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  • A transit-amplifying population underpins the efficient regenerative capacity of the testis.

    28 June 2018

    The spermatogonial stem cell (SSC) that supports spermatogenesis throughout adult life resides within the GFRα1-expressing A type undifferentiated spermatogonia. The decision to commit to spermatogenic differentiation coincides with the loss of GFRα1 and reciprocal gain of Ngn3 (Neurog3) expression. Through the analysis of the piRNA factor Miwi2 (Piwil4), we identify a novel population of Ngn3-expressing spermatogonia that are essential for efficient testicular regeneration after injury. Depletion of Miwi2-expressing cells results in a transient impact on testicular homeostasis, with this population behaving strictly as transit amplifying cells under homeostatic conditions. However, upon injury, Miwi2-expressing cells are essential for the efficient regenerative capacity of the testis, and also display facultative stem activity in transplantation assays. In summary, the mouse testis has adopted a regenerative strategy to expand stem cell activity by incorporating a transit-amplifying population to the effective stem cell pool, thus ensuring rapid and efficient tissue repair.

  • Avoidance of the cytochrome c biogenesis system by periplasmic CXXCH motifs.

    3 July 2018

    The CXXCH motif is usually recognized in the bacterial periplasm as a haem attachment site in apocytochromes c. There is evidence that the Escherichia coli Ccm (cytochrome c maturation) system recognizes little more than the CXXCH sequence. A limited number of periplasmic proteins have this motif and yet are not c-type cytochromes. To explore how unwanted haem attachment to CXXCH might be avoided, and to determine whether haem attachment to the surface of a non-cytochrome protein would be possible, we converted the active-site CXXCK motif of a thioredoxin-like protein into CXXCH, the C-terminal domain of the transmembrane oxidoreductase DsbD (cDsbD). The E. coli Ccm system was found to catalyse haem attachment to a very small percentage of the resultant protein ( approximately 0.2%). We argue that cDsbD folds sufficiently rapidly that only a small fraction fails to avoid the Ccm system, in contrast with bona fide c-type cytochromes that only adopt their tertiary structure following haem attachment. We also demonstrate covalent haem attachment at a low level in vivo to the periplasmic disulfide isomerase DsbC, which contains a native CXXCH motif. These observations provide insight into substrate recognition by the Ccm system and expand our understanding of the requirements for covalent haem attachment to proteins. The possible evolutionary relationship between thioredoxins and c-type cytochromes is discussed.

  • C-type cytochrome formation: chemical and biological enigmas.

    3 July 2018

    C-type cytochromes are proteins that are essential for the life of virtually all organisms. They characteristically contain heme that is covalently attached via thioether bonds to two cysteines in the protein. In this Account, we describe the challenging chemistry of thioether bond formation and the surprising variety of biogenesis systems that exist in nature to perform the difficult posttranslational heme attachment process. We show what insight has been gained into the various biogenesis systems from in vitro and in vivo experiments and highlight some forthcoming challenges in this field.

  • Evolutionary origins of members of a superfamily of integral membrane cytochrome c biogenesis proteins.

    3 July 2018

    We have analyzed the relationships of homologues of the Escherichia coli CcmC protein for probable topological features and evolutionary relationships. We present bioinformatic evidence suggesting that the integral membrane proteins CcmC (E. coli; cytochrome c biogenesis System I), CcmF (E. coli; cytochrome c biogenesis System I) and ResC (Bacillus subtilis; cytochrome c biogenesis System II) are all related. Though the molecular functions of these proteins have not been fully described, they appear to be involved in the provision of heme to c-type cytochromes, and so we have named them the putative Heme Handling Protein (HHP) family (TC #9.B.14). Members of this family exhibit 6, 8, 10, 11, 13 or 15 putative transmembrane segments (TMSs). We show that intragenic triplication of a 2 TMS element gave rise to a protein with a 6 TMS topology, exemplified by CcmC. This basic 6 TMS unit then gave rise to two distinct types of proteins with 8 TMSs, exemplified by ResC and the archaeal CcmC, and these further underwent fusional or insertional events yielding proteins with 10, 11 and 13 TMSs (ResC homologues) as well as 15 TMSs (CcmF homologues). Specific evolutionary pathways taken are proposed. This work provides the first evidence for the pathway of appearance of distantly related proteins required for post-translational maturation of c-type cytochromes in bacteria, plants, protozoans and archaea.

  • Covalent cofactor attachment to proteins: cytochrome c biogenesis.

    3 July 2018

    Haem (Fe-protoporphyrin IX) is a cofactor found in a wide variety of proteins. It confers diverse functions, including electron transfer, the binding and sensing of gases, and many types of catalysis. The majority of cofactors are non-covalently attached to proteins. There are, however, some proteins in which the cofactor binds covalently and one of the major protein classes characterized by covalent cofactor attachment is the c-type cytochromes. The characteristic haem-binding mode of c-type cytochromes requires the formation of two covalent bonds between two cysteine residues in the protein and the two vinyl groups of haem. Haem attachment is a complex post-translational process that, in bacteria such as Escherichia coli, occurs in the periplasmic space and involves the participation of many proteins. Unexpectedly, it has been found that the haem chaperone CcmE (cytochrome c maturation), which is an essential intermediate in the process, also binds haem covalently before transferring the haem to apocytochromes. A single covalent bond is involved and occurs between a haem vinyl group and a histidine residue of CcmE. Several in vitro and in vivo studies have provided insight into the function of this protein and into the overall process of cytochrome c biogenesis.

  • Cytochrome c assembly: a tale of ever increasing variation and mystery?

    3 July 2018

    Formation of cytochromes c requires a deceptively simple post-translational modification, the formation of two thioether bonds (or rarely one) between the thiol groups of two cysteine residues found in a CXXCH motif (with some occasional variations) and the vinyl groups of heme. There are three partially characterised systems for facilitating this post-translational modification; within these systems there is also variation. In addition, there are clear indications for two other distinct systems. Here some of the current issues in understanding the systems are analysed.

  • Loss of ATP hydrolysis activity by CcmAB results in loss of c-type cytochrome synthesis and incomplete processing of CcmE.

    3 July 2018

    The proteins CcmA and CcmB have long been known to be essential for cytochrome c maturation in Escherichia coli. We have purified a complex of these proteins, and found it to have ATP hydrolysis activity. CcmA, which has the features of a soluble ATP hydrolysis subunit, is found in a membrane-bound complex only when CcmB is present in the membrane. Mutation of the Walker A motif in CcmA(K40D) results in loss of the in vitro ATPase activity and in loss of cytochrome c biogenesis in vivo. The same mutation does not prevent covalent attachment of heme to the heme chaperone CcmE, but holo-CcmE is, for some unidentified reason, incompetent for heme transfer to an apocytochrome c or for release into the periplasm as a soluble variant. Addition of exogenous heme to heme-permeable E. coli with a ccmA deletion did not restore cytochrome c production. Our results suggest a role for CcmAB in the handling of heme by CcmE, which is chemically complex and involves an unusual histidine-heme covalent bond.

  • Cytochrome c as an experimental model protein.

    28 June 2018

    Mitochondrial cytochrome c is among the most intensively studied of all proteins. Initial interest was in its role in the respiratory chain and as a model for studies of protein structure, folding and electron transfer. The function of cytochrome c in signalling apoptosis has brought a new wave of research into the protein. Bacterial cytochromes c are more complex and varied in function. This review highlights some of these roles and expands on systems for producing holocytochrome c proteins.

  • Funding Opportunities

    17 July 2018

    OCH invites applications for Training Grants for Allied Healthcare Professionals (deadline 10 Sept).

  • 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.

  • Assertive Communication

    12 March 2018

    Learning and Development Programme

    This workshop aims to help individuals take steps towards a more effective working relationship with their manager/ supervisor and colleagues. This course forms part of the ‘Working Relationships’ strand of the RDM Learning and Development Programme. 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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