NIHRDataInsights/HRCSData huggingface dataset:
Title: Electron cryomicroscopy of viruses and cells
Funder: The Francis Crick Institute

Abstract: We study the structure of large protein assemblies to understand how they control complex biological processes in the cell and how pathogens interact with their hosts. We directly image the structure of frozen-hydrated specimens on a wide range of length scales using electron cryomicroscopy. Recent advances in cryomicroscopy now offer a unique opportunity to extend structural studies of assemblies to high resolution and to obtain structural snapshots of dynamic cellular events in vivo. Our major focus is an understanding of the life-cycle of pathogenic lipid-enveloped viruses. We study the structural organization of influenza virus to understand how protein and membrane interactions govern virus assembly and characterize structural changes that occur during virus entry. We have directly imaged influenza virus fusion with target membranes and shown how structural changes in the hemagglutinin surface glycoprotein as well as ultrastructural changes in the virus are linked to membrane transformations. Identification of new, distinct steps in membrane fusion can lead to new structural targets for blocking infection. These studies will inform our understanding of virus entry by other lipid-enveloped viruses, and also SNARE-mediated membrane fusion in both intracellular and neuronal contexts. We are also interested in related problems in the structure and assembly of retroviruses. We use electron cryotomography to image frozen hydrated cells providing high-resolution images of cell architecture including the cytoskeleton as well as structural information on protein complexes in vivo. We image the structure and dynamic transformations of cellular organelles such as storage granules for von Willebrand factor as a route to understanding how organelles are assembled and how they release their content by exocytosis in response to stimulation. These studies are thematically related to our studies of lipid-enveloped viruses. Defects associated with von Willebrand factor storage and release cause von Willebrand’s disease, a common bleeding disorder. We develop experimental and computational methods to improve the structure determination of biological specimens by cryomicroscopy and extend the range of its application. We optimize computational methods for single particle reconstruction and validation, which we apply to the high-resolution structure determination of large protein assemblies and molecular machines. We are developing new imaging procedures to reduce beam-induced specimen motion, which will improve images for either single particle analysis or tomography.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: SARS-CoV 2 imaging study award to the UK Biobank
Funder: Medical Research Council

Abstract: The Medical Research Council (MRC) has agreed to provide a COVID-19 Support Fund award to UK Biobank to help underpin short-term stability and to avoid deterioration of strategic, national scientific capability as a result of impacts of the COVID-19 pandemic. Purpose By accepting this award, the organisation agrees to use the MRC COVID-19 Support Fund to help ensure MRC objectives continue to be met, the value of MRC investments continue to be realised, and to sustain the research skills and capability within their organisation that will be needed to underpin the post-pandemic national recovery. The award is specifically to maximise the number of participants within the core imaging programme.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Functions of Norovirus VP1: A Multi-Faceted Capsid Protein
Funder: Medical Research Council

Abstract: As positive-sense RNA viruses, noroviruses possess small genomes that produce a limited set of proteins. To compensate for this limitation they have evolved proteins that have manifold functions during the virus life-cycle and increase their "genetic economy". The norovirus structural protein VP1 is an example of a multi-functional protein. It is the major component of viral capsids and must be robust to protect the vulnerable viral genome. It is essential for receptor binding and allowing controlled virion disassembly to deliver the viral genome during endocytosis. Inside infected cells it is involved in regulating viral genome synthesis and is essential for assembly of new infectious virions. As part of my recent work, resources are now in place to understand how VP1 fulfils two essential roles. Using inactivation of infectious virus with structural and molecular biology I have identified a viral particle that has a novel VP1 conformation. I hypothesise that this conformation of VP1 in the capsid is involved in delivery of the viral genome. Using biochemical assays with imaging and structural techniques I will discover how VP1 directs delivery of the viral genome during endocytosis and the factors involved in this process. In contrast to the disassembly of the capsid that must take place during endocytosis, production of nascent virions requires the controlled assembly of VP1 with the viral genome. I have demonstrated that VP1 localises with membrane-associated non-structural proteins believed to be involved in viral RNA replication. I hypothesise that the interaction between VP1 and these viral non-structural proteins is part of a regulated complex required for virion assembly. With my experience studying macromolecular complexes, I will investigate how VP1 interacts with viral factors to assemble virions. By understanding how VP1 functions to regulate entry into the cells and production of virions, improved vaccine and anti-viral approaches can be created.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Medical Research Council Centre for Medical Mycology
Funder: Medical Research Council

Abstract: Creation of the MRC CMM empowered expansion of critical mass that enabled interdisciplinary research in areas of scientific, translational and clinical importance. This has led to numerous discoveries, attracted significant additional funding, facilitated strategic interactions with other national and international groups, and enabled greater public engagement and understanding of our science. We also established the first International satellite centre in the field, the AFGrica Unit. In the next quinquennium, a key objective is to further increase UK and global capacity in medical mycology through the recruitment of excellent Early Career Fellows, PhD students, and clinical trainees. Moreover, we will establish satellite Units in South America and Asia, to facilitate research and training in regions of the world that suffer high burdens of fungal disease. With the recruitment of two scientists in key areas, our research will be focused into the following interdisciplinary themes that will underpin the Centre's scientific and training strategy: a. Fungal growth, adaptation and morphogenesis in the context of human infections, and implications for immunity, disease phenotypes and therapy. b. Fungal components as antifungal drug targets, diagnostics, vaccine antigens and adjuvants. c. Evolution and impact of antifungal drug resistance, and mitigation strategies. d. Host-fungus interactions and key mediators of disease establishment and progression at molecular, cellular and organismal levels. e. Determinants of patient susceptibility, including immunity and comorbidities, to enable directed diagnosis, treatment and prevention of fungal disease. With continued MRC support over the next quinquennium, the MRC CMM will become the largest Centre of Excellence for research and training in Medical Mycology in the world. Our ambitious programme of training, research, engagement and international outreach is focused on tackling the major challenges facing the field.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: The role of 3'-Deoxy-3',4'-didehydro-cytidine in the host response to viral infections.
Funder: Medical Research Council

Abstract: There is an urgent need for both improved diagnostics and a better understanding of the human host response in viral infections. Rapid diagnostics will help direct appropriate antimicrobial therapies and guide infection control precautions. Elucidation of host physiological antiviral defences will help identify risk factors for deterioration and targets for new therapeutics. I recently performed untargeted metabolic profiling of serum samples from patients with different infections, using liquid chromatography coupled with mass spectroscopy (LC-MS). I found, for the first time, that the antiviral small molecule 3'-Deoxy-3',4'-didehydro-cytidine (ddhC) was detectable in human serum and could accurately differentiate viral infections from bacteraemic infections and controls, generating an area under the receiver operator characteristic curve of 0.954. This preliminary data has driven two hypotheses that I plan to explore: Hypothesis 1. ddhC is selectively produced as an acute response to viral infections in adults and children and can be used as a diagnostic tool. I will use LC-MS to characterise the host ddhC response in broader clinical contexts, including infections at different timepoints, paediatric cohorts and other non-viral infections, enabling exploration of its utility in viral diagnostics. I will develop an aptamer-based assay for ddhC by using the systematic evolution of ligands by exponential enrichment method to identify optimised nucleic acid aptamers that can specifically bind ddhC. Hypothesis 2. Viral replication is inhibited by both exogenous ddhC and viperin-derived endogenous ddhC-triphosphate. I will explore the biological role of ddhC and its associated gene viperin in viral infections. I will use in vitro respiratory epithelial cell models to investigate the natural ddhC response to infection and effects of exogenous ddhC addition and viperin overexpression on viral replication, focussing on SARS-CoV-2.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Improving Practice in Ugandan drug shops: a holistic approach to regulation
Funder: Medical Research Council

Abstract: Drug shops are small retail outlets that sell over the counter, antimalarial and antibiotic medicines in low- and middle-income countries in Africa and Asia. In many countries, however, these shops are inadequately regulated, and poor practices include inappropriate the sales of antibiotics. In drug shops, simply limiting access to the antibiotics would create a barrier to lifesaving treatment for many of the world's poorest citizens. To be equitable, therefore, interventions in medicine markets must balance efforts to curtail excess use of antibiotics with the population's needs to secure effective access to lifesaving medicines. This research project will lead to the creation of an affordable, feasible and acceptable intervention that will improve the rational use of antimicrobial medicines by improving the regulation of medicine markets in low- income settings in Africa and Asia. It builds on research among drug shop vendors in Uganda by the research team and seeks to identifying the overlapping social, economic, and professional interests of different (sets of) actors to create novel forms of collective action. The main intervention trial will be a stepped wedged cluster randomised trial with a process evaluation in 10 districts with collaborative Quality Improvement cycles (with policy makers, regulators, drug shop vendors and community members), subsidized commodities for drug shop vendors and material resources (bicycles, regulation forms) for community members to support regulatory work. In this project, we will collect qualitative data among drug shop vendors, policy makers, community members and district officials to identify incentives, training needs, and the feasibility of involving members of the community and drug shops and policy makers in holistic regulation.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Remote-by-Default Care in the COVID-19 pandemic: addressing the micro-,meso-,and macro-level challenges of a radical new service model
Funder: Economic and Social Research Council

Abstract: AIM In the context of COVID-19, to address micro- (technical tools, clinical techniques), meso- (organisational change) and macro (national infrastructure) aspects of a remote-by-default service model in primary care. OBJECTIVES 1. Validate and embed evidence-based tools for remote assessment and monitoring. 2. Support local implementation teams to overcome technical, operational and professional barriers and implement remoteby- default service models rapidly and at scale. 3. Generate and apply insights on how NHS infrastructure can better support - and be supported by - digital innovation in a time of crisis.

Lay abstract: Because COVID-19 is so contagious, the way the NHS works has changed dramatically. For the first time since 1948, you can't walk into a GP surgery and ask to be seen. You must apply online, phone the surgery or contact NHS111. You may then get a call-back (phone or video) from a clinician, or a face-to-face appointment, possibly in a 'hot hub'. These changes to what used to be the family doctor service are radical, frightening and difficult. They cut to the core of what it is to care and be cared for, and what 'good' and 'excellent' health services look and feel like. Will the doctor be able to assess you properly by video or phone? We are an interdisciplinary team specialising in the study of complex, technology-supported change in health and care settings. Using a variety of methods, we want to do three things: - Develop tools to help clinicians assess people effectively by phone or video; - Support the change process through 'action research' - that is, working with GP teams to collect relevant data, analyse it together and support its rapid use; - Using collaborative improvement techniques, strengthen the supporting infrastructure for digital innovation in the NHS.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Investigating how nurse education prior to and during Covid prepares nurses for the pandemic : an analysis of what works
Funder: Economic and Social Research Council

Abstract: The overall project aim is to explore the impact of Covid-19 on second and third year student nurses' clinical placements across the UK. The aim will be informed by the following objectives: 1) to explore whether, and to what extent, student nurses' theoretical and clinical education, including their experience of on-line learning, has prepared them to cope professionally and personally for offering care in all phases of the Covid-19: 2) to explore the extent to which learning in the Covid pandemic has helped student nurses in all four fields of nursing (Adult, Children, Mental Health and Learning Disability) develop transferable skills and describe the learning opportunities identified for each field; 3) to establish whether or not student nurses' experiences of clinical placements during Covid-19 shape their views of nursing and to identify the extent to which these experiences influence their future intentions about nursing as a career choice; 4) to explore whether or not student nurses experience the same or different psychosocial needs during the different phases of Covid and the extent to which they feel supported in having these needs met; we aim to identify potential interventions that can be developed to improve support.

Lay abstract: The Covid-19 pandemic has changed the face of healthcare delivery and has placed ever changing demands on nursing care. This qualitative study will use audio, visual diaries or written diaries kept over four weeks of a clinical placement and telephone or on-line interviews at the end of the placement, to gather data from second and third year student nurses in England, Wales, Scotland and Northern Ireland. Student nurses will describe their experiences of education both before and during the pandemic (including between the first and second waves) and their experience of on-line learning, commenting on what went well and what could have been done better. They will also identify any transferable skills they acquired and how these may be used in nursing to provide optimal care throughout the different phases of the pandemic and beyond.The study will investigate the psychological wellbeing of student nurses and the extent to which their experience within the Covid pandemic influences their identities as nurses and their intentions to pursue a career in nursing.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Will Covid-19 change what the public expect of government?
Funder: Economic and Social Research Council

Abstract: 1. To ascertain whether the COVID-19 pandemic has occasioned a marked change in the aggregate distribution of attitudes in Britain towards the role of the state, moral issues, and aspects of globalisation, together with reported levels of social trust. 2. To ascertain whether the varying experience and affective reactions of individuals in respect of COVID-19 are related to people's propensity to have changed their attitudes towards any of the above topics. 3. To inform policy makers about the extent to which, if at all, the British public's policy preferences have changed in the wake of the COVID-19 pandemic. 4. To undertake two high-quality surveys of attitudes towards the above topics, focusing on questions that have been asked previously on surveys conducted before the pandemic.

Lay abstract: COVID19 has created a major social and economic shock that has impelled government intervention on a scale unprecedented in peace time. A key question that now arises is whether this experience has changed voters' expectations of what government can and should do - and so altered the climate of public opinion with which politicians will have to deal once the public health crisis has ended. This study will use survey research to assess whether attitudes in Britain have changed in three areas. First, has the anxiety created by the crisis and the experience of social distancing made us more or less trusting of others and tolerant of those who behave differently from ourselves? Second, has the economic shock and risk of unemployment changed our attitudes towards government spending and the provision of welfare to those of working age? Third, has the experience of an internationally transmitted disease created an increased wish to control our borders, most notably in respect of immigration? The first survey will be conducted in 2020, the second in 2021. Both will ask questions that were previously asked on surveys before the pandemic, thereby making it possible to see how attitudes have changed.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Stochastic variation and regulation of bacterial DNA repair and mutagenesis
Funder: Wellcome Trust

Abstract: Studying the molecular mechanisms of mutagenesis is crucial to understanding genome evolution and the emergence of drug resistance in pathogens. It is known that cellular stress responses increase mutation rates after DNA damage and antimicrobial treatment. Recent evidence suggests that stochastic effects play key roles in these responses, causing cell-to-cell variation in mutation rates and diversifying cell phenotypes to evade drug treatment. However, existing cell biology, biochemistry, and genetics assays fail to resolve mutation rate dynamics and cellular heterogeneity. By combining live-cell single-molecule microscopy, single-cell manipulation, and DNA sequencing techniques, I will bridge the divide between molecular-level and genome-level approaches. I will visualise mutagenic molecular processes in real-time and link them to genome sequence changes in individual bacterial cells. Ultimately, I will discover how individual mutation events are related to single-cell phenotypes such as DNA repair activities, stress responses, and growth characteristics. My focus will be on the conserved SOS response that globally regulates genome maintenance and has been implicated in the bacterial response to antibiotics. Using a novel method to quantify post-translational modifications of the master SOS regulator, I will uncover the molecular choreography of the SOS response and establish how it contributes to the evolution of antibiotic resistance.

Lay abstract: The rapid evolution and spread of antibiotic resistance is a major threat to global health. It is rooted in the plasticity of bacterial genomes. There is growing evidence that the overuse of antibiotics not only promotes spreading of existing resistance genes, but also accelerates evolution of novel resistance mechanisms. Cellular stress and DNA damage responses appear to increase mutation rates during antibiotic treatment, but the molecular mechanisms remain unclear. My research showed that mutation rates can vary between cells in a population, which may help a small fraction of cells to survive drug treatment and acquire genetic resistance. Conventional experiments on large cell populations cannot show the specific intracellular conditions that lead to a mutation in an individual cell. I will circumvent population-averaging by measuring the movement of single proteins that repair DNA sequence errors inside living cells. I can thus identify mutation events under the microscope and map them to the genome sequence in order to identify the molecular processes that cause mutations. These novel tools will show how antibiotic treatment speeds up the evolution of resistance. My research into the fundamental mechanisms of mutagenesis will also inform on equivalent processes in humans, where mutation accumulation leads to cancer.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION