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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Novak P.,Imperial College London
Neuron | Year: 2013

Direct electrical access to presynaptic ion channels has hitherto been limited to large specialized terminals such as the calyx of Held or hippocampal mossy fiber bouton. The electrophysiology and ion-channel complement of far more abundant small synaptic terminals (≤ 1 μm) remain poorly understood. Here we report a method based on superresolution scanning ion conductance imaging of small synapses in culture at approximately 100-150 nm 3D resolution, which allows presynaptic patch-clamp recordings in all four configurations (cell-attached, inside-out, outside-out, and whole-cell). Using this technique, we report presynaptic recordings of K(+), Na(+), Cl(-), and Ca(2+) channels. This semiautomated approach allows direct investigation of the distribution and properties of presynaptic ion channels at small central synapses. Copyright © 2013 Elsevier Inc. All rights reserved.

Ungless M.A.,Imperial College London | Grace A.A.,University of Pittsburgh
Trends in Neurosciences | Year: 2012

The dopamine system is involved in motivation, reward and learning, and dysfunction in this system has been implicated in several disorders, including Parkinson's disease (PD) and schizophrenia. Key progress in our understanding of its functions has come from extracellular . in vivo electrophysiological recordings from midbrain dopamine neurons. Numerous studies have used a defined set of criteria to identify dopamine neurons electrophysiologically. However, a few recent studies have suggested that a minority population of non-dopamine neurons may not be readily distinguishable from dopamine neurons, raising questions as to the reliability of past findings. We provide an overview of the key findings related to this controversy and assess the criteria used for the electrophysiological identification of dopamine neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA). © 2012 Elsevier Ltd.

Hampshire A.,Imperial College London
NeuroImage | Year: 2015

There has been much recent debate regarding the neural basis of motor response inhibition. An influential hypothesis from the last decade proposes that a module within the right inferior frontal cortex (RIFC) of the human brain is dedicated to supporting response inhibition. However, there is growing evidence to support the alternative view that response inhibition is just one prominent example of the many cognitive control processes that are supported by the same set of 'domain general' functional networks. Here, I test directly between the modular and network accounts of motor response inhibition by applying a combination of data-driven, event-related and functional connectivity analyses to fMRI data from a variety of attention and inhibition tasks. The results demonstrate that there is no inhibitory module within the RIFC. Instead, response inhibition recruits a functionally heterogeneous ensemble of RIFC networks, which can be dissociated from each other in the context of other task demands. © 2015.

Fagan R.P.,University of Sheffield | Fairweather N.F.,Imperial College London
Nature Reviews Microbiology | Year: 2014

The outer surface of many archaea and bacteria is coated with a proteinaceous surface layer (known as an S-layer), which is formed by the self-assembly of monomeric proteins into a regularly spaced, two-dimensional array. Bacteria possess dedicated pathways for the secretion and anchoring of the S-layer to the cell wall, and some Gram-positive species have large S-layer-associated gene families. S-layers have important roles in growth and survival, and their many functions include the maintenance of cell integrity, enzyme display and, in pathogens and commensals, interaction with the host and its immune system. In this Review, we discuss our current knowledge of S-layer and related proteins, including their structures, mechanisms of secretion and anchoring and their diverse functions. © 2014 Macmillan Publishers Limited.

Brickley S.G.,Imperial College London | Mody I.,University of California at Los Angeles
Neuron | Year: 2012

Over the past two decades, research has identified extrasynaptic GABA A receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability. The importance of this tonic inhibition in regulating states of consciousness is highlighted by the fact that extrasynaptic GABA A receptors (GABA ARs) are believed to be key targets for anesthetics, sleep-promoting drugs, neurosteroids, and alcohol. The neurosteroid sensitivity of these extrasynaptic GABA ARs may explain their importance in stress-, ovarian cycle-, and pregnancy-related mood disorders. Moreover, disruptions in network dynamics associated with schizophrenia, epilepsy, and Parkinson's disease may well involve alterations in the tonic GABA AR-mediated conductance. Extrasynaptic GABA ARs may therefore present a therapeutic target for treatment of these diseases, with the potential to enhance cognition and aid poststroke functional recovery. © 2012 Elsevier Inc.

Barnes P.J.,Imperial College London
Nature Reviews Drug Discovery | Year: 2013

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of the peripheral airways and lung parenchyma, which leads to progressive obstruction of the airways. Current management with long-Acting bronchodilators does not reduce disease progression, and there are no treatments that effectively suppress chronic inflammation in COPD. An increased understanding of the inflammatory processes that are involved in the pathophysiology of COPD has identified several new therapeutic targets. This Review discusses some of the most promising of these targets, including new antioxidants, kinase inhibitors and drugs that target cellular senescence, microbial colonization, epigenetic regulation of inflammatory gene expression and corticosteroid resistance. © 2013 Macmillan Publishers Limited. All rights reserved.

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.

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.

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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