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Results

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

Middle Income Country Solutions for a Global AMR Problem: Innovative health financing and the regulation of ‘essential antibiotics’ in Sri Lanka 24 Jan 2017

This project will study the complex bases and impact of Anti Microbial Resistance (AMR) on healthcare in Sri Lanka. Adopting a critical, historical approach, this will be a study of the evolution of antibiotics importation and distribution policies, their connections with the logic and politics of primary health care and universal health coverage, and the interactions between all these trends and the work of the UN, the WHO and their regional and country offices in South Asia. This historical assessment will problematize current government and WHO arguments about AMR and allow critical analysis of current policy trends. Using systematic reviews and health economics to develop a an understanding of current antibiotic use and AMR incidence in hospitals in the country, I will then work towards creating innovative and pragmatic health financing models for regulating the so-called ‘essential antibiotics’. The project’s findings will also be researched and discussed through two WHO Global Health Histories seminars, in Colombo and Copenhagen, that will involve representatives from the WHO HQ, Regional Offices and Country Offices in South Asia, as well as national governments from around the world. The event will be co-organised with the WHO Regional Office for Europe and the Sri Lankan Government.

Amount: £314,996
Funder: The Wellcome Trust
Recipient: University of York

Enhancing electron microscopy facilities at the University of Sussex with High-Pressure Freezing technology 06 Jul 2017

We are requesting a high-pressure freezer (HPF) and freeze-substitution processor (FSP) at the University of Sussex to substantially enhance our transmission electron microscopy research and meet significant unmet demand. HPF/FSP is now the de facto standard for the highest-quality specimen fixation for ultrastructural work, offering key benefits for protein integrity, ultra-rapid controlled fixation, fluorescence preservation for correlative work and penetrative thick-sample fixation. The requested system includes modules for synchronizing optogenetic/electrical stimulation with freezing onset, offering revealing ‘snapshot’ views of rapid and dynamic events. Collectively, these advantages will open up major new directions for existing research programs within the School of Life Sciences, and wider afield. Planned research includes studies aimed at: defining synaptic vesicle recycling pathways in central and sensory terminals, revealing ultrastructural correlates of disease-related neuronal dysfunction, elucidating chromosomal breakage events during mitosis, investigating ultrastructural determinants of centrosome positioning, and characterizing protein organization in ionizing radiation-induced foci. The School has made major recent strategic investment in developing world-class electron microscopy facilities and the HPF/FSP will offer significant enhancements to this equipment for ultrastructural research. The system will be fully-integrated into the new purpose-built Life Sciences building (completion 2019-2020) ensuring its long-term sustainable use within a state-of-the-art dedicated Bio-Imaging centre.

Amount: £337,311
Funder: The Wellcome Trust
Recipient: University of Sussex

Memory and silence: The role of miRNA machinery in tolerisation of macrophages 31 Jan 2017

Macrophages are key mediators of immune responses. Upon encountering microbial antigens, macrophages become activated, which results in pathogen phagocytosis and clearance, and initiation of the adaptive immune response through antigen presentation and inflammatory cytokine secretion. However, uncontrolled macrophage activation can lead to acute systemic inflammation and organ damage (septic shock). Interestingly, exposure to low levels of antigen results in macrophages becoming hypo-responsive following subsequent stimulation (macrophage tolerisation). Furthermore, myeloid cells within a tissue display remarkable heterogeneity in cytokine production. However, the role of population heterogeneity on macrophage tolerisation remains unknown. MicroRNAs are small regulatory RNAs that repress gene expression. They can also decrease noise (stochastic fluctuations) in protein expression and regulate cell-to-cell variability of gene expression. We propose that microRNA-mediated regulation of population heterogeneity is a key mechanism involved in macrophage tolerisation. Here, we will characterize population heterogeneity in wild type and microRNA-deficient (globally or single microRNA) macrophages. We will generate stochastic models to predict phenotypic (tolerisation) switches and validate mathematical outcomes empirically. This research will demonstrate how microRNAs regulate innate immune responses and provide new routes to improve infection and vaccination outcomes.

Amount: £16,771
Funder: The Wellcome Trust
Recipient: University of York

Multi-modal sensors for phenotyping antibiotic resistance. 31 Jan 2017

Anti Microbial Resistance (AMR) is predicted to cause 10 million deaths a year by 2050. The over prescription of antibiotics has contributed significantly to AMR development and there is a clear need for rapid point of care antibiotic susceptibility assays for clinicians. Global surveillance of AMR molecular mechanisms is also essential for informing healthcare strategy. Genetic profiling alone cannot reliably predict AMR and needs to be complemented with phenotypic assays. Urinary Tract Infection (UTI) causing pathogens such as Uropathogenic Escherichia coli (UPEC) are widely resistant to first line antibiotic treatments such as trimethoprim and last-resort drugs such as colistin, and are a cause of significant morbidity and mortality in patients. The prevalence of AMR UPEC make them ideal candidates for developing new AMR assays. This project aims to develop an on-chip multi-modal sensor capable of antibiotic susceptibility and phenotypic profiling assays to provide point of care diagnostic information to clinicians and epidemiological data for AMR surveillance. Electrochemical and photonic crystal biosensors will be integrated into a Digital Microfluidic system to quantitatively detect antibiotic susceptibility by measuring bacterial growth, metabolism and death and AMR phenotypic mechanisms by detecting enzymatic activity and mRNA expression.

Amount: £0
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

China in the Worldwide Eradication of Smallpox, 1949-1980: Recovering and Democratizing Histories of International Health 02 May 2017

The People’s Republic of China (China) exited the WHO and the UN in 1949-50 in protest against the USA’s promotion of China Taipei in the international arena. China remained an ally of the USSR and Warsaw Pact signatories between 1950-1970, responding to Soviet exhortations to expunge smallpox in the early 1950s by creating new epidemiological and vaccination networks. Whist both countries made significant progress in limiting the disease, they struggled to achieve eradication in the face of re-importations from neighbouring countries. Therefore, China worked with the USSR on global eradication efforts from outside WHO-sponsored structures, assisted by the infusion of significant aid – in the form of advisors, public health personnel, vaccine, vaccinating kits, money and technology transfers – from the USSR, Yugoslavia, Czechoslovakia and, latterly, Sweden. Comprehensive vaccination and re-vaccination programmes resulted, allowing China to proudly announce smallpox eradication in the mid-1960s (certified by WHO delegations and an independent international team in the mid-1970s). Unused Swedish aid was returned to a cash-strapped WHO through ostentatious, public ceremonies in Beijing; this money helped Indian, Bangladeshi and East African programmes conclude successfully. I will study how all these inter-linked developments combined to achieve smallpox eradication in 1980.

Amount: £123,951
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

Structure and mechanism of nucleic acid-processing machines in viral biogenesis 05 Apr 2017

The research will focus on analysing the structure and mechanism of nucleic acid machines involved in viral biogenesis. Although the main emphasis is on using structural approaches such as X-ray crystallography and Cryo-EM; we will also use complementary biophysical techniques including surface plasmon resonance, fluorescence-based activity/binding assays, analytical ultracentrifugation and SEC-MALLS, to define composition and stoichiometry of protein-nucleic acid complexes, in addition to the affinity of the interaction. Key goals: To continue investigation into the mechanism of dsDNA packaging motors present in tailed bacteriophages and the closely related human herpes viruses. To obtain high-resolution asymmetric cryo-EM reconstructions of an active motor assembled from components derived from a themostable bacteriophage. To understand the structure-function relationship in FtsK-like DNA packaging motors present in another large class of dsDNA viruses comprising bacterial tectiviruses and eukaryotic poxviruses. To investigate the mechanism of RNA unwinding by 2C helicases present in enteroviruses (such as poliovirus) and to define the RNA-binding surface of the Zika Virus NS3 helicase. To perform pilot studies on exploiting this information for identifying lead compounds for the development of antivirals.

Amount: £1,806,188
Funder: The Wellcome Trust
Recipient: University of York

Mechanisms of cell surface recycling pathways 26 Oct 2016

Cell surface proteins continually recycle through endosomes, where trafficking decisions control protein levels and activity. Yet, we have limited understanding of the mechanisms that regulate this recycling. I have identified a direct trafficking pathway from endosomes back to the plasma membrane in yeast, and have used genetic approaches to identify machinery that controls this. The majority of candidates identified are highly conserved; I now plan to define the fundamental mechanisms used by these molecules to control recycling. My key goal is to understand three specific regulatory units that I hypothesize are required for endosomes to create recycling tubules, into which cargoes are packaged and delivered back to the plasma membrane. I propose experiments to test three specific hypotheses: 1) Nhx1 elevates osmotic pressure in endosomes to drive recycling tubule formation, 2) Rag GTPases catalyse recycling tubule morphogenesis and drive selective cargo sorting, and 3) Ist1 polymerises on endosomes to drive scission of the recycling tubule. These yeast proteins all have clear human orthologues, and a series of experiments is aimed at testing these human versions in recycling. Importantly, I plan to extend these studies in human cells, to validate conserved recycling mechanisms identified in yeast and reveal additional mechanisms.

Amount: £770,616
Funder: The Wellcome Trust
Recipient: University of York

Vacation Scholarships 2017 - University of York 16 Jun 2017

Vacation Scholarships 2017 - University of York

Amount: £5,500
Funder: The Wellcome Trust
Recipient: University of York

Smuggling small molecules probes into bacteria cell walls: a strategy for the selective fluorescent labelling of Vancomycin resistant strains 27 Apr 2017

Vancomycin inhibits bacterial cell wall synthesis by binding to the D-Ala-D-Ala motif integral to peptidoglycan synthesis. However, in a unique resistance mechanism the VanA operon reduces Vancomycin binding affinity for peptidoglycan by exchanging an amide bond for a depsipeptide ester bond; D-Ala-D-Ala into D-Ala-D-Lac. D-Ala is used by bacteria only in peptidoglycan synthesis, which has enabled fluorescent labelling of peptidoglycan cell walls in a range of bacteria, by feeding cells unnatural azides, or alkynes. The azide/or alkynes are incorporated into peptidoglycan and then tagged with fluorescent markers and subsequently imaged. Our strategy is to feed bacteria unnatural D-Lac mimics, as opposed to D-Ala, which should only be metabolically incorporated into peptidoglycan if the VanA operon is present. We will synthesise a range of simple small molecule probes, containing azide, alkynes or even whole fluorophores, in a D-Lac or depsipeptide scaffold and then screen enzymes from the VanA operon in vitro to determine their affinity for unnatural substrates. We will then use these substrates for metabolic feeding to Vancomycin resistant bacteria, using Van resistant Enterococci strains, before finally labelling the peptidoglycan on the cell surface and performing fluorescence miscroscopy imaging studies.

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

Neurophysiological and pharmacological analysis of a fruit fly model of epilepsy 27 Apr 2017

Epilepsy is as a result of overactive neurons exhibiting abnormal activity. The Kcc2 ion channel in neurons is a cause of juvenile epilepsy. We will use drosophila containing the Kcc2 dysfunctional mutant, which is thought to display epileptic tendencies, to display their use as a good model for epilepsy. Drosophila are known to be a good model to study disease, so they will prove to be useful to study epilepsy with. We will prove drosophila to be a useful model using electroretinograms to measure epilepsy displayed in the kcc2 mutant flies. We will test the change of behaviour when treated with the anti-epileptic drug, phenytoin, which should restore some normal function in the flies. Followed by the kcc2 channel inhibitor VU0240551, which in turn should cause a pro-epileptic response in the fly. Using the electroretinogram, this observation should be picked up, thus proving that the drosophila ERG can be used as a reliable model of epilepsy. This can therefore lay groundwork for research into therapeutics and further understanding of drosophila circuitry.

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

Does N1-Src drive neurite outgrowth through N-WASP? 27 Apr 2017

The ubiquitous tyrosine kinase, Src, has a fundamental role in signalling pathways that drive proliferation, adhesion and migration. Src is enriched in the brain, but also undergoes alternative splicing in neurons to yield N1- and N2-Src. The N-Srcs have small inserts in their SH3 domain, a region involved in substrate specificity and kinase activity, and have been implicated in neuronal development and as a prognostic indicator of the childhood cancer, neuroblastoma. We and others demonstrated that the N-Srcs drive neuronal morphology by rearranging the actin cytoskeleton. To discover the physiological substrates of N1-Src, we undertook a pulldown using the N1-Src SH3 domain. A promising candidate was N-WASP, a regulator of the Arp2/3 complex that promotes actin polymerisation and has been implicated in neurite outgrowth in neurons. This project aims to confirm if N1-Src acts through N-WASP to elicit neurite outgrowth. The specific goals are to i) investigate the tyrosine phosphorylation of N-WASP by N1-Src and ii) establish the effect of manipulating N-WASP activity upon N1-Src-dependent neurite outgrowth in cells. The project will therefore provide an excellent grounding in molecular research approaches and insight into the function of a gene relevant to neuronal development and disease.

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

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £1,500,000
Funder: The Wellcome Trust
Recipient: University of York

Global Atlas of Podoconiosis 22 Jun 2016

In 2011, podoconiosis was identified as one of the Neglected Tropical Diseases by the World Health Organization. Many questions remain, however, about the geographical distribution and burden of podoconiosis globally. These include; what is the global distribution of podoconiosis, what global burden does it impose, are factors associated with podoconiosis universal or country specific, and what is the cost of podoconiosis control and elimination? This fellowship will enable these questions to be answered. The proposed work will build upon a nationwide mapping technique which was applied in Ethiopia. First, I will test the universality of factors associated with podoconiosis by conducting a nationwide survey in Cameroon. Second, I will investigate the spatial distribution of podoconiosis globally by conducting surveys and applying geostatistical and boosted regression modeling. Third, I will quantify the population at risk globally and the number of people affected, using a Bayesian meta-regression method, DisMod-MR, employed by the Global Disease Burden studies, to estimate the disability adjusted life years (DALYs) attributable to podoconiosis. Fourth, using a micro-costing approach that allows adjustment for time-variant resource utilization and for heterogeneity, I will estimate the cost of control and elimination. Findings will directly inform the global control and elimination of podoconiosis.

Amount: £660,064
Funder: The Wellcome Trust
Recipient: University of Sussex

The alcohol industry, public health sciences and policy 26 Jan 2016

Society benefits from evidence informed public health policies. Effective and cost-effective policies are needed to ameliorate the large societal and public health burdens of alcohol. Alcohol policy making is undermined by the influence of vested interests, which results in ineffective policies lacking evidential support. This research will develop our understanding of the roles the alcohol industry plays within the UK policy making context and more broadly in influencing global research agendas, science and policy. This research encompasses study of how industry actors influence the processes of evidence production, how evidence is managed within the political strategies of industry actors, and the impacts evidence management has within the policy making process. The research will initially develop a new platform to capture publicly available data and undertake a series of systematic reviews. These will inform subsequent interview, documentary and multi-method studies investigating corporate actors, public health sciences and the science-policy interface. Ethical implications for research will be explored. A public engagement project will be developed with UK policy makers and civil society organisations. The programme will advance global research agendas on vested interests, science and policy, and inform national and international alcohol policies, contributing more broadly to effective population-level prevention strategies.

Amount: £991,008
Funder: The Wellcome Trust
Recipient: University of York