermatogenesis there is clear evidence of an increase in other related problems, notably testicular cancer. The sharply rising trend in this condition started a century ago-decades earlier than sometimes thought. This and other evidence clearly indicates an environmental origin, but there is also a definite genetic component. The relationship of genetics and environment is discussed in the context of the puzzle that infertility is inherited, which appears to be impossible from an evolutionary standpoint. Poor semen quality is related not only to testicular cancer but also to zygote development, in which cancer-like disruption of the genetic apparatus is observed, with serious implications for offspring health. This needs to be seen in the context that human reproduction is prone to a higher degree of impairment than that of other mammalian species, in relation to spermatogenesis, couple fertility, early pregnancy loss and embryonic aneuploidy; female-and male-mediated pathways are both implicated. It is unclear whether such human specificity originated on an evolutionary/genetic or a historico-social timescale, which is important in relation to pathogenesis. The evidence clearly indicates that the currently most popular explanation for male reproductive system impairment, the endocrine disruption hypothesis, cannot explain the main features of the descriptive epidemiology. An alternative pathogenesis is outlined, and some possible exposures considered that could be responsible.


Objective: There is evidence of substantial subnational variation in the HIV epidemic. However, robust spatial HIV data are often only available at high levels of geographic aggregation and not at the finer resolution needed for decision making. Therefore, spatial analysis methods that leverage available data to provide local estimates of HIV prevalence may be useful. Such methods exist but have not been formally compared when applied to HIV. Design/methods: Six candidate methods-including those used by the Joint United Nations Programme on HIV/AIDS to generate maps and a Bayesian geostatistical approach applied to other diseases-were used to generate maps and subnational estimates of HIV prevalence across three countries using cluster level data from household surveys. Two approaches were used to assess the accuracy of predictions: internal validation, whereby a proportion of input data is held back (test dataset) to challenge predictions; and comparison with location-specific data from household surveys in earlier years. Results: Each of the methods can generate usefully accurate predictions of prevalence at unsampled locations, with the magnitude of the error in predictions similar across approaches. However, the Bayesian geostatistical approach consistently gave marginally the strongest statistical performance across countries and validation procedures. Conclusions: Available methods may be able to furnish estimates of HIV prevalence at finer spatial scales than the data currently allow. The subnational variation revealed can be integrated into planning to ensure responsiveness to the spatial features of the epidemic. The Bayesian geostatistical approach is a promising strategy for integrating HIV data to generate robust local estimates. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Sykes R.,Imperial College London
Journal of Antimicrobial Chemotherapy | Year: 2010

Microbes have evolved over 3.5 billion years and are arguably the most adaptable organisms on earth. Restricted genetically by their inability to reproduce sexually, bacteria have acquired several additional mechanisms by which to exchange genetic material horizontally. Such mechanisms have allowed bacteria to inhabit some of the most inhospitable environments on earth. It is thus hardly surprising that when faced with a barrage of inimical chemicals (antibiotics) they have responded with an equal and opposite force. This article compares and contrasts the evolution of antimicrobial resistance to β-lactam antibiotics over the last 70 years in two bacterial species, namely Staphylococcus aureus, a highly evolved human pathogen, and Pseudomonas aeruginosa, an opportunistic nosocomial pathogen. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


Van Bakel S.,Imperial College London
ACM Computing Surveys | Year: 2011

This article will show the usefulness and elegance of strict intersection types for the Lambda Calculus, that are strict in the sense that they are the representatives of equivalence classes of types in the BCD-system [Barendregt et al. 1983]. We will focus on the essential intersection type assignment; this system is almost syntax directed, and we will show that all major properties hold that are known to hold for other intersection systems, like the approximation theorem, the characterization of (head/strong) normalization, completeness of type assignment using filter semantics, strong normalization for cut-elimination and the principal pair property. In part, the proofs for these properties are new; we will briefly compare the essential system with other existing systems. © 2011 ACM.


Chung K.F.,Imperial College London
The Lancet Respiratory Medicine | Year: 2013

Guidelines for asthma management focus on the use of combination inhaled treatment with corticosteroids and longacting β-agonists for symptomatic asthma. In more severe disease, other drugs such as leukotriene blockers and slow-release oral theophylline are added, with oral corticosteroids and anti-immunoglobulin E treatment with omalizumab for the most severe cases of asthma. Once-daily longacting β-agonists and inhaled corticosteroids are being developed. Longacting muscarinic antagonists might also provide additive benefit. New approaches are needed for the treatment of severe asthma, but patients need to be endotyped so that they can be directed for specific treatments. This Review focuses on the role of eosinophilic and neutrophilic inflammation, the attributes of chronic airflow obstruction, and the notion of corticosteroid insensitivity because potential targets for treatment have started to emerge from such analyses. How the best phenotypic or even better, the best endotypic responder with each new treatment, can be established will also be discussed. Newer treatments for asthma will emerge from better endotyping, leading to personalised medicine in asthma. © 2013 Elsevier Ltd.


Crimmin M.R.,Imperial College London | Hill M.S.,University of Bath
Topics in Organometallic Chemistry | Year: 2013

This chapter provides details of the recent progress in heavier Group 2-catalyzed small molecule transformations mediated by well-defined heteroleptic and homoleptic complexes of the form LMX or MX2, where L is a monoanionic ligand and X is a reactive σ-bonded substituent and M = Mg, Ca, Sr, and Ba. The intra- and intermolecular heterofunctionalization (hydroamination, hydrophosphination, hydrosilylation, hydroboration, hydrogenation, and hydroacetylation) of alkenes, alkynes, dienes, carbodiimides, isocyanates, pyridines, quinolines, and ketones is discussed, along with the dimerization of aldehydes, the trimerization of isocyanates, and the dehydrogenation of amine-boranes and the dehydrogenative coupling of amines with silanes. While studies in this field have focused largely on biocompatible and inexpensive catalysts of calcium and the heavier elements, the field has renewed interest in the chemistry of organomagnesium complexes. Graphical Abstract: © 2013 Springer-Verlag Berlin Heidelberg.


Kulkarni C.V.,Imperial College London
Langmuir | Year: 2011

In recent years, lipid based nanostructures have increasingly been used as model membranes to study various complex biological processes. For better understanding of such phenomena, it is essential to gain as much information as possible for model lipid structures under physiological conditions. In this paper, we focus on one of such lipids-monoelaidin (ME)-for its polymorphic nanostructures under varying conditions of temperature and water content. In the recent contribution (Soft Matter, 2010, 6, 3191), we have reported the phase diagram of ME above 30 °C and compared with the phase behavior of other lipids including monoolein (MO), monovaccenin (MV), and monolinolein (ML). Remarkable phase behavior of ME, stabilizing three bicontinuous cubic phases, motivates its study at low temperatures. Current studies concentrate on the low-temperature (<30 °C) behavior of ME and subsequent reconstruction of its phase diagram over the entire temperature-water composition space (temperature, 0-76 °C; and water content, 0-70%). The polymorphs found for the monoelaidin-water system include three bicontinuous cubic phases, i.e., Ia3d, Pn3m, and Im3m, and lamellar phases which exhibit two crystalline (L c1 and L c0), two gel (L β and L β*), and a fluid lamellar (L α) states. The fluid isotropic phase (L 2) was observed only for lower hydrations (<20%), whereas hexagonal phase (H 2) was not found under studied conditions. Nanostructural parameters of these phases as a function of temperature and water content are presented together with some molecular level calculations. This study might be crucial for perception of the lyotropic phase behavior as well as for designing nanostructural assemblies for potential applications. © 2011 American Chemical Society.


Sadri F.,Imperial College London
ACM Computing Surveys | Year: 2011

In this article we survey ambient intelligence (AmI), including its applications, some of the technologies it uses, and its social and ethical implications. The applications include AmI at home, care of the elderly, healthcare, commerce, and business, recommender systems, museums and tourist scenarios, and group decision making. Among technologies, we focus on ambient data management and artificial intelligence; for example planning, learning, event-condition-action rules, temporal reasoning, and agent-oriented technologies. The survey is not intended to be exhaustive, but to convey a broad range of applications, technologies, and technical, social, and ethical challenges. © 2011 ACM.


Understanding the nature of the crust has long been a goal for seismologists when imaging the Earth. This is particularly true in volcanic regions where imaging melt storage and migration can have important implications for the size and nature of an eruption. Receiver functions and the H-κ stacking (Hκ) technique are often used to constrain crustal thickness (H) and the ratio of P to S wave velocities (κ). In this paper, I show that it is essential to consider anisotropy when performing Hκ. I show that in a medium with horizontally transverse isotropy a strong variation in κ with back azimuth is present, which characterizes the anisotropic medium. In a vertically transverse isotropic medium, no variation in κ with back azimuth is observed, but κ is increased across all back azimuths. Thus, estimates of κ are more difficult to relate to composition than previously thought. I extend these models to melt-induced anisotropy and show that similar patterns are observed, but with more significant variations and increases in κ. Based on these observations, I develop a new anisotropic H-κ stacking technique which inverts Hκ data for melt fraction, aspect ratio, and orientation of melt inclusions. I apply this to data for the Afar Depression and show that melt is stored in interconnected stacked sills in the lower crust, which likely supply the recent volcanic eruptions and dike intrusions. This new technique can be applied to any anisotropic medium where it can provide constraints on the average crustal anisotropy. © 2014. The Authors.


Kirchartz T.,Imperial College London
Beilstein Journal of Nanotechnology | Year: 2013

Numerical simulations of current-voltage curves in electron-only devices are used to discuss the influence of charged defects on the information derived from fitting space-charge-limited current models to the data. Charged, acceptor-like defects lead to barriers impeding the flow of electrons in electron-only devices and therefore lead to a reduced current that is similar to the situation where the device has a built-in voltage. This reduced current will lead to an underestimation of the mobilities and an overestimation of characteristic tail slopes if analytical equations are used to analyze the data. Correcting for the barrier created by the charged defects can, however, be a successful way to still be able to obtain reasonably accurate mobility values. © 2013 Kirchartz; licensee Beilstein-Institut.


Woods A.,Imperial College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

The diseases suffered by British livestock, and the ways in which they were perceived and managed by farmers, vets and the state, changed considerably over the course of the twentieth century. This paper documents and analyses these changes in relation to the development of public policy. It reveals that scientific knowledge and disease demographics cannot by themselves explain the shifting boundaries of state responsibility for animal health, the diseases targeted and the preferred modes of intervention. Policies were shaped also by concerns over food security and the public's health, the state of the national and livestock economy, the interests and expertise of the veterinary profession, and prevailing agricultural policy. This paper demonstrates how, by precipitating changes to farming and trading practices, public policy could sometimes actually undermine farm animal health. Animal disease can therefore be viewed both as a stimulus to, and a consequence of, twentieth century public policy. © 2011 The Royal Society.


Barber J.,Imperial College London
Cold Spring Harbor Symposia on Quantitative Biology | Year: 2012

The oxygen in our atmosphere is derived and maintained by the water-splitting process of photosynthesis. The enzyme that facilitates this reaction and therefore underpins virtually all life on our planet is known as photosystem II (PSII), a multisubunit enzyme embedded in the lipid environmentof the thylakoid membranes of plants, algae, and cyanobacteria. During the past 10 years, crystal structures of a 700-kDa cyanobacterial dimeric PSII complex have been reported with ever-increasing improvement in resolution-the latest at 1.9 A. Thus, the organizational and structural details of its many subunits and cofactors are now well understood. The water-splitting site was revealed as a clusterof four Mnions and one Ca ion surrounded by amino-acid side chains, of which seven provide ligands to the metals. The metal cluster is organized as a cubane-like structure composed of three Mn ions and the one Ca2+ ion linked by oxo bonds.The fourth Mn is attached to the cubane via one of its bridging oxygens together with another oxo bridge to an Mn ion of the cubane. The overall structure of the catalytic site provides a framework to propose a mechanistic scheme for the water-splitting process and gives a blueprint for the development of catalysts that mimick the reaction in an artificial chemicalsystem as a means to generate solar fuels. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.


Stuckey D.C.,Imperial College London
Bioresource Technology | Year: 2012

Anaerobic membrane reactors (AnMBRs) have recently evolved from aerobic MBRs, with the membrane either external or submerged within the reactor, and can achieve high COD removals (~98%) at hydraulic retention times (HRTs) as low as 3. h. Since membranes stop biomass being washed out, they can enhance performance with inhibitory substrates, at psychrophilic/thermophilic temperatures, and enable nitrogen removal via Anammox. Fouling is important, but addition of activated carbon or resins/precipitants can remove soluble microbial products (SMPs)/colloids and enhance flux. Due to their low energy use and solids production, and solids free effluent, they can enhance nutrient and water recycling. Nevertheless, more work is needed to: compare fouling between aerobic and anaerobic systems; determine how reactor operation influences fouling; evaluate the effect of different additives on membrane fouling; determine whether nitrogen removal can be incorporated into AnMBRs; recover methane solubility from low temperatures effluents; and, establish sound mass and energy balances. © 2012 Elsevier Ltd.