NIHRDataInsights/HRCSData huggingface dataset:
Title: The C-MaMiE birth cohort: evaluating the impact of free healthcare on child and family outcomes in Ethiopia .
Funder: Wellcome Trust

Abstract: Charging for healthcare in developing countries is controversial, seeming to be an obstacle to health care for the poorest and most vulnerable sectors of society, yet hardly any studies have looked at whether it actually affects health status. An existing Wellcome Trust-funded study (the C-MaMiE study) recruited 1065 pregnant women in 2005/2006 and is continuing to follow-up the mothers and the project child until six years of age. C-MaMiE mothers/children have benefitted from free healthcare at the point of use for most of the follow-up time which provides a golden opportunity to measure the health impact of free care. We will compare the C-MaMiE mothers/children to a group of mothers/children from the same area who were not part of the study and so haven t received free healthcare. We expect that free healthcare will lead to better physical and mental health of mothers/children as well as lower poverty levels, and that this in turn will lead to lower levels of child malnutrition and death. We will obtain important information about the cost-effectiveness of providing free healthcare and, by talking to women about their experiences, improve our understanding of the factors affecting decisions to seek formal health care in response to illness.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Prognostic factors and outcomes for medical emergency admissions.
Funder: Wellcome Trust

Abstract: There are often large differences in prognosis following admission as an emergency across hospitals in the UK. Although some of this variation is linked to differences in the types of patient who are admitted to different hospitals in terms of their age and how ill they are the reasons for much of the variation in death rates is not known. It is also unclear whether this variation across hospitals extends to morbidity outcome measures including hospital infections and high rates of readmis sion. We have designed a large record linkage study across England and Wales that will gain important new insight into factors that are, increasingly, thought to have a possible influence on mortality after emergency hospitalisation. For example, we will establish the extent to which outcomes vary according to whether people are admitted at weekends rather than during the week, according to the size of the hospital, and the specialist services provided by the hospital. We will also establis h whether outcomes have changed over time during the last five years, and determine how they vary according to the condition the patient is admitted for. The study will provide important new findings that will help inform service provision.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Multiple molecular mechanisms of pathogen recognition by glycan-binding receptors.
Funder: Wellcome Trust

Abstract: Different cells are characterised by different patterns of sugars on their surfaces. Receptors that recognise these sugars therefore have the potential to distinguish between different cells within multicellular organisms and also can be used to identify bacteria, viruses, fungi and parasites. Our work is focussed on a family of human sugar-binding receptors that function in the immune system, binding to surface sugars on pathogens and providing innate protection that is particularly important i n early responses to infections. Our goals are to understand how these receptors bind to the diverse sugars found on different types of bacteria and fungi and how they bind selectively to viruses. We particularly aim to understand what can go wrong in human diseases, when variant forms of the receptors result in susceptibility to disease and when viruses such as HIV and Ebola virus subvert them as a means of infecting cells. We are seeking to demonstrate if blocking some receptors may be a way t o prevent attack by viruses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: SPRING (for MDGs): Sustainable Programme Incorporating Nutrition & Games (for Maximising child Development, Growth & Survival in disadvantaged populations).
Funder: Wellcome Trust

Abstract: A large number of children in developing countries lack access to known effective interventions. Almost 9 million die each year before reaching their fifth birthday, and over 200 million children who survive fail to achieve their full growth or developmental potential, trapping them in a cycle of continuing disadvantage. The goal of SPRING, Sustainable Programme Incorporating Nutrition & Games, is to develop an innovative approach to close this access gap, in two of the worst affected countries India and Pakistan using existing community-based agents (CBAs). Extensive formative research will be carried out to help ensure that the content and approach of the SPRING intervention is feasible, acceptable and appropriately targeted. Findings will be reviewed at an intervention development workshop with local and international stakeholders and experts, and the agreed intervention piloted with a few CBAs and their supervisors. Cluster randomised controlled trials will be carried out in ea ch setting to evaluate the impact of SPRING on child growth, development and survival. The programme will include process and economic evaluations to provide information on the total cost of the intervention and its cost effectiveness, as well as development of a framework with lessons learned for implementing SPRING in other settings.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Equitable Access to Human Genetic Resources - Balancing Benefit Sharing and Undue Inducement.
Funder: Wellcome Trust

Abstract: The broader research question (How can access to human genetic resources, suchas blood or DNA samples, be governed to achieve justice for developing countries?) requires the completion of the following tasks: Detail the justice issues arising from accessing human biological resources in developing countries (e.g. contribution to research without access to resulting, life-saving products). Map identified justice issues onto relevant justice theories (e.g. cosmopolitanism, human rights framework). The specific research question (How can benefit sharing be achieved without undue influence through inappropriate inducement?) necessitates the completion of the following tasks: Describe existing benefit sharing mechanisms. Explore what types of benefit sharing mechanisms, if any, amount to undue inducement. Examine current proposals for overcoming the problem (e.g. expanding the CBD) The PhD will close a remaining gap in the current research on benefit sharing by producing recommendations for the equitable access to human biological resources in developing countries.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: UK Biobank: Past progress and future plans for 2010-2015 renewal application
Funder: Wellcome Trust

Abstract: Recruitment into UK Biobank of 500,000 men and women aged 40-69 began in April 2007 and will be completed by July 2010. Previous epidemiological studies have typically been characterised by relatively small numbers of disease cases (which may yield unstable estimates due to random variations); inadequate measures of risk factors (which may yield systematic under-estimates of disease associations); inadequate measures of confounders (which often yield over- or under-estimates); and/or retrospecti ve case-control designs in which the disease may influence risk factor levels ( reverse causality ). By contrast, in UK Biobank, extensive questionnaire data, physical measurements and biological samples have been collected from a very large number of participants. During the next 5 years, major activities will involve: careful curation of the participants samples and data; repeat assessments of subsets of the cohort to allow variation in baseline assessments to be taken into account; linkage t o participants medical and other health-related records to identify prevalent and incident disease; and central adjudication of such information to facilitate the efficient, consistent and rapid use of the resource. UK Biobank will also establish processes and systems that support controlled access to the resource so that research groups can exploit its value fully.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Historical Collections at the John Innes Centre: Improving Access and Usage
Funder: Wellcome Trust

Abstract: This proposal is for £122K for professional archival input into key resources of the John Innes Foundation Historical Collections at the John Innes Centre in Norwich. To help develop the management and broaden the public accessibility of our outstanding material we propose the appointment of a mid-career part-time archivist for 36 months and a budget for associated re-cataloguing into the CALM archive cataloguing software, preservation and conservation resources. We envisage the following steps: a review of our preservation needs and the implementation of conservation measures, the creation of a modern on-line archive catalogue that is compliant with other libraries, and, after these preparatory steps, digitisation of unique materials for the history of genetics. We are willing to share our digital resources with the Wellcome Library. Both the John Innes Foundation Trustees and the John Innes Centre are committed to widening access to resources for the history of genetics. This proposal focuses on key resources within the John Innes Archives and the History of Genetics Library and in particular the collections of two key figures in the early history of genetics: William Bateson and Cyril Dean Darlington.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Using molecular dynamic simulations and diffration pattern prediction as a tool to enable time resolved structure determination
Funder: Wellcome Trust

Abstract: I propose to develop a method for TR structure determination that uses changes in signature reflections to differentiate between alternative structural models and overcome the need for a state reversible system. To achieve this, the following specific aims are proposed: (1) Establish the feasibility of using diffraction pattern simulation software to identify signature reflections that report on local structural changes. (2) Predict the structures of intermediates along reaction pathways using modeling and computational approaches. (3) Experimentally characterize, in a time-resolved fashion, intensity changes in predicted signature reflections as a proof of principle of this approach.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: A Legal and Ethical Analysis of Research Risks Imposed on Children Involved inCluster Trials With More Than Minimal Risk Conducted Between1999-2010 in Kenya.
Funder: Wellcome Trust

Abstract: 1) Review and categorise research risks children are exposed to in different types of 'cluster trials', and explore how these risks are currently regulatedif indeed they are; 2) Test the traditional account of proxy consent and best interests within this context, 3) Examine how the concept of 'minimal' risk is used to see whether it serves to protect or exploit children's multiple vulnerabilities during cluster trials. Key output & goals: mapping and inventory of clinical trials with children andof regulatory framework, critical review of regulatory framework for research involving children, practical suggestions for strengthening local approaches, the engagement of local stakeholders in the review and in the suggestions.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular, genetic and lifecourse epidemiology
Funder: Wellcome Trust

Abstract: The aim of this PhD .is to explore the potential association of quantitative molecular genetic markers in human complex traits and to this end establish reproducible, high throughput quantification techniques for use in large cohort studies. 1) Lab work: Produce protocols that are reliable, accurate, reproducible and high throughput for use in large cohorts. I will develop novel protocols for mtDNA copy number and Telomere quantification and apply an existing protocol for CNV. 2) Application: Due to the variation of these markers in the population and the known functions and preliminary associations reported in the literature one can hypothesis that variation in the population of these markers will indeed have an effect on many common complex disease risk factors related to the functional pathways of the markers. Therefore will explore the relationships between these quantitative genetic markers and common complex disease traits in the Avon Longitudinal Study of Parents and Children (ALSPAC), British Women's Heart and Health Study (BWHHS) and The Caerphilly Prospective Study (CAPS) cohorts.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell Biology: Structural studies on the Dim2-Nob1 complex and investigation of its role in ribosome biogenesis.
Funder: Wellcome Trust

Abstract: The aim of the research proposed in this report is to characterise the interaction between two eukaryotic proteins needed for ribosome biosynthesis: Dim2 and Nob1. The following sub-aims have been created for this purpose: To express and purify the Saccharomyces cerevisiae and/or human proteins To assemble the Dim2-Nob1 heterodimer in vitro To characterise the dimer structurally and biochemically To characterise interactions of the dimer with ribosomal RNA (rRNA) and answer the key questions: How does the presence of Dim2 affect Nob1-RNA interaction? Does Dim2 have an effect on the D-site cleavage by Nob1? To verify interactions and functions observed in vitro using in vivo systems.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell Biology: Investigating the role of Sir2 in centromere function in Schizosaccharomyces pombe.
Funder: Wellcome Trust

Abstract: Centromeres are the chromosomal locations where kinetochores are assembled. Underlying the kinetochore are arrays of unusual nucleosomes in which canonical histone H3 is replaced by the centromere specific histone CENP-A which forms the foundation for kinetochore assembly. A key question is how is CENP-A directed to centromeres rather than other chromosomal locations. A characteristic of eukaryotic centromeres is the presence lysine 9 methylated H3 heterochromatin adjacent to the kinetochore. We have previously shown that this centromeric heterochromatin is required to establish CENP-A heterochromatin and kinetochores on centromeric DNA in fission yeast, Schizosaccharomyces pombe. Our unpublished analyses indicate that the histone deacetylase Sir2 is required to establish CENP-A chromatin at fission yeast centromeres. Surprisingly, we recently found that Sir2 associates with two subunits of monopolin (Mde4 and Pcs1) which is known to be enriched at kinetochores. This project will further dissect the relationship between monopolin and Sir2 and the role of Sir2 in promoting kinetochore assembly. The project has three integrated aims: Aim1: Investigate whether monopolin subunits (Mde4 and Pcs1) are required for CENP-A chromatin establishment and other centromere functions. Does CENP-A assemble de novo on centromeric DNA in the absence of monopolin? Aim2: Determine Sir2, Mde4 and Pcs1 cellular and genomic localization and dependency relationships through the cell cycle. Does Sir2 localisation at centromere depend on Mde4/Pcs1 and vice versa? Aim 3: Determine the features required for Sir2, Pcs1 and Mde4 recruitment to centromere sequences. Is Sir2 recruited independently by heterochromatin? Does association with monopolin in the central domain require heterochromatin?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell Biology: An investigation into links between transcription, chromatin and splicing.
Funder: Wellcome Trust

Abstract: This project aims to elucidate how splicing, transcription and chromatin communicate and influence each other (Figure 1). The chromatin state is known to affect and be affected by transcription6,7,9, and there is also evidence for functional links between transcription and splicing10,11. Emerging evidence now suggests that there may be reciprocal coupling between the chromatin modification state and splicing in mammalian cells12-15. This project will investigate these links in budding yeast, aiming to identify the molecular basis of links between splicing and chromatin and how this relates to RNAPII pausing. Specific aims: Determine whether perturbations to splicing cause changes to chromatin modification, especially H3K36 methylation Determine whether there is a reciprocal effect of H3K36me3 on splicing Establish whether histone methylation marks are lost actively or passively Determine whether histone modifying enzymes are recruited to the paused polymerase Identify factors that link splicing and chromatin


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Elucidating the molecular networks that regulate polarized cell growth, using functional genomics.
Funder: Wellcome Trust

Abstract: Almost every living cell must maintain some degree of polarity, whether permanent or transient, in order to live and function correctly. There are many obvious examples of cell polarity provided by the mammalian system, including epithelial cells, neurons and photoreceptors. However, the fission yeast Schizosaccharomyces pombe provides one of the simplest and most easily studied examples. The rod shaped cells of this organism have two distinct regions, the hemispherical growing tips - where cells expand, with the addition of components to the cell wall and cell membrane - and the non-growing cell sides. Many factors are known to localise specifically to cell ends and organisation of the growth domains is highly dependent on microtubule-dependent intracellular transport mechanisms. However, our understanding of the complex regulatory networks involved in polarized growth regulation are extremely limited, with many regulators and regulatory principles likely remaining to be identified. New semi-automated methods allowing for high-throughput/high-content (HT/HC) data collection and analysis can be applied to rapidly and systematically look for novel genes involved in the regulation of polarized growth, which can then be used as a starting point to more fully elucidate their entire network. Data has already been collected from one such screen providing several interesting candidates. Additionally, in previous work, the motor protein Klp2 involved in microtubule organization during growth was investigated, with some interesting findings with regards to its in vivo activity. This may produce significant results solving a long-standing puzzle in S.pombe research and clarifying how microtubules are organised during interphase. Objectives 1. To continue investigating the regulation of the microtubule organiser Klp2, in particular its interaction with other regulatory proteins 2. To validate and further investigate candidate genes suggested by the previous screen 3. To identify further genes affecting cell polarity by carrying out a HT/HC screen for regulators of microtubule dynamics


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Transgenerational epigenetic inheritance in C.elegans.
Funder: Wellcome Trust

Abstract: Transgenerational epigenetics is the study of changes in gene regulation, inheritable over generations that are not due to changes in the DNA sequence. Although a few examples of epialleles have been observed in nature, and are often associated with inheritable DNA methylation, the molecular mechanisms underlying this alternative type of heredity remain poorly understood. The soil nematode Caenorhabditis elegans exhibits a transgenerational memory of RNAi-instructed gene silencing although this organism does not exhibit DNA methylation. This project aims to determine the mode of transmission of epigenetic marks between generations. We hypothesize that small RNAs will play a role in this process. We will address this question in two ways: 1) We will study the mechanism of transgenerational epigenetic inheritance at a transgene locus, focussing on chromatin and small RNAs as likely candidates. 2) We will determine whether small RNA populations are sensitive to environment and whether this can affect offspring phenotype. A mechanism such as this would enable organisms to fine-tune expression of sensitive genes resulting in a fast, heritable, but reversible response to a changing environment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structual and chemical biology in the design of selective kinase inhibitors.
Funder: Wellcome Trust

Abstract: In summary, this proposal will drive a deeper understanding of the role of critical (non-hinge) residues in kinase active sites through mutation studies and will thereby facilitate the following: The use of selected single point mutations to lock a protein kinase into active or inactive conformations to facilitate the biochemical or biophysical screening of small molecule inhibitors and subsequent soaking of crystal forms to derive X-ray crystal structure information. A general understanding of which active site residues are predicted to be influential drivers of conformational equilibria within specific kinase families. · A deeper understanding of the effect of key active site residues on inhibitor selectivity across the kinome. Insight into the utility of producing conformationally-locked kinases for inhibitor development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: ATP mimetics as inhibitors and probes of ATPases.
Funder: Wellcome Trust

Abstract: The initial aim of this project is to synthesise a small library of ATP-mimetics and probe the heterogeneous ATP binding pockets of the 8 CCT subunits. The compounds will first be tested in steady state ATPase assays (Shimon et al; 2008) and an activity series assembled. Selected molecules would then be used in a chemical genetics screen against yeast CCT and ATP-site mutants in various of its subunits. Recent work in the Willison laboratory has led to an X-ray crystal structure for yeast CCT which is of sufficiently high resolution to guide the design of mutants. This will allow a level of understanding of this complex molecular machine which has not been achieved by any other approach. If time permits, the understanding gained of both the biology of CCT and the small molecules will be used to develop drug-like inhibitors of human CCT.


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