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  • Mitral Valve Diverticulum Presenting with Severe Mitral Stenosis: Case Report.

    15 October 2018

    The case is presented of a non-infectious anterior mitral valve leaflet diverticulum, which appeared as symptomatic mitral stenosis. Unlike previous reports, there was no histological myxomatous degeneration of the valve. To the authors' knowledge, this is the first time a mitral valve diverticulum resulting in severe mitral stenosis has been reported in the literature.

  • Implementation of a modified version of NICE CG95 on chest pain of recent onset: Experience in a DGH

    15 October 2018

    National Institute for Health and Care Excellence (NICE) clinical guideline 95 (CG95) was introduced to rapidaccess chest pain clinics (RACPC) to aid investigation of possible stable angina based on pretest probability of coronary artery disease (CAD). Following a six-month audit of its implementation we introduced a modified version: patients with low/ moderate risk of CAD were referred for computed tomography coronary angiography (CTCA), while those at high/ very high risk were referred for invasive angiography. Patient records of 546 patients referred to our RACPC over a six-month period were retrospectively analysed. Pretest probability of CAD, referral for initial investigation, and outcomes at a minimum follow-up time of six months were documented. Incidence of CAD correlated well with pretest probability. Moderaterisk patients had a low incidence of CAD and revascularisation. High/ very high-risk patients had a high incidence of revascularisation, and this was predominantly for prognostically significant disease. In conclusion, low rates of CAD in lowand moderate-risk groups justifies the use of CTCA as a first-line investigation in these patients. Routine investigation of very high-risk patients allows a high proportion to undergo revascularisation for prognostically significant disease. Strict adherence to NICE CG95 could lead to these patients being missed.

  • Directing an artificial zinc finger protein to new targets by fusion to a non-DNA-binding domain

    7 August 2018

    Transcription factors are often regarded as having two separable components: a DNA-binding domain (DBD) and a functional domain (FD), with the DBD thought to determine target gene recognition. While this holds true for DNA bindingin vitro, it appears thatin vivoFDs can also influence genomic targeting. We fused the FD from the well-characterized transcription factor Kruppel-like Factor 3 (KLF3) to an artificial zinc finger (AZF) protein originally designed to target the Vascular Endothelial Growth Factor-A (VEGF-A) gene promoter. We compared genome-wide occupancy of the KLF3FD-AZF fusion to that observed with AZF. AZF bound to theVEGF-Apromoter as predicted, but was also found to occupy approximately 25,000 other sites, a large number of which contained the expected AZF recognition sequence, GCTGGGGGC. Interestingly, addition of the KLF3 FD re-distributes the fusion protein to new sites, with total DNA occupancy detected at around 50,000 sites. A portion of these sites correspond to known KLF3-bound regions, while others contained sequences similar but not identical to the expected AZF recognition sequence. These results show that FDs can influence and may be useful in directing AZF DNA-binding proteins to specific targets and provide insights into how natural transcription factors operate.

  • Regions outside the DNA-binding domain are critical for proper in vivo specificity of an archetypal zinc finger transcription factor

    7 August 2018

    Transcription factors (TFs) are often regarded as being composed of a DNA-binding domain (DBD) and a functional domain. The two domains are considered separable and autonomous, with the DBD directing the factor to its target genes and the functional domain imparting transcriptional regulation. We examined an archetypal zinc finger (ZF) TF, Kruppel-like factor 3 with an N-terminal domain that binds the corepressor CtBP and a DBD composed of three ZFs at its C-terminus. We established a system to compare the genomic occupancy profile of wild-type Kruppel-like factor 3 with two mutants affecting the N-terminal functional domain: a mutant unable to contact the cofactor CtBP and a mutant lacking the entire N-terminal domain, but retaining the ZFs intact. Chromatin immunoprecipitation followed by sequencing was used to assess binding across the genome in murine embryonic fibroblasts. Unexpectedly, we observe that mutations in the N-terminal domain generally reduced binding, but there were also instances where binding was retained or even increased. These results provide a clear demonstration that the correct localization of TFs to their target genes is not solely dependent on their DNA-contact domains. This informs our understanding of how TFs operate and is of relevance to the design of artificial ZF proteins.

  • de Wet Group

    16 December 2013

    Role of ABC transporters in gut endocrine K-and L-cells

  • Bajo Lorenzana Group

    26 May 2015

    Hearing Loss and Tinnitus

  • Kohl Group

    10 July 2016

    Information encoding in the brain

  • Booth Group

    14 March 2014

    Optical engineering and microscopy for neuroscience and biomedical imaging

  • Ashcroft Group

    10 July 2016

    ATP-sensitive potassium (K-ATP) channels, insulin secretion and diabetes

  • Wade-Martins Group

    10 July 2016

    Understanding molecular mechanisms of age-related neurodegenerative diseases to generate novel molecular therapies

  • Walker Group

    16 September 2013

    We investigate how the activity of neurons in the brain give rise to our perception of sound.

  • Webber Group

    10 July 2016

    Computational Disease Genomics and Networks

  • Wilkins Group

    10 July 2016

    Membrane transport in cartilage and cancer cells

  • Wilson Group

    10 July 2016

    Cell Biology of Exosome Signalling, Secretion and Growth in Normal and Cancer Cells at Super-Resolution