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Results

EVIPNet Europe policy and research scoping tool 18 Jun 2018

I propose to develop a policy and research prioritisation tool for use by EVIPNet Europe countries to improve knowledge translation between research and policy. The goal would be to create a ranking system to help health policy decision-makers pinpoint high-priority policy issues that would benefit from research input in clarifying the problem or framing options for its solution. It should also aid research policy decision-makers to identify where to invest research resources, taking into account policy needs, to create implementable recommendations. Such a tool would encourage decision-makers to analyse quantitative data, for example the burden of disease, and qualitative information, such as public attitudes, and reach agreement when allocating resources to programmes. To create it I would complete a scoping literature review on the merits of various existing tools and combinations of tools. I would gather a variety of evidence, including systematic reviews of best practice, and case studies from the region that explain how these tools have been adapted to work in similar settings. I would consult with the EVIPNet country knowledge translation networks on their particular research and policy needs and challenges so as to select and adapt a context appropriate design for the tool.

Amount: £14,388
Funder: The Wellcome Trust
Recipient: University of York

Using examination questions to assess practical skills in science 26 Jun 2017

The principal aim of the project is to identify the features of written examination questions that discriminate between students who have had substantial hands-on experience of practical work in GCSE science and those who have not. This project is important because recent changes in assessment mean practical skills are now wholly assessed through written examination questions. It is therefore essential to have a valid means of assessing practical skills that rewards students who have undertaken hands-on practical work. A series of classroom interventions will be developed in which students experience a practical activity either as hands-on practical work, a teacher demonstration, a video recording, or through a written description. Students will then complete written examination questions relating to the interventions. The outcomes will be: examples of questions that discriminate between students with different levels of hands-on practical experience, together with insights into characteristic, generalisable features of such questions guidance for examiners to support them in question writing evidence of the validity of the use of written questions to assess practical skills with a view to informing future iterations of the science curriculum. The project Advisory Group comprises representatives of the Awarding Organisations, Ofqual, the learned societies, ASE and science teachers.

Amount: £210,838
Funder: The Wellcome Trust
Recipient: University of York

Re-Engineering Health Policy Research for Fairer Decisions and Better Health 01 Feb 2017

Health inequalities diminish lives and blight communities. Although the determinants of health inequality are well known, policy makers have repeatedly failed to address the issue effectively, and many public health interventions unwittingly worsen inequalities because they disproportionately benefit those with greater resources. This is also a scientific failure. The analytical tools used to inform policy lack a substantial perspective on equity, focusing on averages rather than social distributions, leading to inequitable solutions. In an age of social division driven by rising inequality, new approaches to health policy are urgently required. We propose to re-engineer health policy research. We will develop rigorous methods for measuring the equity impacts of health and social policy interventions, and apply these methods to assess the effectiveness of major public health and healthcare initiatives. In doing so, we will improve our understanding of the structural, behavioural and organizational barriers to delivering equitable health outcomes. Our programme will equip researchers with the necessary tools for measuring equity impacts, and provide policy makers with vital information on who gains and who loses from their decisions. Our ultimate aim is to enable fairer health policy decisions, leading to better health across society.

Amount: £872,588
Funder: The Wellcome Trust
Recipient: University of York

Regulation of immune checkpoint expression in human primary cells 31 May 2018

The host lab investigates post-transcriptional mechanisms that regulate expression of immune checkpoint membrane proteins in human primary dermal lymphatic endothelial cells (HDLECs) and dermal fibroblasts and recently demonstrated that PD-L1 is regulated by miR-155 (Yee et al., 2017, JBC). It has been suggested by others that resistance to therapeutic PD1 blockade is associated with alternative immune checkpoints in cancer cells, specifically the Gal9/TIM3 signalling axis. In this project, expression of Gal9 will be measured in unstimulated cells and cells treated with TNF and/or IFNg and upon over-expression or inhibition of miR-155. Experiments will be performed in both HDLECs and fibroblasts. Using already available small RNA sequencing data in the lab, miRNAs that can potentially suppress Gal9 expression and are significantly regulated upon treatment of HDLECs with TNF and IFNg will be identified. This will allow us to propose post-transcriptional regulatory networks that operate in non-transformed cells to control expression of a therapeutically relevant immune checkpoints. Training will include becoming familiar with cutting edge concepts in immunology and post-transcriptional gene silencing and techniques in primary cell culture and determining protein and mRNA expression, as well as extracting information from large transcriptomics datasets and using online in silico tools.

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

Digital Spatial Profiling in biomedical research 05 Jul 2018

The key aim of this application is to provide capacity for medium throughput targeted transcriptomic and protein expression analysis appropriate for, but not limited to, analysis of scarce and challenging clinical samples. Capital equipment costs are requested for the purchase of a Nanostring Digital Spatial Profiler (DSP) Instrument together with a nCounter Max Analysis System. The DSP will become available commercially in late 2018 and provides a unique approach to non-destructive multiplexed immunohistochemistry and gene expression profiling. Maintenance costs for a five-year period are also requested. To ensure effective, open access to this equipment for researchers across the region, salary support for a dedicated technician for a period of five years will be provided in kind by the University of York. This new 5 year post will be based in the Dept. of Biology’s Biosciences Technology Facility, a core facility with an international reputation for training and technology development in the area of imaging and cytometry. Continuation of this post beyond 5 years will be funded through new grant applications based on the use the instrumentation.

Amount: £449,360
Funder: The Wellcome Trust
Recipient: University of York

Probing the role of outer membrane transport processes in host-­pathogen interactions using computational and single-­molecule biophysical approaches. 31 Jan 2017

The outer membrane (OM) of Gram-negative bacteria is a significant protective barrier. It is composed of an inner leaflet of phospholipids and an outer of lipopolysaccharide (LPS) with OM proteins (OMPs) that span the membrane. Recently OMPs have been shown to be inserted at discrete and non-uniform locations across the membrane, where they remain due to restricted lateral diffusion. These ‘islands’ are pushed to the poles by cell growth, with new material inserted at mid-cell. OM turnover during bacterial growth may have a role in immune system evasion. One key mechanism regulating human immune responses is the assembly of complement components on the OM nucleated by immunoglobulin binding. This process can lead to lysis of bacteria through insertion of pore complexes in the OM. Complex formation depends on localised clustering of antibodies, which is constrained by the location and molecular diffusion of antigens in the OM. In this project we will use computational and single-cell biophysical techniques to test our hypothesis that spatial confinement of LPS and OMPs near their insertion sites influences activation of the antibody-mediated complement pathway. We will test our hypothesis in Escherichia coli and Salmonella typhimurium, where immune evasion has a key role in pathogenesis.

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

Characterising the composition of low temperature air plasma to assess applications for wound infection and healing 31 Jan 2017

Wound infections, coupled with increasing antibiotic resistance are a global issue, and low temperature plasma (LTP) presents an interesting alternative treatment strategy as it has been shown to be bactericidal and to promote wound healing. LTP is characterised by a low degree of ionisation, a non-thermodynamic equilibrium and a dry reactive environment. Here, we propose the development of a nano-/microsecond pulsed, kilohertz repetition frequency air plasma. The plasma will be characterised both experimentally and computationally, in terms of reactive oxygen and nitrogen species concentrations, optical emission and temperature. This is of interest when considering LTP as a low-cost wound treatment, as air plasma should not require expensive bottled gases, thus decreasing running costs and increasing transportability. In terms of biological interaction, the aim is to use the characterised plasma to correlate plasma composition with (1) the difference in tolerance to oxidative stress between bacterial and eukaryotic cells and (2) the effects of plasma on the dynamics of healing-related gene expression in epithelial cells post wounding. The project should offer new insights into the development and characterisation of air plasmas, and their potential for use in biomedical applications, in particular wound infection and healing.

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

The Rowntree Archives: Poverty, Philanthropy and the Birth of Social Science 18 May 2017

The project will arrange, describe, publicise and make publicly available the archives of the Rowntree Trusts and the Rowntree family for the first time. The outputs: open key 20th century archives on public health in the UK, including research about health problems caused by or related to alcohol, unemployment, housing, old age, and betting and gambling; open for research key records documenting the theory and practice of relationships between employers, philanthropy, social justice and public health; provide materials for researching the birth and early development of social science in the UK; will establish regular transfers of records from the Trusts to the Borthwick, thereby securing for public use records yet to be created. We will do this by creating fully searchable online finding aids to international standards, with authority files and access points mediated by current experts in the field, and links to related archives in York and elsewhere. The project’s success measures are: the production of publicly accessible online catalogues; the creation of research projects based on the archives; securing a sustainable future for the archives, including future archives.

Amount: £114,930
Funder: The Wellcome Trust
Recipient: University of York

Understanding Leishmania parasite populations in Brazil. 05 Sep 2017

Leishmaniasis is a globally distributed disease of poverty that infects 700,000 people annually. It is caused by Leishmania parasites, spread by sand flies. The most severe form, visceral leishmaniasis (VL), is generally fatal if untreated. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the disease burden. Leishmania infantum was introduced to Brazil from the old world, and is becoming more common with urbanization, with 6,000 cases of VL in Brazil each year. There are indications of resistance to miltefosine in Brazil, which is an effective drug in other continents. Key goals of this project are to establish an understanding of the dispersal and evolution of Leishmania infantum in Brazil, which will be critical aspects of disease control. To achieve this, we will sequence the genomes of 200 strains of this parasite that have collected from two locations in Brazil that are 1600 km apart, and includes strains archived 20 years ago. By examining the movement of alleles between sites and over time, we can measure migration rates, recombination rates and screen for adaptive evolution. We will also analyse clinical data to examine whether parasite genes influence disease severity.

Amount: £94,476
Funder: The Wellcome Trust
Recipient: University of York

Science is for Parents Too - Extension. 16 Sep 2013

The project will promote adult engagement with biomedical sciences through a sustained learning programme for parents (with limited scientific education) of primary school children. As a result of this science enrichment initiative, parents will be better able to support their children's education and career options with regard to the sciences. Broadly aligned to the Key Stage 2 science curriculum, we will focus primarily on biomedical science, with elements of complementary chemistry, physics a nd maths through a biomedical lens to demonstrate the relationships between the sciences. Our proposition is that raising aspiration is best effected by cascading learning through the family, to ensure that education becomes recognised as a viable proposition for all within a household. The intention is to make an impact on both the adults who engage directly and their immediate family circle, in an attempt to make bioscience a topic for family conversation, encourage scientific questioning, and erode past negative experiences. The learning experience will be delivered in a creative and imaginative way, with practical demonstrations of concepts, complemented by science site visits and experiments which can be undertaken with the family. We perceive this as a pilot which will develop a sustainable teaching resource that could be deployed elsewhere. It will be delivered in partnership with the National Science Learning Centre which will host taught sessions; the possible longer-te rm ambition however is to upscale the project and deliver via the regional Science Learning Centres and NSLC partners in the devolved nations, to gain national coverage.

Amount: £29,560
Funder: The Wellcome Trust
Recipient: University of York

Systems Investigation of Germinal Centre Formation. 24 Jun 2013

Invading pathogens can rapidly infect tissues inducing pathology. The immune system has developed an efficient mechanism for creating large amounts of highly specificantibodies through B lymphocytes undergoing affinity maturation in the germinal centre. The spatial organisation of a germinal center is a key determinant of its efficacy. In order for B cells to achieve high levels of affinity and avidity they must shuttle betweentwo anatomically distinct areas under the influence of specific chemokine gradients. However, the key mechanisms leading to germinal centre formation and chemokine field induction are not well understood. This leads us to ask the following question: Given that germinal centres are heterogeneous structures, how do chemokine mediated signals affect their formation and subsequent spatial organisation; thus determining protective immunity? We propose to combine in silico multi-scale modelling with in vivo experimentation to address our research question and ultimately to gain a novel mechanistic understandingof a complex biological process.

Amount: £149,673
Funder: The Wellcome Trust
Recipient: University of York

Modelling RNA regulatory networks in infectious disease 18 Dec 2012

The strength and duration of the innate immune response is regulated at the post-transcriptional level by miRNAs. miR-132 has been previously shown to suppress the anti-viral response. Interestingly, a miR-132 predicted target is ARGONAUTE-2 (AGO2), a protein involved in miRNA biogenesis and function. These findings create an opportunity to investigate the interaction between miR-132 and AGO2 in the context of the innate immune response. We aim to study the effect of miR-132 on the functional activity of AGO2 in an experiment-and-modelling coupled approach by (a) measuring the abundance of relevant components of the miR- 132/AGO2 interaction system in vitro and ex vivo, and (b) building an agent-based model (ABM) of the interaction in the context of viral infection and the immune response.

Amount: £4,555
Funder: The Wellcome Trust
Recipient: University of York

Dissecting bacterial interactions with the urothelium using emergent mass al spectrometry techniques 25 Jun 2012

Urinary tract infections (UTI) caused by uropathogenic E. coli (UPEC) cause significant levels of morbidity across a broad spectrum of clinical populations. The urothelium is recognised as an active tissue, with important roles in damage response and sensing within the bladder, including its role asthe primary effector of the immune response to UPEC infection. Previous work in the Southgate group has shown that diffusible mediators, such as ATP, play an important role in urothelial response to damage and healing. Evidence exists that extracellular ATP can also stimulate bacterial biofilm formation, offering protection against the immune response. The effects of UPEC-urothelial interaction and its respective effects on UPEC phenotype ad urothelial homeostasis are poorly understood. We aim to develop state of the art mass spectrometry techniques to enable the analysis of the intracellular metabolome and the extracellular secretome of normal human urothelial (NHU) cells in order to further understand the role that diffusible mediators play in the interaction between the urothelium, UPEC, and the urothelial response to damage and repair.

Amount: £150,048
Funder: The Wellcome Trust
Recipient: University of York

Systems Investigation of Germinal Centre Formation. 30 Jan 2015

Invading pathogens can rapidly infect tissues inducing pathology. The immune system has developed an efficient mechanism for creating large amounts of highly specificantibodies through B lymphocytes undergoing affinity maturation in the germinal centre. The spatial organisation of a germinal center is a key determinant of its efficacy. In order for B cells to achieve high levels of affinity and avidity they must shuttle betweentwo anatomically distinct areas under the influence of specific chemokine gradients. However, the key mechanisms leading to germinal centre formation and chemokine field induction are not well understood. This leads us to ask the following question: Given that germinal centres are heterogeneous structures, how do chemokine mediated signals affect their formation and subsequent spatial organisation; thus determining protective immunity? We propose to combine in silico multi-scale modelling with in vivo experimentation to address our research question and ultimately to gain a novel mechanistic understandingof a complex biological process.

Amount: £39,262
Funder: The Wellcome Trust
Recipient: University of York

Medical transformation in Madras Presidency: Military and Civilian perspectives (1890-1940) . 12 May 2015

1) An investigation into the growth of complexity of military medicine and the ways in which it shaped colonial medical policy. 2) An examination of military medicine as a laboratory of clinical, technological and public health innovations, including trials which were later expanded across colonial Madras. 3) An exploration of the transfer of techniques and technology considered successful in these contexts to the civilian medical sphere, through Indian Medical Service officials (in government - and privately-funded medicine). 4) An assessment of the variations within urban contexts, as well as urban-rural differences. Based on an analysis of discussions and debates between IMS and Subordinate Medical Service officials, as well as an analysis of official reports, medical journals and newspapers. 5) An investigation of what is best described as a counter-narrative of success, which often took the shape of arguments about the dangers, limits and expense of new technologies. An examin ation of how these influenced military, civilian, indigenous and European perceptions within Madras Presidency, in relation to what was classed by the colonial authorities as being cutting edge medical technologies and care protocols.

Amount: £123,582
Funder: The Wellcome Trust
Recipient: University of York

Biomedical Vacation Scholarship 25 Jun 2012

Not available

Amount: £7,200
Funder: The Wellcome Trust
Recipient: University of York

Open access award. 20 Sep 2011

Not available

Amount: £60,000
Funder: The Wellcome Trust
Recipient: University of York

Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS) - 'Application of plasma technology for the elimination of intracellular infections in vitro' 31 Aug 2011

Currently, limited approaches are available to treat infections due to inherent and acquired resistance to existing drugs. Ionised gas or "plasma", the fourth state of matter, is of interest for biomedicine for the production of reactive species, electrons, ions and UV light. Plasmas have been demonstrated to have antimicrobial properties. They can eliminate free-living microorganisms in a time- and dose-dependent fashion; however, it is unknown whether they could clear intracellular infections without damaging the eukaryotic host cell. In this project, the student will address the hypothesis that an atmospheric pressure dielectric barrier discharge (AP-DBD) plasma jet can eliminate intracellular pathogens in macrophages without affecting the integrity and viability of the host cell. This will be a proof-of-principle study using intracellular growth within a macrophage of the bacterial pathogen Salmonella enterica in vitro as a model. We will define parameters for reproducible plasma treatment with AP-DBD plasma jet and will identify the main biological

Amount: £146,502
Funder: The Wellcome Trust
Recipient: University of York

Gene Transfer Agents: Prevalence, Biology and Impact on Bacterial Genetic Diversity. 21 Oct 2015

Gene transfer agents (GTAs) have been discovered in diverse prokaryotes, however, the prevalence of functional GTAs in pathogenic species is unknown. I have preliminary evidence that GTAs are present in numerous pathogens and experimental evidence of GTAs in Burkholderia. This project aims to understand the role of GTAs in the evolution of bacterial pathogens. Specifically: 1) To gain an understanding of the prevalence of GTAs in pathogenic bacteria by screening a bank of pathogenic bacteria for GTA production (e.g. Pseudomonas, Burkholderia, Neisseria, Clostridia). Discovery of a broader database of functional GTAs will allow robust identification of GTAs by bioinformatics. 2) To assess the impact of GTAs on the transfer of antibiotic and virulence genes between pathogenic bacteria using microcosms that approximate environmental and clinical conditions, and by exposing the producer bacteria to environmentally relevant stresses such as antibiotics or competitor species. 3) To understand the regulation of GTA induction using a bespoke flow cytometry cell sorting technique to separate GTA-producer cells from non-producers for analysis with transcriptomic and epigenetic analyses. 4) To determine the mechanism of random DNA packaging using in vitro and in vivo packaging assays based on established techniques from enterobacteria phage T4.

Amount: £847,836
Funder: The Wellcome Trust
Recipient: University of York