As we age, blood flow becomes impaired, starving the brain of essential oxygen and nutrients and preventing the removal of waste products. The blood vessels within our brain also become leaky, allowing the entry of toxic substances from the blood causing brain tissue injury. These vascular changes can be detected up to 20 years before the clinical onset of Alzheimer's disease. The extent of blood flow reduction and degree of blood vessel leakiness correlates strongly with the onset of cognitive decline and accelerates disease pathology. We propose that drugs that can prevent or reverse damage to blood vessels will slow or even stop the development of AD (if given early enough). Recent findings using a new method to measure the expression of genes in individual cells in blood vessels isolated from post-mortem brain tissue have provided new insights into the biological processes responsible for causing blood vessel abnormalities in Alzheimer's disease. To date, however, all of these studies have focussed on end-stage disease. This may provide limited insights into the causes of vascular damage which begin prior to disease onset in Alzheimer's disease. We will therefore undertake a large study, which will measure the activity of genes within blood vessels at both early and late stages of AD, across multiple regions of the brain that are known to develop disease pathology at different stages of disease. This study will enable us to identify the genes and pathways responsible for abnormal blood vessel function likely to contribute to the onset and the development of Alzheimer's disease and will inform future studies aimed specifically at restoring vascular function in at-risk individuals. Damaged cells within blood vessels release proteins that can be detected in the cerebrospinal fluid that bathes the brain, obtained via lumbar puncture. These markers of blood vessel injury provide a window into the brain's vascular health. In complementary studies, we will measure novel markers of vascular injury in cerebrospinal fluid from living patients to determine whether these markers can be used to identify people in the very early pre-clinical stages of Alzheimer's disease. We plan to monitor the relationship between CSF levels of vascular damage and the onset of cognitive decline and markers of disease progression such as amyloid and tau levels using CSF samples from the same individuals who have been followed up and clinically assessed spanning a period of up to 20 years. These data will indicate whether vascular damage is indeed an early event in the development of the disease, as we suspect based on our preliminary work. This study will help to identify potential biomarkers that can be useful to identify the existence of vascular damage in patients in the early stages of Alzheimer's disease who will most likely benefit from drugs that can be used to restore vascular function within the brain. It will also contribute to a better understanding of the genes and molecular pathways involved in causing vascular breakdown in the early stages of Alzheimer's, which will help efforts to identify and develop novel therapeutic targets for the disease.

The field of quantum information arises from a desire to overcome the challenges of solving complex or intractable problems on classical computers by harnessing quantum mechanics to provide efficient and scalable algorithms. Whilst there has been tremendous recent progress in the realisation of small-scale quantum circuits comprising several quantum bits (``qubits''), research indicates that a fault-tolerant quantum computer capable of harnessing the power of quantum mechanics will require a network of thousands of qubits. This goal is presently beyond the reach of any existing implementation based on a single physical qubit type. Hybrid quantum information processing is an alternative approach that exploits the unique strengths of disparate quantum technologies, and offers a route to overcome the drawbacks associated with of a single-qubit architecture in direct analogy to the design of classical computing hardware. This proposal aims to combine three different technologies: i) Superconducting circuits, with very fast (10 ns) gate times for fast processing, ii) Neutral atoms, with long (10 s) coherence times for long lived quantum memory, iii) Optical photons, for long distance fibre communication, to create a novel hybrid quantum interface capable of storing, processing and generating highly entangled states of photons for quantum networking and cryptography applications, overcoming the short coherence time associated with the scalable superconducting circuit systems. This also offers applications in quantum metrology for conversion from optical to microwave domain quantum information, making it possible to extend the interface to incorporate a wide range of alternative solid-state based qubits. The interface relies on use of highly excited Rydberg states, which have incredibly large dipole moments and transitions in the microwave regime, which can resonantly couple to superconducting qubits embedded in planar microwave waveguide cavities. The large Rydberg dipole also leads to strong, controllable interactions between atoms to provide a collective enhancement in the coupling to single photons for efficient storage and retrieval of light. The first stage of the experiment is to trap spatially addressable atomic ensembles above a superconducting microwave resonator operating at 4 K to demonstrate strong coupling to the waveguide mode, a key milestone for implementing the hybrid interface. The ensembles will then be utilised to perform coherent storage and retrieval of optical photons, as well as generation of single photons using four-wave mixing. The second stage is to exploit the off-resonant interaction with the cavity to achieve controllable long distance (~1 cm) entanglement between a pair of ensembles trapped within a single microwave resonator. This will then be used to generate entangled photon pairs, exploring the benefits of collective encoding within the ensembles for achieving entanglement in the polarisation degrees of freedom for long-distance cryptographic quantum key distribution. The resulting hybrid quantum interface provides an ideal building block for establishing quantum networks. Long term this can be integrated with existing superconducting qubit technologies, making a significant step towards the realisation of scalable quantum computing.

Recent reviews of how much marine sedimentary rock remains preserved on land have highlighted just how variable that record is from different time periods, both in terms of environmental representation and absolute rock volume. As a result we now know that the rock record over the continental shelf is very cyclical in structure. At its most fundamental level the Phanerozoic rock record comprises two cycles defined primarily by changes in the ratio of marine to terrestrial rock. These cycles are evident across both Northern and Southern hemispheres although their precise timing differs slightly. They arise in response to major global tectonic cycles of plate assembly and rifting. Superimposed on these are shorter-term (ca. 50 My) cycles, which are largely independent in timing from continent to continent and which reflect regional tectonic events and local sea level changes. Marine biodiversity, as measured by counts of macrofossils, also shows a cyclical pattern. These cycles match changes in the extent of continental flooding and thus could be generated through one of two processes: they could arise because of sampling bias, as the amount of marine sedimentary rock of a particular age that is ultimately preserved varies as seas expand and contract over the continents; or biological diversity could be rising and falling in tandem with the expansion and contraction of shallow marine seaways. At present it is not clear which is the predominant driver of the marine fossil record because there is high spatial heterogeneity of faunas within shallow water environments leading to a very strong species-area effect (the wider an area sampled the more species will be found). So far all the attention has been focussed on the rock and fossil records of the continental shelves. Large scale analyses of the nature of the deep-sea record and whether it correlates with marine diversity have never been explored. There are strong grounds for thinking that the deep-sea rock and fossil records might be different from that preserved on the continental shelves. For one thing much of the sedimentary record comprises near continuous biogenic deposits derived from planktonic microorganims which only rarely encroaches far onto the continental shelves. Furthermore, in the open oceans marine plankton are widely dispersed, so that any species-area effect is much less evident. Yet we also know there are hiatuses and barren intervals in the deep sea due to non-preservation, and the numbers of cores yielding fossiliferous rocks of a specific age is unlikely to be uniform over time. What is more, planktonic foraminiferans are reported to show a 30 myr cyclical rise and fall in diversity. To clarify whether fossil diversity patterns are causally linked to rock sampling patterns we will focus on the fossil record of two important planktonic groups, coccolithophorids and planktonic foraminifera. We will first identify any possible biases in the deep-sea record by assessing the distribution of gaps and non-preservation hiatuses in the sampled record of the central Atlantic, and test how much these actually affect diversity counts (for geographically widespread taxa variation in density of sampling should have a minimal effect). By recording their diversity through time from deep-sea cores and comparing this with their diversity patterns as derived from land-based outcrops, we hope to be able to show whether the 30-Myr cyclicity is a genuine biological signal or an outcome of the extent to which open oceanic sedimentation encroaches onto the continental blocks during high sea-level stands. We will also compare the nature of the deep-sea sedimentary rock and fossil records with rock and fossil records derived from land-based sections on adjacent continents to find out whether the deep-sea fossil record is immune from many of the biases affecting the shallow water record, or whether both covary in quality.

Geothermal energy provides an important alternative to fossil fuels, both for heating and for electricity generation. EGS (enhanced geothermal systems) enables the targeting of deep rock formations, at ~2 to 5 km depth for heat extraction. However, few attempts at EGS development have reached the commercial stage. A recent review identifies ~30 EGS sites in granites or other crystalline rocks worldwide, a large proportion of which have failed. One main reason is difficulty in developing EGS without generating unwanted seismicity. In the UK, the unsuccessful Rosemanowes project, in the Carnmenellis granite pluton in west Cornwall, was shut down in the early 1990s, after years of hydraulic fracturing failed to establish any significant inter-well hydraulic connection. This failure killed UK EGS R&D for a generation. Most recently, starting with drilling in 2019, a second project - at the United Downs site - has proceeded in the Carnmenellis granite. However, although the developer has not yet made any official announcement, for months the UK geothermal community 'grapevine' has discussed reasons why this project is in trouble, involving both seismicity and the lack of hydraulic connection between wells. This latest failure, involving the loss of a ~£20 million investment, highlights the need for greater expertise in EGS. Despite the body of research on reservoir stimulation, the general processes that govern the evolution of in-situ stress during reservoir stimulation, and the associated anthropogenic seismicity, still remain poorly understood. For example, how does chemical stimulation change the mechanical state of a fault surface? Will chemical reactions, creating new secondary minerals, alter the frictional properties of a fault in a manner that favours instability? How does the traction on a fault evolve as material is removed by dissolution? How do we manage fluid injection rates and pressures to avoid anthropogenic seismicity? This project aims to create a new multidisciplinary environment and identify key scientific questions that need to be addressed to mitigate risks of failure for future EGS projects. We have assembled a team of enthusiastic early-career and more senior researchers with high international standing and expertise in geoscience, geomechanics, and geophysics, from University of Glasgow (UG) in the UK, University of Wisconsin-Madison (UW) and Lawrence Berkeley National Laboratory (LBNL) in the USA, and Sinopec Research Institute of Petroleum Engineering (SRIPE) in China. Only by working together, can we use our complementary expertise, advanced laboratory facilities, unique field resources and site data to cover multiple scales and aspects that cannot be achieved by individual institutions. We will apply integrated laboratory, modelling and field approaches to develop new scientific understanding of how anthropogenic seismicity caused by geothermal reservoir stimulation can be controlled and eliminated. UW and LBNL will lead the experimental study using their laboratory facilities. The laboratory study will provide data for coupled modeling, which will be led by UG. SRIPE will lead field study and bring in unique resources and data from their Gonghe EGS site (the first and the most important EGS site in China). The field study at the unique Gonghe EGS site will provide vast future collaboration opportunities. We have also designed outreach and partnership activities to facilitate interaction and collaboration between researchers, and to develop long-term sustainable collaborations. These activities include two site visits (to Gonghe EGS site), annual 2-day workshops (in 2022 at UW and in 2023 at UG), 6 online smaller group meetings, and a project website. We expect this project will have significant impact on public and governmental attitudes to EGS in the UK and worldwide by contributing to evidence-based seismicity control and thus to breaking the existing pattern of EGS project failure.

'Brecht into English' is a major international research project devoted to a critical appraisal of the transmission of Brecht's writings and ideas into English, to a historical assessment of the reception of Brecht in the English-speaking world, and to the development of principles of edition and translation. It will advance our understanding of the ways in which, not just Brecht, but foreign literatures in general and across the full range of genres, negotiate cultural difference. It will result in major research publications, both in articles and special issues of internationally respected journals and in significant additions to the corpus of Brecht's writings in the English language. It will also provide integrated opportunities for cultural interchange with non-academic institutions through a programme of workshops and the like. Brecht is, internationally, one of the most performed of all writers for the theatre, often accounted second only to Shakespeare. His work is of huge significance for the professional theatre, in Britain and elsewhere, as well as for schools and drama colleges. At the same time, his cultural theoretical writings underpin work in media and cultural studies (esp. film) and in the development of a critical cultural theory. And, thirdly, he is widely recognised as the most important German poet of the twentieth century and enjoys an international reputation as one the greatest of Modernist poets. The translation, edition and transmission of the works of such an author in the English language is as important as that of Freud or Marx, e.g., yet it has been the subject of little critical analysis and engagement. 'Brecht into English' aims to set that right, by engaging an international network of leading Brecht scholars to reflect critically on the processes of translation and cultural transmission in the English-speaking world, both in the theatre and in print, and finally to contribute key volumes to the ongoing critical edition in English of Brecht's huge and varied oeuvre. The project will be coordinated by Dr Tom Kuhn who, as an editor of the 'Methuen Drama' Brecht list (some 40 titles) since 1996, has enjoyed a privileged overview of Brecht translation and reception. He is one of the leading scholars of Brecht in the English-speaking world, with numerous publications. Having, over decades, nurtured relationships, not only with Brecht scholars, but also with the Brecht heirs (the copyright holders) and with the relevant publishers, Dr Kuhn has persuaded the interested parties to embark on several important new publications: a thoroughly revised Brecht on Theatre and a further volume, Brecht on Performance (much of the material appearing in English for the first time) which together will complete the 4-vol. set of theoretical writings; an entirely new 5-vol. edition of the Collected Poems; and a critical edition of the Berliner Ensemble Adaptations, to complete the 9-vol. Collected Plays. The translators, editors and other scholars assembled in this context represent a Core Team, poised to exploit an exciting opportunity to reflect both on the pragmatics of translation and on theories of intercultural exchange. Central questions about the practices of translation, adaptation and cultural hybridity will be addressed in workshops and conferences. It is expected that the project will attract the International Brecht Society's (triennial) conference to Britain in 2016 on the theme 'Recycling Brecht'. There will be an exchange with theatre practitioners, led by the director Di Trevis, which will feed directly into the planned publications and into a parallel cultural programme. The project will have outputs, not only in the critical editions enumerated above, but also in special issues of major publications, including the Brecht Yearbook, research articles in peer-reviewed journals, and, finally, workshop protocols and films.