Neurological diseases cause a substantial and increasing personal, social and economic burden. Although there have been exceptions, there is increasing frustration at the limitations of learning from animal models, emphasising the importance of studying human tissue. Neuropathologists work in NHS hospitals examining samples from the brain and related tissues derived from operations (biopsies) or post mortem examinations. Their job is to identify abnormalities, make a diagnosis and try to understand how the abnormalities arise. Neuropathology has existed as a specialty in the UK for 40-50 years and, as a consequence of this work, substantial archives of diagnostically verified tissue have been established nationwide. These archives contain a wealth of tissue from a great variety of neurological conditions, including common conditions such as stroke, head injury, tumours, infections, psychiatric disorders, developmental disorders and many rare conditions, and represent an underutilised resource for research. BRAIN UK (the UK BRain Archive Information Network) networks the tissue archives of neuropathology departments based in 26 regional NHS Clinical Neuroscience Centres to form a virtual brain bank, acting as a "matchmaker" linking researchers needing tissue to the appropriate samples. Through BRAIN UK researchers can gain access to >400,000 samples from a wide range of diseases affecting the brain, spinal cord, nerve, muscle and eye. BRAIN UK has ethical approval which covers the majority of projects, saving the researchers considerable time as they would otherwise have to obtain this approval independently. Over the past 4 years BRAIN UK has supported 48 research projects in many centres around the UK and overseas. In the coming 4 years we want to continue to provide tissue to researchers from existing resources and add newly obtained samples of which >16,000 are becoming available each year. We also aim to gather the results of researchers' studies performed on tissue obtained through BRAIN UK to form a central register of findings which will benefit new researchers wanting to perform new studies on these tissue samples. Finally, we will link BRAIN UK with UK Biobank, which has 500,000 intensively studied participants from the general population, in order to learn more about the origins of neurological disease. As far as we are aware, the BRAIN UK network is unique in the world and is very economical as it makes use of tissue samples already being stored in NHS archives which would otherwise be unused and unavailable to researchers.

This project aims to deliver transformative advances in the development of nanoparticle constructs for use in precision surgery and beyond (e.g. therapeutic drug delivery). This will be achieved by bringing together experts with complimentary expertise in calixarene chemistry, nanochemistry, PET (positron emission tomography) imaging and surgical imaging. By developing the chemistry of calixarenes, we will optimize the galectin receptor binding affinity and demonstrate selective cancer cell targeting. Our preliminary studies reveal that radiolabelled (18F) 'Clicked' calixarenes are readily accessible, with improved HPLC purification (achieved via guest incorporation), which enables in vivo bio-distribution, highlighting ideal (renal) clearance. A major benefit of employing a calixarene-based scaffold is the ability for further functionalization. With this in mind, using standard protocols (Click chemistry), the calixarene will be further modified with the addition of a NOTA motif. The incorporation of such a strongly binding motif will allow us to develop the radiolabelling of this new platform technology, with maximum flexibility i.e. with both 18F and 68Ga radionuclides. The functionalized calixarene scaffold will be immobilized on luminescent conjugated polymer nanoparticles to enhance the imaging capabilities. The biodistribution and tumour uptake of the delivery platform will then be accessed (PET imaging), and results will be fed back into the synthetic programme to allow us to optimize the results. Following successful in vitro studies, in vivo tumour uptake will be assessed; tumour and organ uptake will be quantified to assess biodistribution and tumour targeting. The final phase of the project will explore opportunities for using this technology for the collection of spectra in vivo, by combining with a customizable dual camera head. To evaluate depth sensitivity and multimodal guidance an endoscopic gamma probe will be used for multi-functional probe identification. Such a combined approach will be suitable for pre-clinical imaging with a focus on high resolution and signal quality.

The PromethION24 is a device used to analyse the nature of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in detail in clinical samples, and in bacteria, viruses or fungi identified from samples. The information generated by a PromethION24 can inform doctors and researchers about unique 'signals' within clinical samples, or the DNA/RNA of bacteria, viruses, or fungi, identified from such samples, which can help understanding of the processes that cause disease and develop new diagnostic tests, and/or inform about how an infection spreads within a population. This in turn can inform about how to control and/or improve the treatment of a condition. This so-called "genomics" technology (sometimes called "omics" which is a broader term for related research) has been used extensively in the COVID-19 pandemic. Hull University Teaching Hospitals (HUTH) has a rapidly expanding range of research, in areas of work the MRC is interested in funding. In collaboration with the University of Hull and Hull York Medical School, doctors at HUTH are applying "omics" to a range of clinical samples, which has resulted in local expertise using a related, but much lower throughput device called MinION. Capacity and capability to grow further is currently severely limited by this lower throughput technology. The PromethION24 will be housed in a laboratory based in the Daisy Building on the Castle Hill Hospital campus of HUTH. All co-applicants are based here, with Hull Royal Infirmary and the University of Hull close by, allowing easy transport of samples and close collaboration between clinical doctors and researchers. The PromethION24 delivers 24-times to 120-times more throughput, retains a low laboratory 'footprint', and overall reduces the cost of analysing each sample. High quality laboratory space in the Daisy Building at HUTH is dedicated to the careful storage and processing of patient samples for this type of research. Such analyses require powerful computers to analyse, interpret and store the produced data and this will be supported by the University of Hull VIPER supercomputer, which is one of the most powerful in the north of England, and supports current research. The Dept. of Research & Development, HUTH will oversee use and governance via a new "omics" committee, that will allow new research questions of notable local and national importance to be addressed with a focus initially on infection and wound related projects. Early projects will include studies of: the nature of bacteria in wounds and how they influence healing; the fungi on the skin and in the mouth of patients with acute leukaemia before, during and after they receive intensive chemotherapy and how this links to antifungal drug use and whether they develop an infection (linked to a NIHR funded trial, BioDriveAFS); bacteria that cause bloodstream infections in people who inject drugs compared to those who do not, and how this links to their infection and the spread of these bacteria in the community; the relationship between the nature of antibiotic resistant bacteria and how well a two antibiotic based therapy works against them in the laboratory; and the bacteria and unique 'signals' identified in the large joint fluid (e.g. knee) of patients with and without bacterial (septic) arthritis. Access will be available to other HUTH clinicians, and partner organisations, in keeping with our intended collaborative use, leading to data to support a programme of related future external funding applications, and a step-change in "omics" research locally. Importantly, the technology will increase research participation opportunities for local patients, who live in an area with high disease burden and that has been underserved by research activity. The award will also provide a platform for expanding "omics" education of local healthcare professionals and researchers, as well as facilitating increasing contributions to national genomics research projects.

Theranostics is a new approach in personalised medicine that is starting to have a major clinical impact. It typically uses two almost identical pharmaceuticals, one to diagnose and image disease, the other to treat. One branch of theranostics uses elements that emit radiation, meaning a theranostic pair can be obtained by simply switching a single atom. This works as some elements produce radioactive energy emission that can pass straight through the body and are well suited for diagnosis, using imaging techniques such as positron emission tomography, while others give off radioactive particles that are absorbed by the body and can be used to kill the diseased tissue (e.g. tumour). The major difference compared to conventional external beam radiotherapy is that theranostics are selective as they recognise the specific tissue that is diseased such that healthy tissue damage is much lower. This leads to dramatically reduced side effects for patients. Using the corresponding imaging pharmaceutical can also allow treatment response to be accurately assessed meaning the ideal dose can be administered (i.e. enough to ensure that the tumour has been treated but without causing harm to the patient). In this research, we will investigate a new way of transporting the radioactive element to the diseased tissue. This method uses a miniature cage that can house the radioactive element, so that when it is attached to a recognition part of the pharmaceutical the radiation is transported to the diseased tissue. Moreover, this miniature cage has been designed to lock in different elements so it is incredibly facile to switch between a diagnosis and therapeutic pharmaceutical. This will make the development of new personalised therapies that can target and treat different diseases much more accessible and reduce regulatory hurdles.