London, United Kingdom

Imperial College London
London, United Kingdom

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 201215 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.

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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.

Robinette S.L.,Imperial College London
Accounts of chemical research | Year: 2012

Small molecules are central to biology, mediating critical phenomena such as metabolism, signal transduction, mating attraction, and chemical defense. The traditional categories that define small molecules, such as metabolite, secondary metabolite, pheromone, hormone, and so forth, often overlap, and a single compound can appear under more than one functional heading. Therefore, we favor a unifying term, biogenic small molecules (BSMs), to describe any small molecule from a biological source. In a similar vein, two major fields of chemical research,natural products chemistry and metabolomics, have as their goal the identification of BSMs, either as a purified active compound (natural products chemistry) or as a biomarker of a particular biological state (metabolomics). Natural products chemistry has a long tradition of sophisticated techniques that allow identification of complex BSMs, but it often fails when dealing with complex mixtures. Metabolomics thrives with mixtures and uses the power of statistical analysis to isolate the proverbial "needle from a haystack", but it is often limited in the identification of active BSMs. We argue that the two fields of natural products chemistry and metabolomics have largely overlapping objectives: the identification of structures and functions of BSMs, which in nature almost inevitably occur as complex mixtures. Nuclear magnetic resonance (NMR) spectroscopy is a central analytical technique common to most areas of BSM research. In this Account, we highlight several different NMR approaches to mixture analysis that illustrate the commonalities between traditional natural products chemistry and metabolomics. The primary focus here is two-dimensional (2D) NMR; because of space limitations, we do not discuss several other important techniques, including hyphenated methods that combine NMR with mass spectrometry and chromatography. We first describe the simplest approach of analyzing 2D NMR spectra of unfractionated mixtures to identify BSMs that are unstable to chemical isolation. We then show how the statistical method of covariance can be used to enhance the resolution of 2D NMR spectra and facilitate the semi-automated identification of individual components in a complex mixture. Comparative studies can be used with two or more samples, such as active vs inactive, diseased vs healthy, treated vs untreated, wild type vs mutant, and so on. We present two overall approaches to comparative studies: a simple but powerful method for comparing two 2D NMR spectra and a full statistical approach using multiple samples. The major bottleneck in all of these techniques is the rapid and reliable identification of unknown BSMs; the solution will require all the traditional approaches of both natural products chemistry and metabolomics as well as improved analytical methods, databases, and statistical tools.

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.

Byrne B.,Imperial College London
Current Opinion in Structural Biology | Year: 2015

The methylotrophic yeast Pichia pastoris is a widely used recombinant expression host. P. pastoris combines the advantages of ease of use, relatively rapid expression times and low cost with eukaryotic co-translational and post-translational processing systems and lipid composition. The suitability of P. pastoris for high density controlled culture in bioreactors means large amounts of protein can be obtained from small culture volumes. This review details the key features of P. pastoris, which have made it a particularly useful system for the production of membrane proteins, including receptors, channels and transporters, for structural studies. In addition, this review provides an overview of all the constructs and cell strains used to produce membrane proteins, which have yielded high resolution structures. © 2015 The Authors.

Leitinger B.,Imperial College London
Annual Review of Cell and Developmental Biology | Year: 2011

Collagen, the most abundant protein in animals, is a key component of extracellular matrices. Not only do collagens provide essential structural support for connective tissues, but they are also intimately involved in controlling a spectrum of cellular functions such as growth, differentiation, and morphogenesis. All collagens possess triple-helical regions through which they interact with a host of other proteins including cell surface receptors. A structurally diverse group of transmembrane receptors mediates the recognition of the collagen triple helix: integrins, discoidin domain receptors, glycoprotein VI, and leukocyte-associated immunoglobulin-like receptor-1. These collagen receptors regulate a wide range of behaviors including cell adhesion and migration, hemostasis, and immune function. Here these collagen receptors are discussed in terms of their molecular basis of collagen recognition, their signaling and developmental functions, and their roles in disease. © 2011 by Annual Reviews. All rights reserved.

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.

Walczak H.,Imperial College London
Immunological Reviews | Year: 2011

Tumor necrosis factor (TNF) is crucial for innate immunity, but deregulated TNF signaling also plays an eminent role in the pathogenesis of many chronic inflammatory diseases and cancer-related inflammation. The signals that mediate both the beneficial and the harmful effects of TNF are initiated when TNF binds to its receptors on the surface of target cells. TNF receptor 1 (TNFR1) is ubiquitously expressed, whereas TNFR2 is mainly expressed on lymphocytes and endothelial cells. This review focuses on the molecular and physiological consequences of the interaction of TNF with TNFR1. The different outcomes of TNF signaling originate at the apical signaling complex that forms when TNF binds to TNFR1, the TNFR1 signaling complex (TNF-RSC). By integrating recently gained insight on the functional importance of the presence of different types of ubiquitination in the TNF-RSC, including linear ubiquitin linkages generated by the linear ubiquitin chain assembly complex (LUBAC), with the equally recent elucidation of the mode in which ubiquitin-binding domains interact with specific di-ubiquitin linkages, this review develops a new concept for the way the concerted action of different ubiquitination events enables the TNF-RSC to generate its signaling output in a spatio-temporally controlled manner. Finally, it will be explained how these new findings and the emerging concept of differential ubiquitination governing the TNF-RSC may impact future research on the molecular mechanism of TNF signaling and the function of this cytokine in normal physiology, chronic inflammation, and cancer. © 2011 John Wiley and Sons A/S.

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.

Chung K.F.,Imperial College London
The Lancet | Year: 2015

Asthma is a common heterogeneous disease with a complex pathophysiology. Current therapies based on inhaled corticosteroids and longacting β2 agonists are effective in controlling asthma in most, but not all patients, with a few patients falling into the severe asthma category. Severe asthma is characterised by poor asthma control, recurrent exacerbations, and chronic airflow obstruction despite adequate and, in many cases, high-dose treatments. There is strong evidence supporting the role for interleukins derived from T-helper-2 (Th2) cells and innate lymphoid cells, such as interleukins 4, 5, and 13, as underlying the eosinophilic and allergic inflammatory processes in nearly half of these patients. An anti-IgE antibody, omalizumab, which binds to circulating IgE, a product of B cells from the actions of interleukin 4 and interleukin 13, is used as treatment for severe allergic asthma. Studies examining cytokine blockers such as anti-interleukin-5, anti-interleukin-4Rα, and anti-interleukin-13 monoclonal antibodies in patients with severe asthma with recurrent exacerbations and high blood eosinophil counts despite use of inhaled corticosteroids have reported improved outcomes in terms of exacerbations, asthma control, and forced expiratory volume in 1 s. The US Food and Drug Administration's recommendation to use an anti-interleukin-5 antibody for the treatment of severe eosinophilic asthma suggests that there will be a therapeutic place for these anti-Th2 agents. Biomarkers should be used to identify the right patients for such targeted approaches. More guidance will be needed as to which patients should receive each of these classes of selective antibody-based treatments. Currently, there is no treatment that targets the cytokines driving asthma associated with non-eosinophilic inflammation and low Th2 expression. © 2015 Elsevier Ltd.

Vassilicos J.C.,Imperial College London
Annual Review of Fluid Mechanics | Year: 2015

This article reviews evidence concerning the cornerstone dissipation scaling of turbulence theory: , with Cε equals const., ε the dissipation rate of turbulent kinetic energy , and an integral length scale characterizing the energy-containing turbulent eddies. This scaling is intimately linked to the Richardson-Kolmogorov equilibrium cascade. Accumulating evidence shows that a significant nonequilibrium region exists in various turbulent flows in which the energy spectrum has Kolmogorov's -53 wave-number scaling over a wide wave-number range, yet CεRemIRenL, with m≈1≈n, ReI a globalinlet Reynolds number, and ReL a local turbulence Reynolds number. Copyright © 2015 by Annual Reviews. All rights reserved.

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