King's College London

London, London, United Kingdom

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School of Medicine
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Institute of Psychiatry
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Department of Psychology
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  • [Show abstract] [Hide abstract]
    ABSTRACT: The heart and blood vessels express a range of anion currents (e.g. ICl.PKA) and symporter/antiporters (e.g. Cl(-)/HCO3(-) exchanger) that translocate chloride (Cl(-)). They have been proposed to contribute to a variety of physiological processes including cellular excitability, cell volume homeostasis and apoptosis. Additionally there is evidence that Cl(-) currents or transporters may play a role in cardiac pathophysiology. Arrhythmogenesis, the process of cardiac ischaemic preconditioning, and the adaptive remodelling process in myocardial hypertrophy and heart failure have all been linked to such channels or transporters. We have explored the possibility that selective targeting of one or more of these may provide benefit in cardiovascular disease. Existing evidence points to an emerging role of cardiac cell anion channels as potential therapeutic targets, the 'disease-specificity' of which may represent a substantial improvement on current targets. However, the limitations of current techniques hitherto applied (such as developmental compensation in gene-modified animals) and pharmacological agents (which do not at present possess sufficient selectivity for the adequate probing of function) have thus far hindered translation to the introduction of new therapy.
    Pharmacology & therapeutics. 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heart muscle is activated by Ca(2+) to generate force and shortening, and the signaling pathway involves allosteric mechanisms in the thin filament. Knowledge about the structure-function relationship among proteins in the thin filament is critical in understanding the physiology and pathology of the cardiac function, but remains obscure. We investigate the conformation of the cardiac troponin (Tn) on the thin filament and its response to Ca(2+) activation and propose a molecular mechanism for the regulation of cardiac muscle contraction by Tn based uniquely on information from in situ protein domain orientation. Polarized fluorescence from bifunctional rhodamine is used to determine the orientation of the major component of Tn core domain on the thin filaments of cardiac muscle. We show that the C-terminal lobe of TnC (CTnC) does not move during activation, suggesting that CTnC, together with the coiled coil formed by the TnI and TnT chains (IT arm), acts as a scaffold that holds N-terminal lobe of TnC (NTnC) and the actin binding regions of troponin I. The NTnC, on the other hand, exhibits multiple orientations during both diastole and systole. By combining the in situ orientation data with published in vitro measurements of intermolecular distances, we construct a model for the in situ structure of the thin filament. The conformational dynamics of NTnC plays an important role in the regulation of cardiac muscle contraction by moving the C-terminal region of TnI from its actin-binding inhibitory location and enhancing the movement of tropomyosin away from its inhibitory position.
    Journal of Molecular and Cellular Cardiology 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review focuses on the role of orientated cell division (OCD) in two aspects of epithelial growth, namely layer formation and growth in the epithelial plane. Epithelial stratification is invariably associated with fate asymmetric cell divisions. We discuss this through the example of epidermal stratification where cell division plane regulation facilitates concomitant thickening and cell differentiation. Embryonic neuroepithelia are considered as a special case of epithelial stratification. We highlight early ectodermal layer specification, which sets the epidermal versus neuronal fates, as well as later neurogenesis in vertebrates and mammals. We also discuss the heart epicardium as an example of coordinating OCDs with delamination and subsequent differentiation. Epithelial planar growth is examined both in the context of uniform growth, such as in Xenopus epiboly, the Drosophila wing disc and the mammalian intestinal crypt as well as in anisotropic growth, or elongation, such as Drosophila and vertebrate axial elongation and the mouse palate. Coupling between growth perpendicular to and within epithelial planes is recognised, but so are exceptions, as is the often passive role of spindle orientation sometimes hitherto considered to be an active driver of directional growth.
    Seminars in Cell and Developmental Biology 07/2014;


  • Address
    Borough wing, Guy's Hospital, SE1 9RT, London, London, United Kingdom
  • Head of Institution
    Prof Reba rezavi
  • Website
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Top publications last week by downloads

International Journal of Nursing Studies 05/2007; 44(4):574-88.
Magnetic Nanoparticles: From Fabrication to Clinical Applications edited by N. T. K. Thanh, 07/2012: chapter Magnetic Microbubbles: pages 499-522; CRC Press.

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