After spinal cord injury, nerve cells are lost and never replaced. Attempts to replace the lost nerve cells are met with limited success in mammalian models. Alternatively, dormant stem cells, which do exist in mammals, could be reactivated to produce new nerve cells, but these cells do not receive the right signal in the injured spinal cord. In contrast, zebrafish stem cells are reactivated after injury and produce nerve cells that are integrated in the injured spinal cord, and fish fully recover from paralysis. As any injury, spinal cord injury elicits an inflammatory reaction, and we have previously shown that this is necessary for regeneration of nerve cells in the zebrafish. However, the identity of the molecular signals that are received by the stem cells in the injured nervous system are unclear. We have analysed the genes that are expressed in single immune cells and stem cells and found specific matching signal (semaporins) and receptor genes (plexins) to be present. Here, we want to test whether this signal/receptor interaction is crucial for regeneration of nerve cells in zebrafish, by mutating the genes in turn and determine whether regeneration is impaired. This research can thus identify the 'language' in which immune cells communicate with spinal stem cells to bring about regeneration. Ultimately, similar signals may be used in therapeutic approaches to instruct the stem cells in mammals to produce nerve cells after an injury and thus bring about repair.

After few decades of investigations just a handful of materials undergoing singlet fission are known despite the strong interest for fundamental science (photophysics, quantum dynamics, quantum chemistry) and the acknowledged potential for technological applications in photovoltaics and other optoelectronics devices. The limited number of available materials is very concerning because one needs a large pool of compounds to optimize device performance, processing and integration with other materials. Moreover, the fundamental understanding is severely limited when the systems that can be studied are so few. This proposal will address the key limitation of the field, identifying a set of materials suitable for singlet fission by an innovative high-throughput computational screening approach. For all the new candidates found within this project a synthetic route is available and the crystal structure is known, i.e. the prediction will be about EXISTING MOLECULAR MATERIALS rather than hypothetical molecules. Unsuitable molecular arrangements in the crystal are taken into account and all the criteria for singlet fission can be imposed in parallel. The prediction will be accompanied by a level of confidence obtained by calibrating the method against a large number of know experimental data (Objective 1). Our preliminary work on a small sample of the compounds to be screened and on the calibration of the methodology has already led to the discovery of few highly promising candidates. Our projections indicate that more than a hundred new molecules (not already known to undergo singlet fission) can be discovered in this way. The computational screening is followed by a thorough post-processing analysis to identify new design rules for singlet fission and assess the validity of the old ones. These rules will guide the development of new singlet fission materials from the lead compounds identified by this work (Objective 2). The preliminary experimental validation of the prediction is part of this project (Objective 3). A small sub-set of molecules to be characterized optically will be selected among those easier to obtain from collaborators or commercially. The optical characterization will be performed by our partner Prof. S. Reineke (TU, Dresden).

More intense drought and increased temperatures reduce tree growth and drive tree die-back and mortality across the globe. While this problem has been recognized for some time, the processes and geographical extent of forest growth reduction and die-off are not well understood. Predicting the response of Europe's forests to drought and temperature change a key challenge because forests have enormous economic and ecological benefits that will be impacted as climate warms and becomes more extreme. Addressing this problem requires an interdisciplinary approach that brings together world-leading expertise in in forest ecology, Earth observation, dendroecology and process-based modelling. Our team has a strong record of scientific excellence and method development as well as expertise in transferring scientific advances into practical applications with international policy and economic impact. We use European beech as an indicator species to study this problem because it is the most widespread broadleaf tree in Europe covering over 15 million hectares. Beech produces valuable wood with very diverse uses and it is known to be at high risk from drought-linked die-back and mortality. Our research is highly novel because it will link together satellite observations and process-based models calibrated from the European Beech Tree Ring Network, a data network that provides a detailed picture of tree growth from about ten thousand individual trees across 25 countries. These data will enable us to model the processes of tree growth suppression and to map and monitor drought-stress vulnerability across the entire range of beech in near real-time. We will advance knowledge of the response of beech to environmental variation and produce models that predict tree growth based on local climate and soil moisture across Europe. The models and tree ring data will provide a detailed picture of growth suppression and dieback risk. Furthermore, we will combine the site-specific models with satellite data to establish an open-source web-based monitoring platform that will form the basis for decision support for forest managers and policy makers. This project is highly timely, since cloud-based computer processing of satellite imagery now avoids the need to download and pre-process large volumes of satellite data. Such cloud processing makes data analysis at this scale efficient and cost effective, with outputs available to all via a simple web-based interface. We will contribute major new scientific insights into forest growth reduction and die-off in response to drought, with substantial benefits for improving our understanding of impacts on our ecoststems and atmosphere. Furthermore, we will apply our research to provide operational guidance on species suitability and growth predictions for forest management. In the UK this will be achieved by working with Forest Research to improve their Ecological Site Classification Decision Support System for beech. The system is open to all and is widely used by foresters and policy advisers. Once adapted using our results for beech, these changes to decision support tools can be extended to other forest-forming tree species and will also underpin future planning of semi-natural woodland in the UK. Our project outputs will give broad benefit from cutting edge research to forest decision support. We will map early-warning signals of growth decline and mortality and impacts of drought on growth across the entire range of European beech. We will predict future impacts of climate change on forest growth and mortality, improve estimates of forest carbon uptake and provide the tools to monitor these effects using satellite data. Overall, our research will substantially advance our understanding of past, present and future drought impacts on beech forest across Europe and provide the capability to monitor and manage our forests for the future.

The elucidation of the structure of DNA in 1953 kick-started the revolution in life science research and marked the beginning of modern molecular biology. While we do know the structure of DNA at atomic level resolution, it is still mysterious how DNA is packaged in the cell. Human genomic DNA that, if it were stretched out, would reach over two meters in total. In a cell, all this DNA needs to be compacted into a micron-sized nucleus. One basic unit of coiling DNA is the nucleosome, which has for decades been viewed as the first step in condensation of the DNA. However, it is now clear that the main function of nucleosomes is not to enable large-scale genome packaging. Instead, higher-order genome folding is mediated by Structural maintenance of chromosomes (SMC) proteins, an ancient class of ATPases that is found in all domains of life. SMC proteins are large, ring-shaped proteins that act by DNA loop extrusion. While the details are currently unknown, the consequences are that SMC proteins organise DNA into large, dynamic loops. It is becoming increasingly apparent that this chromosome folding reaction is important for many of the most fundamental aspects of genome biology: control of gene regulation by distant regulatory elements, genome replication and repair as well as chromosome segregation during mitosis and meiosis. There are indications that mutation of cohesin subunits plays an important role in a number of cancers and 'cohesinopathies'. We here propose to address two key aspects of this genome folding reaction catalysed by cohesin, on such SMC protein complex. We aim to understand: 1. The structural mechanism of how cohesin catalyses 3D genome folding, and 2. The mechanism that allows cohesin to be deployed during a number of different genome transactions. To achieve these goals, we need to understand better the structure of cohesin holocomplexes and how they interact with DNA and catalyse folding. We also need to address how cohesin interacts with regulators that allow specific deployment during different genome transactions. The different protein subunits of the cohesin complex are mutated in many 'Cohesinopathies' that range from cancer to developmental disorders. More specifically, cohesin dysregulation during meiosis in oocytes can lead to mis-segregation of chromosomes resulting in cells with the wrong number of chromosomes, a hallmark of Down's syndrome (Trisomy 21) and a leading cause of age-related aneuploidy and infertility. Mutations in the cohesin complex are associated with genetic diseases such as Cornelia de Lange and Roberts syndrome which result in severe development defects. Cohesin mutations also can result in genomic instability due to mis-processing of chromosome loops, dysregulation of chromosome replication, repair or segregation. Mis-processing of loops may be at the origin of extrachromosomal DNA loops that overexpress oncogenes and have been identified with high frequency in half of all solid tumor cancers. We therefore need a much better understanding of the molecular mechanisms of cohesin function, regulation and deployment in different chromatin transactions. This will allow us to better understand how mutations contribute to disease. This in turn will allow us to better understand the molecular mechanisms underlying different diseases and to potentially develop new approaches in treatment against cohesin-related cancer and Cohesinopathies. The long-standing challenge will be to understand how the molecular mechanism of genome folding leads to hierarchical genome organisation, and how such organisation leads to emergent properties of genome function (such as long-range gene regulation) and how dysregulation contributes to disease.

There is growing recognition that reducing global AMR requires integrated surveillance of clinically relevant markers (e.g., genes associated with specific resistant pathogens, "drug-bug" combinations). However, there is no consensus regarding which markers to target and what exposures are safe, or what technologies are most suitable for monitoring the selected markers. The proposed TEXAS project will define a suite of genetic markers that best describe AMR status of a targeted location, and integrate them into multiplexed platforms using new technologies that do not require cultivation of bacteria. A digital droplet PCR (ddPCR) platform (suitable for high income regions) will quantify clinically relevant markers in a diverse range of environments, generating large and synchronized datasets that can be exploited for comparative AMR status, facilitating understanding of AMR across different One Health sectors. In tandem, an electrochemical biosensor will provide a means for high-throughput on-site monitoring of selected AMR markers. The biosensor does not require special equipment or trained operators, and thus can be applied in low income regions that lack sophisticated infrastructure. The multidisciplinary TEXAS consortium includes experts in electrical and water engineering, genomic epidemiology, molecular microbial ecology, public health, and policy guidance. Consequently, we are confident that the project will generate implementable technological solutions that can be adopted by stakeholders for integrated surveillance that will be fundamental to reducing global AMR.