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  • Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

    13 October 2018

    Islet β-cells are responsible for secreting all circulating insulin in response to rising plasma glucose concentrations. These cells are a phenotypically diverse population that express great functional heterogeneity. In mice, certain β-cells (termed ‘hubs’) have been shown to be crucial for dictating the islet response to high glucose, with inhibition of these hub cells abolishing the coordinated Ca2+ oscillations necessary for driving insulin secretion. These β-cell hubs were found to be highly metabolic and susceptible to pro-inflammatory and glucolipotoxic insults. In this study, we explored the importance of hub cells in human by constructing mathematical models of Ca2+ activity in human islets. Our simulations revealed that hubs dictate the coordinated Ca2+ response in both mouse and human islets; silencing a small proportion of hubs abolished whole-islet Ca2+ activity. We also observed that if hubs are assumed to be preferentially gap junction coupled, then the simulations better adhere to the available experimental data. Our simulations of 16 size-matched mouse and human islet architectures revealed that there are species differences in the role of hubs; Ca2+ activity in human islets was more vulnerable to hub inhibition than mouse islets. These simulation results not only substantiate the existence of β-cell hubs, but also suggest that hubs may be favourably coupled in the electrical and metabolic network of the islet, and that targeted destruction of these cells would greatly impair human islet function.

  • The reproducibility of 31-phosphorus MRS measures of muscle energetics at 3 Tesla in trained men.

    13 October 2018

    OBJECTIVE: Magnetic resonance spectroscopy (MRS) provides an exceptional opportunity for the study of in vivo metabolism. MRS is widely used to measure phosphorus metabolites in trained muscle, although there are no published data regarding its reproducibility in this specialized cohort. Thus, the aim of this study was to assess the reproducibility of (31)P-MRS in trained skeletal muscle. METHODS: We recruited fifteen trained men (VO(2)peak = 4.7±0.8 L min(-1)/58±8 mL kg(-1) min(-1)) and performed duplicate MR experiments during plantar flexion exercise, three weeks apart. RESULTS: Measures of resting phosphorus metabolites were reproducible, with 1.7 mM the smallest detectable difference in phosphocreatine (PCr). Measures of metabolites during exercise were less reliable: exercising PCr had a coefficient of variation (CV) of 27% during exercise, compared with 8% at rest. Estimates of mitochondrial function were variable, but experimentally useful. The CV of PCr(1/2t) was 40%, yet much of this variance was inter-subject such that differences of <20% were detectable with n = 15, given a significance threshold of p<0.05. CONCLUSIONS: 31-phosphorus MRS provides reproducible and experimentally useful measures of phosphorus metabolites and mitochondrial function in trained human skeletal muscle.

  • In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy.

    13 October 2018

    AIMS: The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice. METHODS AND RESULTS: Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility) using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV) and right ventricular (RV) systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy. CONCLUSIONS: MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.

  • Weighted averaging in spectroscopic studies improves statistical power.

    13 October 2018

    PURPOSE: In vivo MRS is often characterized by a spectral signal-to-noise ratio (SNR) that varies highly between experiments. A common design for spectroscopic studies is to compare the ratio of two spectral peak amplitudes between groups, e.g. individual PCr/γ-ATP ratios in 31 P-MRS. The uncertainty on this ratio is often neglected. We wished to explore this assumption. THEORY: The canonical theory for the propagation of uncertainty on the ratio of two spectral peaks and its incorporation in the Frequentist hypothesis testing framework by weighted averaging is presented. METHODS: Two retrospective re-analyses of studies comparing spectral peak ratios and one prospective simulation were performed using both the weighted and unweighted methods. RESULTS: It was found that propagating uncertainty correctly improved statistical power in all cases considered, which could be used to reduce the number of subjects required to perform an MR study. CONCLUSION: The variability of in vivo spectroscopy data is often accounted for by requiring it to meet an SNR threshold. A theoretically sound propagation of the variable uncertainty caused by quantifying spectra of differing SNR is therefore likely to improve the power of in vivo spectroscopy studies. Magn Reson Med 78:2082-2094, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

  • Novel ketone diet enhances physical and cognitive performance.

    13 October 2018

    Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.

  • Varying degrees of ventricular unloading in the heterotopic rat heart transplant model demonstrated by magnetic resonance imaging.

    13 October 2018

    OBJECTIVE: Left ventricular assist device placement is an increasingly common treatment for cardiac failure, resulting in cardiac unloading and potentially reversing the remodelling changes seen in heart failure. A popular animal model for human ventricular unloading is the rodent heterotopic non-working heart transplant; the volume loading status of this preparation is important to interpreting the resulting reverse remodelling yet has not been previously investigated. This study was designed to assess the variability of left ventricular volume loading in the rodent transplant model. METHODS: Heterotopic abdominal heart transplant was performed on syngeneic rats; high resolution cine magnetic resonance imaging was subsequently performed on the heterotopic transplanted hearts in anesthetised rats, after variable post-transplant recovery times, in order to assess ventricular loading status. RESULTS: Highly variable left ventricular volume loading status was demonstrated, with some hearts exhibiting considerable ventricular filling and ejection. CONCLUSIONS: These observations call into question the assumption that studies using this model are consistently examining fully unloaded ventricles, and indicate the desirability of in vivo imaging of such hearts to quantify the degree of ventricular loading.

  • Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1-13C]pyruvate.

    13 October 2018

    Hyperpolarised (13)C MRI can be used to generate metabolic images of the heart in vivo. However, there have been no similar studies performed in the isolated perfused heart. Therefore, the aim of this study was to develop a method for the creation of (13)C metabolite maps of the perfused rat heart and to demonstrate the technique in a study of acute and chronic myocardial infarction. Male Wistar rat hearts were isolated, perfused and imaged before and after occlusion of the left anterior descending (LAD) coronary artery, creating an acute infarct group. In addition, a chronic infarct group was generated from hearts which had their LAD coronary artery occluded in vivo. Four weeks later, hearts were excised, perfused and imaged to generate metabolic maps of infused pyruvate and its metabolites lactate and bicarbonate. Myocardial perfusion and energetics were assessed by first-pass perfusion imaging and (31)P MRS, respectively. In both acute and chronically infarcted hearts, perfusion was reduced to the infarct region, as revealed by reduced gadolinium influx and lower signal intensity in the hyperpolarised pyruvate images. In the acute infarct region, there were significant alterations in the lactate (increased) and bicarbonate (decreased) signal ratios. In the chronically infarcted region, there was a significant reduction in both bicarbonate and lactate signals. (31)P-derived energetics revealed a significant decrease between control and chronic infarcted hearts. Significant decreases in contractile function between control and both acute and chronic infracted hearts were also seen. In conclusion, we have demonstrated that hyperpolarised pyruvate can detect reduced perfusion in the rat heart following both acute and chronic infarction. Changes in lactate and bicarbonate ratios indicate increased anaerobic metabolism in the acute infarct, which is not observed in the chronic infarct. Thus, this study has successfully demonstrated a novel imaging approach to assess altered metabolism in the isolated perfused rat heart.

  • Funding Opportunities

    17 July 2018

    OCH Training Grants for Allied Healthcare Professionals

  • Defence and Counter-defence: The interplay between Zika virus and the immune system

    Virus infection triggers a multitude of immune responses. Detection of virus presence by the innate immune system is a crucial event mediated by germ-line encoded receptors inside cells. These sensors of virus presence signal for the induction of innate immune response genes, such as those encoding type I interferons. Many of these receptors sense viral nucleic acids. For example, RIG-I recognizes the RNA genomes of viruses such as influenza A virus (Rehwinkel et al., Cell 2010). Viruses in turn have developed strategies to counteract and evade detection by innate immune receptors. As such, cells and viruses are in a dynamic arms race in which host defence mechanisms and viral counter-measures rapidly co-evolve. One of our aims is to understand the molecular basis of host pathogen interactions.

  • Investigating innate immune signalling with CRISPR-Cas9 screens

    Genome editing using CRISPR-Cas9 is a powerful system to study gene function and can be used in genome-wide screens. This project will make use of this transformative technique to identify novel regulators of innate immune responses. Our group is interested in signalling pathways that allow cells to detect invading viruses. Indeed, detection of virus presence by the innate immune system is a crucial event mediated by germ-line encoded receptors inside cells. These sensors of virus presence signal for the induction of innate immune response genes, such as those encoding type I interferons. Many of these receptors sense viral nucleic acids. For example, RIG-I recognizes the RNA genomes of viruses such as influenza A virus (Rehwinkel et al., Cell 2010) and cGAS detects viral DNA. In addition to their roles in virus infection, these sensors are also important in some autoinflammatory diseases and in cancer.

  • Funding Options

    17 May 2017

    Most of our students, whether basic scientists or clinical fellows, are fully funded. The department is able to offer full funding at a generous level for basic scientists and our Principal Investigators have considerable experience in supporting clinicians in their applications for Clinical Research Fellowships (CRF).

  • How to apply

    31 August 2017

  • Graduate Studies

    16 August 2017

    The Radcliffe Department of Medicine provides graduate students with exceptional teaching, training and career development in a broad spectrum of sciences related to medicine. With around 150 graduate students currently in the Department, most of whom are studying for a four year DPhil, the Department is committed to training the next generation of researchers in biological and clinical sciences.

  • WIMM Prize Studentships

    18 May 2017

    The MRC Weatherall Institute of Molecular Medicine (WIMM) is an internationally renowned Institute that aims to unravel the mechanisms of disease and build on these findings to improve human health. For those who would like to work at the WIMM, the Institute offers a number of four year Prize Studentships to outstanding students of any nationality.

  • Identification of the atrial transcriptional signature of patients who develop atrial fibrillation

    Microarray expression analyses have identified differences in the expression of gene sets related to ion channel function and transcription factors in atrial tissue from patients with paroxysmal or persistent atrial fibrillation (AF) versus normal sinus rhythm (SR) and differential expression of miRs involved in the regulation of ion channel subunits have been identified between similar patient groups. However, it is unclear whether these changes are a cause or a consequence of AF.

  • RDM Governance

    16 August 2017

  • Anti-bullying week 2017: Responsible Bystander Workshop

    13 November 2017

    Learning and Development Programme

    In this 90 minute workshop we explore your options as a bystander to bullying and harassment. This workshop, which will be opened by Prof Hugh Watkins, pulls together some of the theories behind why we act the way we do, with some practical ideas on what you can do in the moment and/or after an event. The session is part of Anti-Bullying Week 2017 (13-17 November).

  • Writing for a Public Audience

    1 February 2018

    Learning and Development Programme

    Looking to sharpen your communications skills for a public audience? This course forms part of the ‘Communications’ strand of the RDM Learning and Development Programme.

  • AVIC Symposium - 2017

    23 November 2017

    Research

    We would like to invite you to a one day symposium on acute vascular disease at the Richard Doll Building on Thursday 23rd November 2017. The day will consist of neuro and cardiac themed talks that span development / validation and applications in clinical research.

  • Feedback conversations

    29 November 2017

    Learning and Development Programme

    This workshop enables individuals to practise the necessary skills to give and receive feedback in a clear, positive and constructive manner. This course forms part of the ‘Communications’ strand of the RDM Learning and Development Programme and is open to all RDM staff and students. Registration for this course is now open to all staff and students in RDM. Places are limited to 24.

  • Managing working relationships: difficult conversations

    6 December 2017

    Learning and Development Programme

    Through this course you will learn how to influence people and approach difficult conversations. This course forms part of the ‘Communications’ strand of the RDM Learning and Development Programme and is open to all RDM staff and students. Registration for this course is now open to all staff and students in RDM. Places are limited to 24.

  • Introduction to Public Engagement

    12 December 2017

    Learning and Development Programme

    An introduction for those looking to get started in public engagement with research covering the basics of what it is, how to get started and a chance to be inspired by those already doing it. This course forms part of the ‘Communications’ strand of the RDM Learning and Development Programme. Registration for this course is now open to all staff and students in RDM.

  • Fellowships and other funding options

    15 January 2018

    Learning and Development Programme

    This workshop is for students and postdocs considering fellowship applications. This course forms part of the ‘Career Development’ strand of the RDM Learning and Development Programme. Registration for this course is now open to researchers in RDM.

  • Emotions and resilience at work

    7 February 2018

    Learning and Development Programme

    In this workshop you will learn how to develop an awareness of self and others, in order to engage positively with colleagues. This course forms part of the ‘Working Relationships’ strand of the RDM Learning and Development Programme. Registration for this course is now open to all staff and students in RDM. Places are limited to 24.

  • Making the most of PDR

    14 February 2018

    Learning and Development Programme

    After this workshop you will be able to carry out and take part in PDRs effectively and have a platform from which to reflect on, and refine, your practice. This course forms part of the ‘Career Development’ strand of the RDM Learning and Development Programme. Registration for this course is now open to all staff and students in RDM. Places are limited to 24.

  • Diabetes, Metabolism and Endocrinology

    28 March 2017

    Our focus is on finding the causes of metabolic and endocrine disease and capitalising on these discoveries to yield new treatments. We are world leaders in both large-scale genetic studies and global clinical trials, taking an international approach to advance our understanding and treatment of type 1 and type 2 diabetes. From target discovery for type 2 diabetes and probing the biochemistry of fat, through to understanding islet physiology and transplantation, investigating liver disease and unravelling the mechanisms behind rare endocrine tumours, our research truly spans the bed to bedside journey.

  • Cardiovascular Science

    28 March 2017

    We aim to better understand, diagnose and treat heart and vascular disease through our extensive cutting edge research programmes. We have a particular focus on understanding disease mechanisms and on new approaches to stratifying patients. Our expertise encompasses genetic studies to identify causative and risk genes, cardiovascular physiology and cellular biology to understand health and disease, the development and application of advanced imaging, experimental medicine and clinical trials.

  • Haematology and Pathology

    28 March 2017

    We seek to understand the causes of diseases of the blood and other malignancies, from a molecular to systems level, with a focus on blood cancers, rare inherited conditions and the tumour microenvironment. We use and develop innovative techniques to drive research in this area, and are committed to bringing about change in clinical diagnosis and practice. Our pathologists discovered many of the biomarkers now used routinely in clinical practice, translate laboratory findings into clinical tests and are developing digital pathology initiatives.

  • Experimental Therapeutics

    28 March 2017

    Building on critical findings from our research streams, we are initiating new drug discovery programmes. Many of our researchers are engaged in target discovery and target validation research – elucidating molecular pathways that can be manipulated for disease modification.

  • Geratology

    28 March 2017

    With an ageing population, it’s critical that we better understand diseases associated with old age. We have particular strengths in acute stroke research, with a two pronged approach encompassing molecular and clinical aspects to better understand the factors influencing stroke recovery.

  • Clinical Imaging

    28 March 2017

    We have world-class clinical imaging facilities aimed at better understanding, diagnosing and treating disease. Our clinical studies feedback into molecular research, taking learnings from the clinical setting to ask further questions in model systems. We have particular strengths in cardiovascular imaging and our facilities integrate clinical care with the latest research.

  • Cellular and Preclinical Imaging

    28 March 2017

    Using a range of imaging modalities, our researchers can probe – at the molecular level – the events that underpin cellular health and dysfunction.

  • Clinical Studies and Trials

    28 March 2017

    We are committed to translating our innovative research into clinical benefit. From new methods of diagnosing chronic conditions, to finding the latest treatments for diabetes, cancer, heart disease, stroke and rare diseases, our department is involved in hundreds of clinical studies every year.

  • Genetics, Genomics and Genome Biology

    28 March 2017

    Employing a range of genetic techniques, we probe the fundamental causes of disease. Our expertise spans identification of causative genes in rare inherited diseases, through to elucidating complex gene regulatory pathways and exploration of susceptibility to common disease through genome-wide association studies. We use cutting edge techniques to manipulate the genome to determine how particular genes work and study how variants in regulatory DNA may contribute to common disease. An important overall aim is to improve the management of human genetic diseases.

  • The slimy jelly that helps us respond to infection

    26 June 2017

    A fully functioning immune system is dependent on good communication between many different types of cell. We know that one set of cells detects damage and infection, while another leaps into action to defend the body. But we weren’t entirely clear how the two ‘talked’ to each other. New research by the Jackson lab suggests that a special type of carbohydrate acts as the broker between the two.

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    28 March 2017

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