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Preservation survey of school examination papers collection 31 Mar 2014

Funding is requested for a preservation survey of the IOE's collection and also the Cambridge Assessment collection from which the bulk of the digitisation will be done. Gaps in the IOE collection will be filled by material contributed by collaborating organisations as listed above. Cambridge Assessment has a significant quantity of material which we will likely need to use hence this request also covers their collection. Other collaborating organisations have indicated they have either had similar work done, or are able to supply duplicates from their collections hence no risk to their archive. We would specifically benefit from the consultant reporting on the physical condition of the material, the risks associated with digitising it and recommendations on how to avoid or minimise those risks. Both IOE Library and Cambridge Assessment Archives will be retaining print copies post-digitisation. Physical format varies.

Amount: £6,215
Funder: The Wellcome Trust
Recipient: Institute of Education

Condition and content survey (scoping study) of three NRS record collections. 17 Jan 2014

Research Resources in Medical History award

Amount: £11,650
Funder: The Wellcome Trust
Recipient: The National Records of Scotland

Digitisation of medical manuscripts 17 Jan 2014

The medical collection at Pembroke consists of seven bound volumes of manuscripts, dating from the early twelfth to the fifteenth century, each containing a mixture of texts. They appear to have been bound at approximatelythe same time, and possibly by a local binder. It is thought that they may have been in the possession of Thomas Clayton (1575-1647), the Master of Broadgates Hall, and later Pembroke College, and who was Regius Professor of Medicine at Oxford University. The manuscripts are written on a mixture of parchment and vellum in a range ofhands. Most of the pages are in good condition, many have tabs cut from the side for ease of reference. Six are of a similar size, about 22cm high, with one being considerably smaller at 15cm. All are bound in white parchment whichhas dried and warped considerably, making the original binding extremely tight. They range from 108 to 230 folios in length, with the smaller volume having 278 folios. A large number of the texts are recipes, mostly from well-known medieval sources, and annotated with a number of marginalia. There are also inserted pages or notes at various points where either the compiler or the original owner has added to the text. As well as the recipes and lists of herbs, there are urine charts and two diagrams, one of the Zodiac and the other of the human brain. These texts are fairly typical of the medical canon of their time, and are particularly useful to scholars studying the dissemination of information through the medieval world. They can be used to trace the spread of particularcopies of medieval medical texts, and compared with other known texts in orderto establish the most likely original versions. Very little work has been doneon the Pembroke manuscripts beyond a brief description, and digitisation wouldmake them available to a wider world of scholarship for study and comparison. The final project would be to digitise all seven of the manuscripts, as well as carrying out important conservation work on them. While the binding is currently in reasonable condition, it has become very stiff, making the books themselves difficult to open. If they continue to be used, the binding will deteriorate, and so digital images would save the books from unnecessary stress. They are also currently unboxed, and relatively unprotected, which maycontribute to future deterioration. In order to ensure that the manuscripts are suitable for digitisation and to establish what, if any, conservation work is required, we need to first undertake a conservation survey, which will help us with the final digitisation project.

Amount: £1,600
Funder: The Wellcome Trust
Recipient: Pembroke College

Elucidation of the roles of PTN and ISG15 in RSV cytopathogenesis: possible biomarkers of severe disease?. 25 Jun 2014

Respiratory syncytial virus (RSV) is the commonest cause of severe lower respiratory tract infection in young infants, typically causing bronchiolitis and pneumonia. Prematurity is a risk factor for severe disease. How RSV causes human disease is poorly understood. Neonates, particularly preterms, are vulnerable to life-threatening infections and innate immune defences are critical. Innate immune responses are deficient in newborn infants relative to adults, with differential responses also evi dent between preterm versus term infants. RSV primarily targets airway epithelium and induces innate antiviral and pro-inflammatory chemokine responses. The host laboratory has developed a novel model of RSV infection based on well-differentiated primary paediatric nasal (WD-PNEC) epithelial cells that reproduces several hallmarks of severe disease. Using WD-PNECs derived from infants with histories of severe or mild RSV disease, microarray studies identified 2 genes that were differentially exp ressed between the cohorts, including ptn and isg15.The genes encode proteins with antiviral and/or anti-inflammatory properties. Preliminary data confirmed this differential expression and also suggest that these genes/proteins may be implicated in susceptibility to severe RSV infection.Therefore, this project will study the role of these genes/proteins in RSV cytopathogenesis, with particular emphasis on their expression kinetics, antiviral properties and the consequences of gene knockdown.

Amount: £212,118
Funder: The Wellcome Trust
Recipient: Queen's University Belfast

From Genes to Disease: Investigating the Role Of ECM1 Variants in the Pathogenesis of Inflammatory Bowel Disease. 25 Jun 2014

Inflammatory bowel disease affects 1:250 people in the UK. It is a chronic condition associated with significant morbidity. It comprises two principle forms; Crohns Disease and Ulcerative Colitis (UC). Genome wide association scanning has identified gene variants involved in maintenance of the intestinal epithelial barrier as being associated with UC including ECM1. In yeast models ECM1 binds and inhibits matrix metalloproteinase 9 (MMP9), a protease involved in tissue remodelling which has been implicated in colitis pathogenesis. I propose to investigate the function of ECM1 and its variants and to define the interaction between ECM1 and MMP9 within a disease appropriate model. The hypothesis is that ECM1 variants cause functional attenuation reducing the inhibitory effect on MMP9 leading to increased tissue breakdown and thereby a dysfunctional intestinal epithelial barrier. My research objectives are: 1. To determine the conditions under which ECM1 and MMP9 associate i n human colonic epithelial cells 2. To determine the requirement for ECM1 in maintaining epithelial cell barrier integrity. 3. To determine the impact of ECM1 variants on ECM1 function This may allow us to stratify patients susceptibility to IBD and highlight potential therapeutic targets.

Amount: £145,051
Funder: The Wellcome Trust
Recipient: University of East Anglia

Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography - The Vision Study. 25 Jun 2014

Clinical events in atherosclerosis are largely driven by inflammation. Molecular atherosclerosis imaging can potentially identify high-risk lesions, help guide treatment and illuminate underlying pathophysiology. 18F-FDG PET is the gold-standard nuclear molecular imaging technique with well-established roles in atherosclerosis imaging. However, the arterial 18F-FDG signal is non-specific for inflammation and coronary artery imaging is difficult due to high background myocardial uptake. 68Ga-DOTA NOC is a somatostatin receptor PET tracer used in cancer imaging, which we think is more specific for inflammation and lacks myocardial uptake. VISION is a prospective study designed to investigate plaque inflammation using 68Ga-DOTANOC PET. In the proposed study, 50 participants with atherosclerosis will undergo sequential 68Ga-DOTANOC and 18F-FDG PET imaging, along with CT carotid and coronary angiography. Autoradiography and immunohistochemistry of excised carotid plaques will be used to vali date imaging data. Post-hoc computational imaging analysis will also be performed to derive mechanical stress patterns in relation to vascular inflammation detected by 68Ga-DOTANOC. If successful, 68Ga-DOTANOC imaging will offer a cheaper, more specific non-invasive measure of inflammation than 18F-FDG, particularly in the coronary arteries. This should result in better risk stratification for patients with atherosclerosis and could provide a non-invasive platform to test the effects of novel an ti-atherosclerosis drugs.

Amount: £227,171
Funder: The Wellcome Trust
Recipient: University of Cambridge

Gestation of delivery of twins - influence on perinatal mortality and morbidity and childhood educational outcomes. 18 Jun 2014

The purpose of this work is to guide clinicians on the optimum timing of the elective delivery of twins. This information is crucial in attempting to reduce perinatal mortality and morbidity in twin pregnancies. The following specific research aims will be investigated in this study: 1. To determine the gestation specific perinatal and neonatal mortality and morbidity in twins following (i) spontaneous delivery and (ii) elective delivery in the absence of maternal or fetal complications. T his research aim has been prompted by NICE following the multiple pregnancy guideline which acknowledges a lack of evidence to support its current recommendation on elective delivery of twins. 2. To determine the perinatal risk index in twin pregnancies according to gestation at delivery. Calculating this risk index for twin pregnancies will be useful in guiding the optimum timing of delivery of twins 3. To determine the long term educational outcomes of twin deliveries by gestational age The above questions have been answered in singletons and I believe that it is essential that similar data are available for women with twin pregnancy.

Amount: £262,646
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Microfluidic Platform for Investigating the Kinetics of Extracellular Vesicle Induced Metastatic Niche Formation 21 May 2018

Extracellular vesicles (EVs) are believed to be important messengers in the progression of metastatic cancer that prime distant organs for tumour cell colonisation. However, due to an inadequacy of relevant tools, we have a poor understanding of how EVs distribute to, diffuse into and remodel organs into metastatic niches. The goal of this project is to develop novel microfluidic platforms for performing real-time continuous quantification of EV kinetics over multiple days in physiologically-relevant microenvironments. Towards this end, I propose three aims: Develop Microfluidic Metastatic Niche Platforms to explore the interaction of extracellular vesicles with liver tissue and vasculature. Investigate the kinetics of EV distribution, uptake and diffusion in liver and vasculature compartments of Microfluidic Metastatic Niche Platforms. Explore the influence of EV kinetics (distribution, uptake and diffusion) on the ability of cancer cells to attach, invade and proliferate in Microfluidic Metastatic Niche Platforms. The results of this project will enhance our understanding of metastatic cancer progression and will contribute valuable data for numerous follow-up studies aiming to inhibit or even prevent the development of metastatic niches.

Amount: £99,951
Funder: The Wellcome Trust
Recipient: Imperial College London

Mechanisms and pharmacodynamics of antifungal agents for cryptococcal meningitis. 30 Sep 2018

Cryptococcal meningitis (CM) is an infection of the brain and surrounding tissues (the meninges). It is caused by a yeast called Cryptococcus and is responsible for approximately 180,000 deaths annually (26). The most effective drug is amphotericin B (AmB) which needs to be given for 2 weeks and causes dangerous side-effects. A modified formulation, liposomal amphotericin B (LAmB), may be easier to administer to patients because it can be given as a single dose, and appears to be as effective as 2-weeks of conventional AmB (12, 15, 23). This observation raises a number of questions: 1) What is the optimal dosing strategy for LAmB? I will measure drug levels and describe their relationship with reduction in Cryptococcus levels. 2) How does one dose of LAmB exert a prolonged effect? i will image the movement of LAmB in mouse brains and meninges to assess how long LAmB stays in these regions. During treatment for CM, the rate of decline of yeast in spinal fluid is highly variable (24, 25, 27). Therefore, another question is: 3) Do different groups of yeast vary in teir response to treatment? I will collect samples of Cryptococcus and characterise their survival ability in various conditions.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Liverpool

Clinical Characterisation of a Broad Spectrum of Genetic Variation in the General Population 30 Sep 2018

Inborn errors of metabolism (IEM) are severe and extreme changes in metabolism caused by mutations in a single gene. Recent large-scale human studies have shown that genes causal for IEM are associated with nutrients, or ‘metabolites’, in the blood. However, whether these associations cause disease or adverse health outcomes is unknown. In this project, I will use IEM genes identified in these studies to link genetic variation to clinical features in a large human population. To do this, I will assemble a list of IEM genes of interest that were identified in the literature and in large population datasets. I will then test for associations between the variants I find in these genes and a wide range of clinical features found in open-access population datasets. As the IEM genes used in this study have been associated with blood metabolites previously, linking variants in these genes to clinical features will shed light on the molecular mechanisms underlying genes and disease in the general population. Understanding how genetic variation affects disease will help identify novel therapeutic targets and enable health professionals to better manage disease risk.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

LMIC Travel Scholarships for Global Climate and Health Forum 30 Sep 2018

The Global Climate and Health Forum is a one-day, high-level convening of global climate and health leaders designed to mobilize stronger health sector engagement in and commitments to climate action. The Forum will bring together 250 leaders from national and local governments, health systems, public health agencies, civil society, and international organizations to build the community of climate and health professionals, strengthen collaboration across sectors, and raise the health voice for climate action. The Forum will be held at the University of California, San Francisco on September 12th, 2018. The Forum is an affiliate event of the Global Climate Action Summit, and co-hosted by the UCSF Global Health Group, Health Care Without Harm, Global Climate and Health Alliance, and US Climate and Health Alliance. In order to make the Forum a truly global event, it is imperative that the Forum includes speakers and participants from low- and middle-income countries who are leading climate mitigation, adaptation, and resilience work in the most vulnerable regions and communities. Funding from the Wellcome Trust will be used to support five travel scholarships for participants from the global South, including all registration, travel, accommodation, and event-related expenses.

Structure and mechanism of the Ino80 chromatin remodelling complex 28 Nov 2017

Compaction of the genome into chromatin helps to protect the genetic material but also causes problems in regard to access for essential processes such as transcription, replication and repair. Chromatin remodelling complexes alter the state of chromatin through a number of processes that includes chemical modifications of nucleosomes and sliding their position on DNA. Nucleosome sliding is catalysed by a number of protein complexes, one of which is the multi-subunit INO80 complex. INO80 contains an ATP-dependent translocase motor, that is common to all nucleosome sliders, but also a variety of other subunits, most of which have unknown roles. Furthermore, not only does it require two INO80 complexes interacting with a single nucleosome to promote sliding, but the complex also has an ability to "sense" the presence of other nucleosomes to space them evenly on DNA indicating interactions with multiple nucleosomes. The mechanism for this process is poorly understood, particularly at a molecular and structural level. INO80 is highly regulated in several distinct ways, including chemical modifications, small molecule effectors and subunit interactions but none of these are well understood. Finally, how the various subunits, many of which are ATPases in their own right, contribute to INO80 activities is also unclear.

Amount: £1,701,911
Funder: The Wellcome Trust
Recipient: Imperial College London

Growth and secretion by Campylobacter jejuni under anaerobic conditions 31 May 2018

Campylobacter jejuni is the leading cause of bacterial gastroenteritis and thus poses a significant health risk. The bacteria is part of the natural microbiome of the chicken caecum where it appears to function as a non-invasive commensal but in the human intestine the organism becomes invasive and pathogenic. The Ó Cróinín group have recently reported that DNA supercoiling plays a key role in inducing this invasive phenotype and that relaxation of DNA supercoiling is associated with an increase in invasion and the appearance of an invasion associated secretive. This group have also unpublished data which reveals that DNA supercoiling allows the bacteria to survive and grow under anaerobic conditions which normally do not support growth. Given the anaerobic nature of some areas of the human intestine this could indicate that relaxation of DNA supercoiling could be critical in allowing this bacteria to both secrete virulence factors as well as to survive and grow under anaerobic conditions. The aim of this study is thus to investigate and characterise the effect of DNA supercoiling on the ability of the bacteria to grow under anaerobic conditions as well as to compare the secretion of proteins by microorganisms grown under anaerobic and microaerophilic conditions

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Suppression of adaptive immunity by Salmonella 28 Nov 2017

Dendritic cells (DCs) have a crucial role in the development of adaptive immunity to bacteria. DCs transport the intracellular pathogen Salmonella from intestinal Peyer’s Patches to mesenteric lymph nodes where they present bacterial antigens to CD4+ T cells using MHCII molecules. DCs also secrete cytokines that stimulate recruitment and activation of T and NK cells. Salmonella is a globally important intracellular pathogen that survives in DCs and interferes with the processes of DC migration, cytokine production/sensing and T cell activation. The overall goal of this application is to understand mechanisms by which Salmonella interferes with these processes. Recently we identified an effector of the SPI-2 type III secretion system (SteD) that reduces the number of mature MHCII molecules on the surface of DCs. A significant component of the planned work is to understand its mechanism of action in detail. We will use candidate-based and unbiased screens, along with molecular cell biological approaches to characterize mechanisms involved in suppressing DC migration, production of IL-12 and IFN-gamma-stimulated host cell signaling. Collectively, this research will advance the field by providing novel insights into different mechanisms by which a bacterial pathogen subverts the development of adaptive immunity.

Amount: £2,170,670
Funder: The Wellcome Trust
Recipient: Imperial College London

Intra-Africa Mobility Initiative on Science, Language and Culture 30 Sep 2018

The Alliance for Accelerating Excellence in Science in Africa (AESA), Wellcome Trust (WT) and the Institut Pasteur International Network propose a researcher mobility program which would support African researchers (who share our ambition) to break down language and cultural barriers that impede greater African research collaboration in the biomedical and health sciences.Over the next 5 years, we aim to support at least 50 researchers to undertake mobility favoring the enhancement of their scientific careers while also increasing the understanding and interconnections of the African research community within different cultural and linguistic environments. Where language is the barrier we will look for flexible ways of providing support and funding language training. The program will aim to; Strengthen scientific collaboration between Anglo and Francophone speaking African scientists Build language skills/capabilities in English and French among African scientists Improve cultural understanding between English and French speaking African scientists The program will build out from the DELTAS and H3Africa researcher communities and the Institut Pasteur network, Our indicator of success will be; By December 2020, 50 African researchers will have experienced the mobility program and report positively on breaking down language and cultural barriers to research.

Amount: £198,662
Funder: The Wellcome Trust
Recipient: African Academy of Sciences

Investigating the Structure of FcγRIIa and its Interactions within the Membrane 30 Sep 2018

Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Leeds

Design and testing of allele specific gene editing tools. 31 May 2018

The Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a programmable RNA guided endonuclease, which is effective at gene editing in mammalian cells. These highly specific and efficient RNA-guided DNA endonucleases may be of therapeutic importance to a range of genetic diseases. The CRISPR/Cas9 system relies on a single catalytic protein, CRISPR associated protein 9 (Cas9), which can be guided to a specific DNA sequence anywhere in the genome by the substitution of a 20-nucleotide sequence, complimentary to the particular target, within a single RNA molecule (sgRNA).A number of computer programs have been developed to predict the sgRNA that cuts the intended target most efficiently with the least off-targetting. I aim to identify, design and characterise sgRNA molecules that could be used to target mutant corneal dystrophy genes by using molecular biology techniques such as in silico identification of mutations in corneal dystrophy genes suitable for CRISPR/Cas9 gene editing with in vitro testing of selected guides, design of sgRNA to target the identified mutation and comparison of sgRNA design and off-target prediction tools.

Amount: £0
Funder: The Wellcome Trust
Recipient: Ulster University

C. elegans – a model system to study causation in the microbiome-gut-brain axis 06 Sep 2018

Metagenomic approaches are generating a long list of health and disease states associated with the microbiome (the microbes inhabiting our digestive tract) but without mechanistic understanding. The challenges arise from the enormous complexity of the microbiome, including genetic, environmental and dietary variations, microbe-microbe interactions, and the cost associated with studying the microbiome using murine models. If the field is to move beyond association, simple, well-controlled and cost-effective models allowing unbiased high-throughput studies are needed. The nematode C. elegans is a genetically tractable model, ideally suited for mechanistic and causative studies of host-microbiome and microbe-microbe interactions shaping host physiology and metabolism. Aims: 1) Establish an experimental microbiome in C. elegans based on strains from the human microbiome associated with health, disease and ageing 2) Generate fluorescent labelled bacterial strains and perform real-time imaging of gut colonisation 3) Characterise the effects of the experimental microbiome on the microbiome-gut-brain axis during ageing The experimental microbiome in C. elegans will be an important contribution to the field, complementing existing models. It will allow me to establish important collaborations, form a basis for my future research and address one of the most important questions of modern biology: the effects of the microbiome on host physiology.

Amount: £99,905
Funder: The Wellcome Trust
Recipient: Queen Mary University of London