The common, life-shortening inherited disease cystic fibrosis (CF) is characterised by defective anion transport across cell membranes. The proposed research aims to develop chemicals which are capable of transporting anions across cell membranes, and are ready for testing in humans after safety studies are completed. Almost 11,000 people live with CF in the UK and >70,000 worldwide. The disease is caused by malfunction of a protein, the cystic fibrosis transmembrane conductance regulator (termed CFTR), which allows the transport of anions (e.g. chloride and bicarbonate) across cell membranes. When CFTR is faulty or missing from the cell membrane, ducts and tubes in the body become blocked by thick, sticky mucus. In the lungs, this triggers a vicious cycle of infection and inflammation that destroys lung tissue, leading to breathing difficulties, poor quality of life and premature death. A novel approach to treat the root cause of CF is "CFTR replacement therapy" using anionophores (anion carriers). Anionophores are synthetic small molecules which are designed to replace the action of CFTR, by picking up anions on one side of the membrane, carrying them across, and releasing them on the far side. After their delivery to the lungs by inhalation and insertion into cell membranes, anionophores could rescue normal levels of anion transport and, through a chain of effects, restore the healthy mucus which is easily cleared from the lungs. In earlier work, we and others have shown that it is indeed possible to design small molecules which insert into membranes and mediate transmembrane anion transport. Some of our systems are capable of very high activity approaching that of CFTR. Importantly, a few anionophores, with drug-like properties, are capable of efficient delivery to cell membranes, where they work for prolonged periods, transporting anions into and out of cells, without signs of toxicity. Based on our previous results, there is good reason to believe that anionophores could be used to treat CF. This project will take critical steps towards realising this goal. The work will be performed by a collaboration involving chemists and physiologists in Bristol, and a chemistry group in Sydney, Australia (funded separately). Initially we will work towards optimising activity in cells, identifying the best candidates for closer examination. We will then apply a series of tests on tissues lining ducts and tubes (as opposed to individual cells) designed to validate our hypothesis that anionophores can restore normal function in CF patients. Meanwhile we will perform in-depth studies on anionophore behaviour, in both synthetic and natural membranes, so that biomedical development can rest on firm foundations. This will include selectivity and mechanistic investigations, as well as fluorescence microscopy to ascertain anionophore distribution in cells. We will also test new delivery systems which could be used to help anionophores reach cell membranes. At the end of the project we will have set the stage for clinical studies, potentially leading to treatments for CF.

This project is to develop a rapid and inexpensive screening device that predicts how a patient will respond to leukaemia chemotherapy within hours. The test will initially be used for Acute Myeloid Leukaemia (AML), a potentially fatal cancer in which white blood cells multiply rapidly and unchecked in the bone marrow and blood. AML patients are usually treated with the anticancer agent cytarabine (Ara-C) in different doses or combined with other agents including Fludarabine, to increase the effectiveness of Ara-C. Up to 40% of patients do not respond to first course of chemotherapy treatment; lack of response is only seen after weeks when a patient may have suffered severe side effects. The nature of AML means it is vital to treat it as soon as possible; a delay of weeks can have severe consequences. This project will develop a quick and simple multi-drug test device based on blood or bone marrow samples BEFORE the start of treatment, to show response to COMBINED drugs used for treatment. The results of the multi-drug test will ensure that a patient receives the right combination of chemotherapy drugs, in the correct dose, to meet their needs and so prevent any delay in effective treatment. The test device will be particularly useful to patients whose leukaemic cells are sensitive to low doses of chemotherapy, allowing them to be treated with minimum drug doses, with less side effects. For elderly patients, where AML incidence and mortality rates are increasing, and where other health conditions may rule out aggressive chemotherapy, this screening test could be particularly timely. We have previously devised, published and patented details of a rapid test to measure response of AML patient blood or bone marrow samples, within 8 hours, to the SINGLE drug Ara-C. The test uses a bioluminescent bacterial biosensor that has been genetically modified to give increased light output in response to the active form of Ara-C within leukaemic cells; it gives an accurate measure of drug uptake and conversion to the active drug form. We have used our biosensor test on 71 patient samples and shown good agreement with a standard laboratory cytotoxicity test and a test efficiency of 83% when compared with 53 known patient outcomes. The single drug test will be extended to include other commonly used chemotherapeutics and the amount of patient cells per test reaction will be minimised, so that multiple drugs can be tested on a small clinical sample, vital for bone marrow testing, where sample volume is limited. Preliminary studies indicate that our device predicts the effectiveness of combined Ara-C/fludarabine chemotherapy. The test device will be extended to include other relevant drug combinations to exploit its full usefulness for AML treatment. The main aims of this project are to find the optimum conditions for a multi-drug test device that will predict how a patient responds to clinically relevant doses of combined drug chemotherapy, within 12 hours, using minimal number of patient cells. Also to validate the test device by retrospective testing of 500 clinical samples to correlate biosensor assay results with patient outcomes. This will produce a test device with a simple protocol suitable for routine laboratory use, which will be brought to 'regulatory approval' stage. The main application of our test device is in AML, to rapidly predict effectiveness of combined drug chemotherapy BEFORE treatment begins. Benefits include determining the most suitable treatment for an individual patient. Those with cytarabine resistant cells can be given effective combined chemotherapy that will enhance survival outcomes; patients with responsive cancer cells can be effectively treated with lower drug dose, reducing acute and long-term side effects including severe infection, infertility, secondary cancer, whilst enhancing quality of life and saving costs of hospitalisation.

With the prevalence of data-hungry deep learning approaches in Artificial Intelligent (AI) as the de facto standard, now more than ever there is a need for labelled data. However, while there have been interesting recent discussions on the definition of readiness levels of data, the same type of scrutiny on annotations is still missing in general: we do not know how or when the annotations were collected or what their inherent biases are. Additionally, there are now forms of annotation beyond standard static sets of labels that call for a formalisation and redefinition of the annotation concept (e.g., rewards in reinforcement learning or directed links in causality). During this Fellowship we will design and establish the protocols for transparent annotations that empowers the data curator to report on the process, the practitioner to automatically evaluate the value of annotations and the users to provide the most informative and actionable feedback. This Fellowship will address all these through a holistic human-centric research agenda, bridging gaps in fundamental research and public engagement with AI. The Fellowship aims to lay the foundations for a two-way approach to annotations, where the paradigm is shifted from annotations simply being a resource to them becoming a means for AI systems and humans to interact. The bigger picture is that, with annotations seen as an interface between both entities, we will be in a much better position to guide the relation of trust in between learning systems and users, where users translate their preferences into the learning systems' objective functions. This approach will help produce a much needed transformation in how potentially sensitive aspects of AI become a step closer to being reliable and trustworthy.

There are at least a billion people on this planet who possess 'misfitting' bodies and who are consequently directly affected by disability. Many more people encounter different abilities when families, friends, and colleagues are taken into consideration. Disability - and the structures that create it - really matters. It may be marginal, but it is hardly a minority experience. Indeed, when we take time to look at the animal world, we find that 'extraordinary' bodies are all around us. Some dart through the darkness mapping the world through the art of echolocation. Others flourish in underground rivers via senses that allow them to 'see' without eyes. The way in which people in Britain and North America have understood these ways of surviving and thriving in the world have an important history, and that history reveals much about transforming cultural assumptions about what we have thought to be 'normal' bodies and abilities. Since the early nineteenth century, unusual nonhuman bodies have been imagined as variously 'deficient', 'super', 'expendable' and, most recently, highly 'vulnerable' in the face of environmental transformation. These are familiar labels; we find them at the heart of contemporary and historical conversations relating to human disability Centred on a deep case study of the nineteenth- and twentieth-century imagination of dark-dwelling creatures and the impact of human systems and structures on their shrouded worlds since the mid-nineteenth century, this cutting-edge research project is really about the ways in which notions of what it means to be 'normal', 'able' and 'vulnerable' have been refracted through the multifarious bodies of animals that live in ways that are radically different from our own. Nocturnal creatures are among the most misunderstood creatures on earth, and that is principally because they are active in an environment from which we are normally excluded. This has facilitated the imagination of nocturnal animal bodies as variously 'abnormal', 'extraordinary', and 'deficient'. Ultimately, misunderstandings of these more-than-human bodies have also rendered them highly vulnerable to exclusion from environments to which they are adapted. By building this case study and generating a brand new research agenda, the project offers an important intellectual and methodological intervention into the allied fields of animal history, environmental history and disability studies. While each of these fields are concerned in varying degrees with the production of identity and the impact of identity politics on the material world, they are yet to interact with each other in mutually generative ways. More-than-human histories need to embrace disability studies approaches in order to better appreciate the wide array of engagements which constitute human relationships with the natural world and the ways in which abled and disabled identities have been constructed and refracted through and via the bodies of our animal kin. Disability studies needs to turn to the more-than-human world as a means of pivoting around the concept of disability itself; to challenge what we think we know about historical discourses of ability and normativity, re-energising a stagnating conversation about the conditions that exclude and marginalise the 'differently-abled'. This research is crucial in other ways, too. In exposing connections between discourses of normalcy, ability, vulnerability and adaptation across the human and more-than-human realms, it may be possible to generate recognition of shared vulnerabilities that transcend the human-nonhuman divide that has permitted the marginalisation of living beings across the course of modernity. Engagement and impact activities benefiting Key Stage 2 children, their teachers, sight-impaired individuals and vision clinicians highlight the potential of thinking creatively about diversity and vulnerability as issues that unite rather than isolate all living beings.

Stents are used today to treat the blockages of the vessels of the heart in patients who have angina or suffered a heart attack. In most of these patients, stent treatment is effective and improves symptoms and life expectancy. However, there is a small proportion of patients where the stents fail and block, causing either death or a major heart attack. Studies in animals have shown that the blood flow patterns following stent implantation can predict stents that are at risk to block. However, there is lack of data about the role of blood flow on stent blockage in humans. This is because it is very difficult to create models of the vessels of the heart that have been treated with stents. This study aims to address this problem. We will analyse images of the vessels of the heart taken by a wire that is advanced in these vessels. In these images we can see details of the vessel wall and of the stent. We will use these images to create models of the vessels treated with stents using a new method that we have developed and then we will simulate blood flow in these models to assess the flow patterns. We will do that at scale in 120 patients of whom 40 had a heart attack because of a blocked stent. We will then compare the flow patterns in stents that blocked and caused a heart attack and in vessels treated with stents that did not cause an event. We believe that this research will allow us to identify the flow patterns that can cause stent blockage. This information is important as it will help us to improve the design of future stents and also the way that we put stents so as to reduce the risk of stent blockage and future heart attacks.