NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Predicting HLA-specific humoral alloimmunity to improve histocompatibility and immunological risk assessment in transplantation.
Funder: Medical Research Council

Abstract: An important strategy to offset the risk of alloimmunity and maximise transplant outcomes is to minimise the number of HLA mismatches between donor and recipient. However, current assessment of HLA incompatibility is inadequate, limited by the assumption that all mismatches within an HLA locus are equally significant. The principal aim of the proposed research is to explore the full potential of applying advanced bioinformatics modelling techniques, incorporating different mechanistic aspects of the immune system and capitalising on analysis of large clinical datasets, to develop new and improved methods for predicting HLA immunogenicity, determining HLA compatibility and defining HLA related immunological risk. Building on previous work, we will develop a computational algorithm to analyse the structure and physicochemical properties of HLA molecules and identify immunodominant B-cell epitopes on donor HLA based on their unique surface electrostatic properties compared to recipient HLA. Similarly, immunodominant CD4+ T-cell epitopes on donor HLA will be detected by investigating the potential of recipient HLA class II molecules to present donor HLA-derived peptides, thus accounting for the indirect pathway of alloreactivity. This immunoinformatics approach to determining donor HLA immunogenicity will be tested and refined by analysis of HLA-specific alloantibody responses and by detection of CD4+ allospecific T-cells in HLA-sensitised patients. The combined HLA immunogenicity algorithm, accounting for both B-cell and T-cell aspects of humoral alloreactivity, will then be validated in large, national, clinical datasets by examining its capacity to assess the risk of alloantibody development after kidney transplantation and whether it leads to improved assessment of HLA incompatibility, compared to conventional HLA mismatching, by enabling selection of HLA incompatible donor-recipient combinations that are favourable in terms of long-term kidney graft survival.


Research Activity Codes: 6.4 SURGERY
Health Categories: RENAL AND UROGENITAL
Award Title: Preemptive discovery of insecticide cross-resistance mechanisms for next generation malaria control products
Funder: Medical Research Council

Abstract: Malaria control is being impacted by insecticide resistance but newly-available and oncoming insecticides offer the opportunity to effectively manage resistance, provided mechanistic knowledge and monitoring tools become available to inform rational deployment. Genomic and transcriptomic comparisons of resistant and susceptible mosquitoes, which we and others are applying as part of ongoing and recent programmes are powerful for identification of resistance candidates, but lack capacity to pre-emptively identify mechanisms of resistance and cross-resistance for new insecticides. Novel complementary approaches are required to meet this challenge and  we propose to combine transcriptomic and functional genomic approaches with a novel chemico-proteomic approach, Activity Based Protein Profiling (ABPP ). We will apply dual pipelines: the first integrates comparative transcriptomic and ABPP analyses to identify differentially expressed genes and correspondent differentially binding enzymes between Anopheles strains with contrasting resistance to the key current IRS insecticide pirimiphos methyl (PM). The second pipeline will apply competitive inhibition of ABPs with insecticide or their reactive metabolites to identify modes of toxicity for each and generate an insecticide-enzyme interaction matrix for identification of cross-resistance candidates. The most promising candidates from each pipeline will be tested using a third functional validation pipeline involving heterologous expression and metabolism, transgenic expression in Drosophila and Anopheles and RNAi to investigate resultant gains and loss of resistance. Our results will provide new knowledge and pre-emptive diagnostic tools for resistance management programmes, and pipelines readily adaptable to future insecticides


Research Activity Codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION
Award Title: Preferences for facial sexual dimorphism across culture and the sexual orientation spectrum
Funder: The British Academy

Abstract: Judgments of attractiveness have many important social outcomes, highlighting the need to understand how people form these judgments. One aspect of appearance that impacts perceptions of attractiveness is facial sexual dimorphism (femininity/masculinity). However, extant research has focused primarily on White, Western, heterosexual participants’ preferences for sexual dimorphism, limiting generalisability. Indeed, recent research indicates that these preferences vary by culture, and other work finds differences between gay/lesbian and heterosexual individuals. However, aspects of identity such as culture and sexual orientation do not exist in isolation from one another, but rather intersect, leaving a critical gap in understanding. Our research therefore aims to bridge across these hitherto separate areas of inquiry to provide a comprehensive and generalisable understanding of sexual dimorphism preferences. We will test how individuals’ culture, sexual orientation (including, crucially, bisexual individuals), and gender predict their sexual dimorphism preferences for White and East Asian faces.


Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Preventing and Tackling Mental Ill Health through Green Social Prescribing Project Evaluation
Funder: Department for Environment, Food and Rural Affairs

Abstract: The aim of this project is to evaluate the Green Social Prescribing Project, in order to iteratively feed into project design and implementation throughout the funded period, and to inform wider rollout of green social prescribing following the initiative. The evaluation will assess processes, outcomes, and value-for-money, and improve understanding of what works, for whom, in what circumstances and why.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: MENTAL HEALTH
Award Title: Prioritising patients for emergency surgery or not: the impact of COVID-19 (ESORT-C19)
Funder: The Health Foundation

Abstract: Many patients with common acute conditions, such as appendicitis, are admitted to hospital in an emergency. Some patents have emergency surgery, but others receive ‘conservative management’, which includes the possibility of later surgery. For many patients, it is unclear whether the benefits of emergency surgery are greater than the risks.

Following the COVID-19 outbreak, planned surgery in the NHS was cancelled. As a result, NHS waiting lists are now approaching 10 million patients. The NHS urgently needs evidence to inform which patients should be prioritised for emergency surgery. Information for patients on the risks and outcomes of emergency surgery must recognise the impact of COVID-19.

This research study will assess the effect of COVID-19 on access to emergency surgery for different patient groups, and will report on the effectiveness and cost-effectiveness of emergency surgery versus conservative management following the COVID-19 outbreak. Evidence-based recommendations, which can be quickly incorporated into NHS guidelines, will be developed on which patients should be prioritised for emergency surgery in the COVID-19 recovery phase.

The project team will use Hospital Episode Statistics (HES) data on emergency admissions to NHS hospitals for acute conditions during the COVID-19 pandemic, and discussions with clinicians and patients will provide insights about the impact of the pandemic on decisions made about emergency surgery versus conservative management.

The analysis will look at emergency hospital admissions for five acute conditions where there is clinical uncertainty about which patients should have emergency surgery: acute appendicitis, cholelithiasis, diverticulitis, acute (groin) hernia and intestinal bowel obstruction.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Probabilistic machine learning for high-dimensional applications in health
Funder: Wellcome Trust

Abstract: Deep learning is a way to train computers to do complex tasks by learning from large amounts of data. Developing rapidly over the last decade, it has been particularly successful in the understanding of images and natural language. However, deep learning has not had a large impact in important tasks of medical science and healthcare. Traditional statistical techniques are favoured due to their advantages in terms of interpreting their results and understanding the decision-making process. However, such techniques are often difficult to scale up to larger patient populations or to the large amounts of data produced by new technologies like smartphones and fitness trackers. This PhD project aims at combining statistical concepts with recent deep learning technology. In particular, I am interested in developing these methods for estimating the effect of a treatment on a patient’s outcome. I intend to extend existing technology to provide a tool to assess when such an estimation is feasible. Further, I am interested in the stability of such methods when data is corrupted by some controlled mechanism trying to trick the algorithm. I aim at enabling novel data science methods that help health data scientists, health practitioners and ultimately patients to make better decisions.


Research Activity Codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Prosensory signals: from discovery to application using inner ear organoids
Funder: Medical Research Council

Abstract: In the UK alone, one in six people has a hearing disability, rising to one in two for over 70 year-old. The main cause of sensorineural hearing loss is the loss of auditory hair cells residing in the inner ear. A potential therapy for hearing loss could be to induce in the damaged auditory organ the regeneration of new hair cells - a process that is occurring spontaneously in non-mammalian vertebrates. However, the current strategies relying on the manipulation of the molecular signals controlling hair cell differentiation alone are relatively inefficient. An alternative approach could be to re-activate the developmental signals that drive the formation of the 'prosensory' cells, which are the progenitors for both hair cells and their associated supporting cells. However, this requires a better understanding of the molecular mechanisms of prosensory specification.  In our previous MRC-funded project, we have uncovered a new role for the Wnt signalling pathway as a dose-dependent regulator of prosensory specification. We also started RNA-Seq and functional screenings aimed at identifying new genes participating to this process. Here, we will pursue this research with new methods to maximize our chances of identifying key regulators of prosensory specification. We will use Crispr/Cas9 mediated gene-knockdown for testing the function of candidate factors, such as the Tcf/Lef effectors of the Wnt pathway, in the embryonic chicken inner ear. We will use single-cell RNA-Seq to characterize mouse prosensory cells and bioinformatics methods to pinpoint the key genes associated to prosensory specification. Finally, we will translate our findings to 3D inner ear organoids, using a mouse stem cell line carrying a fluorescent reporter of Sox2, a prosensory marker. The outcomes of this research could be exploited in the future to induce hair cell regeneration by means of gene therapies or to improve existing protocols for the generation of hair cells in 3D organoids.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.2 CELLULAR AND GENE THERAPIES
Health Categories: EAR
Award Title: Protein lipidation in cancer: discovery, mechanisms and target validation
Funder: Cancer Research UK

Abstract: *Background: Protein lipidation is a diverse class of post-translational modification (PTM), regulated by over 40 enzymes targeting >1000 protein substrates at >3000 sites. The importance of protein lipidation in cancer is well-recognised, with >150 oncogenes and drug targets known to be lipidated and two classes of protein lipid transferase inhibitors progressed into clinical trials. However, the full spectrum of protein lipidation and its dysregulation in cancer remains unexplored, in contrast to widely studied similarly common PTMs (phosphorylation, ubiquitination…). Through CRUK-funded research we have developed expertise at the forefront of this field through invention and application of novel chemical biology tools to probe lipidation, delivery of novel lipidation inhibitors into preclinical development for cancer, and new company formation, supported by a network of outstanding academic and industry collaborations.

*Aims: We will determine actionable liabilities and modes of action for two key classes of protein lipidation in specific cancer contexts. A toolbox of highly novel chemical biology approaches will enable us to explore deregulation of co-translational N-terminal lipidation, and identify novel targets in the S-acylation network, the most diverse and dynamic class of protein lipidation regulating up to 25% of all known oncogenes. These ground-breaking studies will be empowered by an integrated technology development platform, and cross-cutting studies to understand co-regulation and crosstalk between the major classes of protein lipidation in cancer.

*Methods: The Programme will be delivered in three work packages: (1) Deliver the next step change in chemical biology tools to enable and support the Programme. (2) Determine the roles of key substrates in mode of action of lipidation inhibitors currently in clinical and preclinical development. (3) Identify liabilities and dysregulated oncogenes in the substrate networks of the key zDHHC S-acyltransferases implicated in cancer.

*Impact: We will identify and validate novel and actionable liabilities in the protein lipidation machinery in cancer, including identification of novel drug combinations and markers for sensitive cancers which can directly impact patients in ongoing clinical trials, and enable design of future trials to expand the applications of drugs targeting protein lipidation. We will also identify targets for future drug discovery, including emerging target classes. Furthermore, dissemination of our results and novel technologies will empower labs worldwide to study protein lipidation in cancer and cell biology.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Protein transport and quality control in the secretory pathway
Funder: Medical Research Council

Abstract: A key component of cellular physiology is the accurate deployment of every gene product to the correct cellular compartment. Fully one third of the proteins encoded in eukaryotic genomes navigate the secretory pathway, entering this system via the endoplasmic reticulum (ER). Research in the Miller lab is broadly aimed at understanding basic mechanisms of secretory protein biogenesis, focusing on aspects of protein quality control within the ER. We use the budding yeast, Saccharomyces cerevisiae, as a model system, which affords facile biochemical, genetic, genomic and proteomic tools that can be brought to bear on this fundamental biological problem. By using such a tractable model system, we can rapidly discover new pathways and dissect mechanisms that may be directly relevant to a number of human diseases, most notably cystic fibrosis and similar diseases of protein misfolding.  The molecular basis for vesicle formation from the ER is relatively well understood and relies on cytoplasmic coat proteins known as the COPII coat. Yet, despite a relatively deep understanding of the mechanisms that drive COPII vesicle formation and cargo capture, we know very little about how this process is regulated to prevent improper traffic of misfolded proteins. We study this problem from two angles: a “cargo-centric” approach examining the folding and trafficking of an individual protein, and a systems-level approach to characterize quality control more broadly. We use high throughput yeast genetics to identify new components that act in various aspects of protein quality control, and biochemical approaches to dissect mechanism. One long-term goal is to understand how vesicle abundance and architecture can adapt to changing physiological needs with respect to cargo load.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Psychological Influences on Citizen COVID-19 Preventive Behaviours and Vaccine Engagement in the UK and US with particular regard to the importance of ethnicity
Funder: The British Academy

Abstract: This research will review systematically empirical psychological research on citizen reactions during the COVID-19 pandemic in order to establish what robust conclusions can be drawn and to identify limitations.  One objective is to examine whether the international research effort might have been better co-ordinated and communicated to support the pandemic response and subsequent readiness. Secondary analyses of largescale datasets collected through the pandemic will be used to assess contextual, localised and sub-group differences in COVID-19 responses.  New data, from ethnically diverse samples in the UK and US, will be used in conjunction with our earlier series of surveys to establish changes in COVID-19 vaccine hesitancy and its predictors over time.  Predictors considered will include identity resilience, power differentials, mistrust, perceived risk and fear.  To inform policy development, forms and effects of uncertainty regarding vaccines and variants are also explored.  Analyses will encompass both quantitative and qualitative approaches.


Research Activity Codes: 3.4 VACCINES
Health Categories: INFECTION
Award Title: Pushing for Patient-Driven Tinnitus Research
Funder: Wellcome Trust

Abstract: This project aims to promote patient-driven tinnitus research.    The project will combine direct patient-researcher interaction with the creative use of online tools to bring insights from patients around the world. We will have tinnitus patients discuss and vote online on the most promising recent publications in the field of tinnitus. We will deliver those insights to researchers. Over time, a core panel of patients will develop sufficient expertise to formulate recommendations for how tinnitus research can become more patient-centred. Finally, we’d like to see at least one study being funded that explicitly follows these recommendations.    This project will build on:     • Tinnitus Hub’s experience with facilitating patient peer-to-peer interaction and patient-researcher interaction;   • Our online engagement tools, including our support forum;   • Our connections with tinnitus researchers and our own research experience (including several academic publications).    Ultimately, we hope to see tinnitus researchers develop an enhanced understanding of the needs of tinnitus patients, and for these needs to inform and shape their research questions and methods. And we would like tinnitus patients to have the knowledge and means to steer research in a direction that is beneficial for them.


Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Quantification of head and trunk control for children with neuromotor and neuromuscular disorders
Funder: Medical Research Council

Abstract: This imaging analysis tool will be trained to provide detailed, objective information of the segmental trunk control status of children with cerebral palsy (CP), and spinal muscular atrophy (SMA). Two core processes in the identification of trunk control will be automated: i) measurement of alignment of head and trunk segments to the vertical and ii) identification of when the hands and arms are free from contact with the body and any external surface. A cross sectional dataset (400 CP, 20 SMA1, 40 TD) and small exploratory dataset (40 NMD) will be acquired with each child tested using the Segmental Assessment of Trunk Control (SATCo).  This subjective test will be recorded using two "RGB-D" cameras each giving 3D information as raw video and depth images. The CP sample (Manchester, Liverpool and Cheshire community services) and SMA sample (Oswestry Hospital and linked centres) would include the range of trunk control problems and body morphology of these populations.  Two experienced SATCo clinicians, verified by a third, will label the video identifying i) segmental alignment i.e. when the child loses postural alignment; ii) upper limb support i.e. when the upper limbs contact the trunk or bench; and iii) trunk control status. Using contemporary machine learning methods, the raw RGB-D images and associated labels will train and test our networks through a cross validation process. (For motor function c.f. Case for Support). Exploitation of results includes: a) publication of a substantial public database of (400+20) cases representing trunk control impairment in children with CP and SMA1. This disseminates a public reference and training resource with data, software and instructions enabling inexperienced clinicians to reach the highest standard of clinical assessment of trunk control; b) acquisition of a 6-12-month longitudinal dataset of (20 CP, 5 SMA) children within our clinical network to provide power calculations necessary to plan clinical trials.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: MUSCULOSKELETAL