NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Phase coding in the visual system: neuronal processing coordinated by brain oscillations
Funder: Wellcome Trust

Abstract: The visual system receives a wealth of information of which only little is processed. My aim is to uncover the mechanisms involved in prioritizing information processing of visual scenes. To this end, I will test a novel hypothesis that explicitly predicts how brain oscillations serve to prioritize the flow of sensory information. The core idea is that neuronal oscillations serve to coordinate computations by organizing a temporal code. The theoretical framework predicts that alpha (8–13 Hz) oscillations support a ‘phase coding scheme’ in which a set of neuronal representations will activate sequentially within an alpha cycle. This mechanism serves to convert a complex visual scene into a temporal code: a ‘to-do list’ that can be processed sequentially by downstream regions. Spatial attention and saliency will determine the order in the list by differentially biasing the excitability of the individual representations. I will test this framework using intracranial recordings and magnetoencephalography (MEG) in combination with a new approach: ‘rapid frequency tagging’. Using a novel approach for visual entrainment of the alpha rhythm, I will test the model causally. The mechanism may generalize to brain networks beyond the visual system, thereby providing a general principle for neuronal coding and inter-regional communication.

Lay Abstract: When driving down a busy street, we receive a wealth of visual input. Our brains are unable to process all this input but have a remarkable ability to decide what to process and what to ignore. My previous research work suggests that ‘brain oscillations’ are essential for controlling the visual flow. Brain oscillations are generated by coordinated activity of thousands of neurons. The strongest oscillation measured in awake humans is the ‘alpha rhythm’ which is produced by neural activity pulsing ~10 times per second. I propose a novel neuronal mechanism according to which different objects in a visual scene are represented sequentially along an alpha cycle. According to this framework information between brain regions is exchanged when the regions oscillate together. This ground-breaking theory provides a mechanistic explanation for how brain oscillations coordinate neuronal activity in order to prioritize the information flow which is presently lacking. We will test the theory by measuring brain oscillations from many brain regions simultaneously using MEG as well as intracranial recordings. The research program will eventually also help us to understand what goes wrong in individuals who have problems focussing in busy settings such as ADHD patients.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Placental chemokine compartmentalisation by atypical chemokine receptors.
Funder: Medical Research Council

Abstract: We have recently described a novel mechanism of mammalian molecular control whereby the atypical chemokine receptor ACKR2, which scavenges inflammatory chemokines, operates within trophoblasts to block maternal inflammatory chemokine entry to the embryonic circulation. When this control process is disrupted in Ackr2-/- embryos, aspects of intra-embryonic macrophage migration are disrupted. In addition in some mouse backgrounds, and particularly following induction of maternal inflammation, impaired chemokine compartmentalisation is associated with reduced embryonic survival. Importantly ACKR2 is not the only atypical chemokine receptor expressed on trophoblasts. Two other members of this receptor subfamily, ACKR3 and ACKR4, are also expressed on trophoblasts. These two receptors scavenge chemokines of known developmental importance. This Programme Grant application describes studies aimed at gaining an in-depth understanding of the process of chemokine compartmentalisation at a molecular and cellular level. Much of the grant will focus on ACKR2 but, to determine whether this is a broader mammalian phenomenon, we will also study chemokine compartmentalisation in mice in which Ackr3 has been selectively depleted from trophoblasts. Defective chemokine compartmentalisation in the context of ACKR2 has implications for embryonic development, miscarriage and adult immune/inflammatory development. With ACKR3, the major ligand for which is the chemokine CXCL12, we hypothesise that impaired chemokine compartmentalisation will be reflected in defective haematopoietic and vascular development in the embryo and infertility and cognitive impairment in surviving offspring.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Plasma-cell depletion therapy for severe Graves' disease
Funder: Medical Research Council

Abstract: Patients with severe Graves' disease, defined by severe hyperthyroidism, large goitre and inflammatory eye disease, have unmet clinical need and a poor response to conventional treatments. Many patients are ultimately managed by surgical thyroidectomy, with bilateral orbital decompression surgery followed by strabismus and eyelid surgeries. This aggressive autoimmune disease is caused by high concentrations of directly pathogenic TSH-receptor stimulating antibodies (TRAb), which are secreted from terminally differentiated B lymphocytes known as plasma cells. Daratumumab is a recently licenced anti-CD38 monoclonal antibody that selectively depletes plasma cells and thus has the potential to directly target the pathogenic TRAb-secreting cell type in Graves' disease. This adaptive trial will investigate proof of the concept that daratumumab has disease-modifying activity in Graves' disease. We will recruit 30 adult patients with severe Graves' disease defined by TRAb antibody concentrations above 10U/L (normal <1.0), with either severe hyperthyroidism (FT4 >50pmol/L), inflammatory thyroid eye disease (clinical activity score >3), large goitre or thyroid dermopathy. Initially, four different doses of daratumumab and placebo will be given in a randomised dose-response study (5 x n=3 groups). Following an interim analysis, the most promising dose(s) and placebo will be trialled in a further 15 patients. The primary analysis will be a comparison of the percentage reduction in serum TRAb concentration between baseline and 12 weeks in each active IMP group and the placebo group. Secondary outcomes will include changes in serum thyroid hormones (FT3, FT4); subjective and objective measures of thyroid eye disease; thyroid volume measured by ultrasound; participant safety and subjective tolerability. Our adaptive design study will determine whether daratumumab has the potential to change the natural history of this common and morbid condition.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Platelets, fibroblasts and macrophages: A pathogenic or protective triad in Rheumatoid Arthritis ?
Funder: Versus Arthritis

Abstract: 2.   In the future, the potential to provide coordination and guidance to increase harmonisation of standards at specific points across the entire biosample lifecycle;


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: PomBase: A FAIR community resource advancing research from fission yeast to humans
Funder: Wellcome Trust

Abstract: Because basic molecular mechanisms are shared universally, model organism databases are pivotal resources and drivers of research across species. We will enhance PomBase, the fission yeast model organism database, to place investigations using fission yeast in contexts that illuminate equivalent processes in other species, particularly human. Through data stewardship, literature curation, and data integration, we will create emergent knowledge of eukaryotic cell biology, encompassing how proteins are connected into pathways, how pathways are connected to each other, what genes and pathways relate to human diseases, and what proteins remain unstudied across species. We will develop generic open-source, modular, customisable tools to integrate diverse data types, thereby providing clear, user-responsive presentations of increasing volumes of complex data. We will continue to make substantial contributions to the development of shared infrastructures for semantic standardization of biology, supporting increased data propagation and re-use. We will engage closely with the research community through outreach activities. Our proposal addresses four interconnected key objectives: A1 Enabling fresh biological insights across organisms from quality-assured, standardised curation. A2 Improving core infrastructure and providing innovative tools. A3 Enhancing data acquisition, interoperability, and dissemination. A4 Increasing outreach, community curation and promoting the fission yeast model system.

Lay Abstract: Because basic molecular mechanisms are shared universally, research using model organisms fuels biological insight across species. Databases dedicated to model species provide critical support for scientists to generate, share, and use results.PomBase, the fission yeast model organism database, works to ensure that researchers can easily find, retrieve, and combine information from diverse sources. We place fission yeast biology in contexts that illuminate equivalent processes in other species, particularly human, yielding emergent knowledge of eukaryotic cell biology. We focus on how proteins are connected into pathways, how pathways are interconnected, what genes and pathways relate to human diseases, and what proteins remain unstudied across species.To present increasingly complex data intuitively, we develop shareable tools to handle multiple data types as well as data quality assurance procedures. Our work helps build a shared infrastructure to standardise biological language, and supports further data propagation and re-use throughout the research community.

Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Precision Medicine Centre of Excellence
Funder: Public Health Agency, NI

Abstract: Precision medicine (also referred to as personalised or stratified medicine) aims to provide early and accurate diagnosis and select the right drug, at the right dose at the right time for patients. It aims to take into account individual differences in people’s genes, environments, and lifestyles when prescribing medication to treat disease. One of the cornerstones of achieving success in precision medicine is to identify biomarkers which are measurable and characteristic to the patient and can be used to predict response to treatments. This will allow potentially costly drugs to be used more effectively by being prescribed only to those that can benefit from them. There is intense interest in the precision medicine approach to treating cancer, partly because current treatments such as chemotherapy affect normal as well as cancer cells leading to unacceptable side-effects, but also because knowledge of the genetic make-up of cancers is developing so rapidly. Precision medicine can also help avoid side-effects by restricting interventions to specific molecular targets in cancer cells, so minimizing ‘collateral damage’ to healthy cells. Innovate UK has made a significant investment in the Catapult Programme - Catapults are intended to help businesses to adopt, develop and exploit innovative products and technologies - the next stepping-stone on the journey to commercialisation. Catapult Centres offer concentrated expertise in areas vital for that journey - such as manufacturing processes, test facilities, type approval and accreditation or supply chain development. Many provide access to cutting-edge equipment and specialist facilities to develop and test ideas in reality. The Catapult vision is to bridge the gap between these ambitious businesses and the expertise of the UK’s world-class research communities. Catapults exist to: • reduce the risk of innovation • accelerate the pace of business development • create sustainable jobs and growth • develop the UK’s skills and knowledge base and its global competitiveness. Precision Medicine was the focus of the 11th proposed Catapult, and in January 2015, Northern Ireland was invited, alongside other regions in the UK, to submit a bid to host the Precision Medicine Catapult (PMC). A robust bid was submitted with strong support across government, academic and industry partners. On consideration of the bids, Innovate UK initially decided that no single centre would be capable of hosting all aspects of the PMC requirement and established a multi-centre Catapult with a central hub in Cambridge and six Centres of Excellence, of which one would be located in Belfast, with a focus on Northern Ireland’s strength in diagnostics development. The Centre of Excellence would be located in the NI Molecular Pathology Laboratory (NIMPL), a hybrid laboratory operated by the Belfast Trust and the Centre for Cancer Research and Cell Biology (CCRCB) at Queen’s University.


Research Activity Codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Precision-Panc: a dynamic therapeutic development platform for pancreatic cancer
Funder: Cancer Research UK

Abstract: Our increasing understanding of the molecular diversity of cancer is creating opportunities and challenges for   therapeutic development. An approach that aligns discovery, pre-clinical and clinical development is required   in order to optimise therapeutic development strategies. Pancreatic cancer in particular does not have   significantly effective therapies, and does not have a dominant actionable subtype that can be targeted. We   have established a stratified therapeutic development platform for pancreatic cancer called PRECISION-Panc.   The UK- wide network aligns through development strategies underpinned by innovative science that   uncovers key vulnerabilities, and through forward and backward translation aims to define optimal   therapeutic strategies for specific molecular segments. In this proposal we focus on opportunities that arise   through defects in DNA maintenance, through targeting DNA damage response defective tumours and   through immune therapies, aimed at the immunogenic subtype we recently described. We propose 3 initial   clinical trials that utilise tissue biopsy to define predictive biomarkers of therapeutic response. In addition, we   propose a study with pre- and post-treatment biopsies and liquid biopsies to define clonal evolution arising   from treatment selection based on recent data that implicate the rapid emergence of resistance in pancreatic   cancer. Central to this is significant pre-clinical activity aimed at further refining these therapeutic strategies   and defining novel approaches through laboratory experimentation to inform the development path, and   trial data that inform laboratory investigation in an iterative process.


Research Activity Codes: 5.1 PHARMACEUTICALS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Preclinical Precision Pancreas
Funder: Cancer Research UK

Abstract: Every year around 340,000 people die of pancreatic cancer worldwide, and by 2030 pancreatic cancer is predicted to be the second commonest cause of cancer death in the western world. Most patients present too late for surgery, with aggressive invasive or metastatic disease. Furthermore, current chemotherapies offer little benefit, so we urgently need to better understand the disease and identify better options for clinicians and patients. To do this, we model different genetic subsets of the disease in genetically engineered models. These models mimic human tumours in terms of the genes altered, and also because they develop a dense desmoplastic stroma of fibroblasts, stellate cells, immune cells, and extracellular matrix proteins such as collagen. By studying our models, we can determine the importance of specific genetic and transcriptomic changes identified in human tumours, identify novel targets for therapy, both in tumour cells and in the microenvironment, and test new therapies pre-clinically.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Preclinical development of an innovative electric field therapy device for the treatment of Glioblastoma
Funder: Innovate UK

Abstract: Glioblastoma is the most common and aggressive primary adult brain cancer. Global incidence is 3-5/100,000 persons and rising, with c.3000 UK diagnoses/year. There is no cure and the 5-year survival rate is ~3.4%.



Electrotherapy is a new form of cancer treatment applied after tumour resection that directly interferes with cell division, slowing tumour recurrence and prolonging life. However, the only available electrotherapy device for glioblastoma is not recommended for use on the NHS by NICE due to poor patient quality-of-life and low cost-effectiveness.



QV Bioelectronics (QVB) is developing a novel approach to deliver electrotherapy in a focal and continuous manner that will potentially double glioblastoma patient life expectancy, leading to up to 10-times higher 5-year survival rates whilst overcoming quality-of-life issues associated with the existing electrotherapy treatment. QVB has developed a working prototype and will perform pre-clinical safety testing as part of this Innovate UK funded project as well as working on other development aspects of their technology. QVB's device is still undergoing pre-clinical development and will not be ready to be prescribed to patients for several years. QVB's technology will be expanded to other types of brain tumours in future, with our research and innovation hub creating a significant number of jobs in the UK, creating a combined global market opportunity worth over £3Bn/year. This will cement the UK's position as global leaders in the growing field of bioelectronics.


Research Activity Codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Predicting Antibiotic Resistance Evolution through Mechanistic Understanding of Genotype-to-Phenotype Mapping
Funder: Wellcome Trust

Abstract: Antibiotic resistance is one of the biggest public health challenges, causing over a million deaths annually. In order to slow down the emergence of resistance, there is a critical need for predictive approaches grounded in experiment. Knowing the effects of mutations and interactions between them (epistasis) is critical for predicting outcomes of selection. Unlike most studies, which are limited to describing these phenomena, my research aims to provide a causal understanding of how existing molecular mechanisms define the effects of mutations and epistasis. Without such causal understanding, predicting evolution is limited to those systems that have been fully experimentally characterized. My goal is to provide the first mechanistic genotype-phenotype map for two regulatory systems consisting of a protein and its DNA-binding site. Doing so would dramatically improve our ability to predict evolutionary outcomes for one of the major forms of resistance (multi-drug resistance through changes in transcriptional regulation of AcrAB-TolC efflux pump) by allowing predictions of DMEs and epistasis without the need to fully experimentally characterize them first. Being able to predict multiple antibiotic resistance evolution from first principles, before any patients take the drug, would improve treatment strategies, while also enabling better evaluations of novel drugs during their development.

Lay Abstract: Imagine an architect, tasked with converting an old football stadium into a building with a different function, without completely demolishing it. While she might contemplate turning the stadium into a housing project, a shopping mall, or an office space, she will not consider turning it into an airport. This is because the existing architecture of a stadium imposes certain constraints: namely, the walls that surround it prevent airplanes from landing. Evolution operates in much the same way as the architect: the existing molecular structures impose constraints that make it more difficult to evolve certain forms compared to others. I study precisely this – how the existing molecular structures shape the likelihood of evolving antibiotic resistance. By identifying those structures that are less likely to evolve resistance, we can better select potential new targets for drugs, so that the time it takes for bacteria to evolve resistance would be prolonged.

Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Predicting CBT response from fear conditioning
Funder: Wellcome Trust

Abstract: Responses to psychological interventions for anxiety vary greatly. Clients and clinicians want better ways to predict outcomes. One contender is fear extinction, the process through which exposure, the “behavioural” part of Cognitive Behavioural Therapy (CBT) is thought to work. Whilst there are robust differences in fear extinction between individuals with anxiety disorders versus controls, evidence that extinction predicts CBT response is modest. 
 
 We first became interested in fear extinction as a mechanistic tool to help understand how CBT works. In order to build algorithms from numerous potential predictors, including fear extinction, we needed to undertake fear conditioning at a scale. We developed a smartphone App FLARe, that remotely delivers a fear conditioning paradigm. Our validation studies showed that fear extinction data from our App mirror that from gold-standard in-lab delivery. 
 
We now want to test the extent to which App-delivered fear extinction data predicts CBT response. We will assess young adults with high anxiety using our App before enrolling them in CBT. We will test the strength of correlation between fear extinction and treatment outcome. We will also explore the extent to which this association is stronger in specific sub-groups (e.g. those who completed more exposure homework during treatment).


Research Activity Codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: MENTAL HEALTH