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We will build on this to address the responsible use of natural resources by: (i) quantifying how climate and human stressors impact water resources and identifying the appropriate water abstraction technologies and how these are governed to ensure they remain functional in the long term; (ii) enhancing the understanding of the mineral and energy resource potential in the region to facilitate informed policy development, support effective governance mechanisms, and aid inward investment; and (iii) using geological science to increase agricultural productivity and tackle micronutrient deficiencies by carrying out research linking bedrock geology and minerals to soil type thus informing decisions on improving soil quality, use of fertilisers, water retention, and plant nutrition. Asian cities (RP2) are exposed to multiple natural hazards, the pace of urbanisation is often overwhelming and their resilience to environmental change unknown. Our research will: (i) identify how innovative use of data-informatics, sensor technologies, and modelling systems can improve urban planning; (ii) assess the effect of multiple environmental and demographic stresses on the city and its rural catchment, and the extent to which further urbanisation can be sustained; and (iii) determine inter-dependencies between human and Earth systems in cities, and whether this understanding can be used to make city services more resilient. Natural geological hazards and their associated risk (RP3), including volcanoes, earthquakes, and landslides, and their impacts, are of key concern to long-term economic growth. Our research, focused on Latin America and the Caribbean, and the regions covered by RPs 1 and 2, will: (i) advance research into environmental processes and the interactions of multi-hazards (e.g., an earthquake triggering landslides); (ii) develop and utilise novel data collection, monitoring, and communication/ visualisation techniques to improve disaster resilience; and (iii) build on our humanitarian assistance activities, and long-term planning experience to co-develop proactive systems to support NGOs, governments and mandated authorities when geohazards occur. Research will be co-designed using participatory workshops. It will aim to build sustainable networks of scientists, policy makers, NGOs, and communities. The long-term benefits of this research are knowledge exchange and its contribution to achieving the SDGs. Throughout the project, the RPs will act as a catalyst for BGS and UK-based research applications to GCRF, Newton, Royal Society and other funds. 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I will explore these techniques for the transmission model, and also in statistical modelling aiming to account for the observed patterns of drug-resistance. The transmission model will ultimately be extended to include different types of drug resistance. As new treatments and vaccines emerge, those with responsibility for public health will want to understand the potential impact these new technologies can have in terms of gains in health, and changes in spending. Producing cost-effectiveness and budget impact evidence requires a model that includes transmission, in order to account for indirect benefits accrued by avoiding secondary cases. We will use our model to provide guidance to decision-makers seeking to maximise health gain with limited resources. 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Malaria deaths across Africa in particular have plummeted since a peak in the 1990s, when failure of the drugs chloroquine and sulphadoxine-pyrimethamine precipitated a rise in infant and child deaths. A key component in all the currently effective drug combinations is the plant-derived chemical called artemisinin. The parasite-killing ability of artemisinin has recently been threatened by the emergence of reduced susceptibility in the Mekong region: this is manifest as a slowing of artemisinin clearance of P. falciparum from the blood of treated malaria patients. Although under combination treatments these patients should eventually experience a full cure in most cases, in this region the combination partner drugs are also failing in some patients. Careful monitoring and vigilance of malaria drug resistance is therefore needed. A parasite gene has been identified in Cambodia and the surrounding region which contributes to the loss of effectiveness of the artemisinin drug - this gene, which encodes a kelch-domain protein and is called K13, has accumulated a variety of mutations. These are strongly associated with the loss of effectiveness of artemisinin against these parasites. However, this same phenomenon has not yet been observed in African malaria parasites - in the small number of cases where drug treatment does not work, K13 mutations are not implicated as the cause. In the past 2 years, gene-editing studies by ourselves and others have successfully demonstrated a direct effect of 3 genes in reducing susceptibility to artemisinin : pfap2mu, pfubp1 and pfcoronin. Variants of these genes elicit increased parasite survival in vitro in the ring-stage artemisinin survival assay (RSA). In the case of trafficking adaptor potein subunit AP-2mu, we have shown that the role of this protein in P. falciparum is unlike in other organisms as it does not interact with clathrin, but is associated with an as yet unknown compartment in the cell that appears to also contain K13, although we found no evidence of direct interaction between AP-2mu and the K13 protein. There is, however, good evidence of direct interaction of AP-2mu with a different kelch protein , K10. Polymorphisms in the gene encoding the K10 protein have been previously identified as a genetic component of parasites from the Mekong region in which the K13-dependent reduced artemisinin susceptibility originally arose. This work was carried out by PhD student Ryan Henrici, who completed his doctoral studies in 2018 and has moved on. We now request support to extend this work, using gene editing to test the effect of new mutations. In preliminary studies of both field samples and UK isolates, we have already identified a number of such new mutations in our current five genes of interest - pfk13, pfap2mu, pfubp1, pfcoronin and pfk10 (see Case for Support). For each new isolate (either from the UK or from our collaborator Dr Bismarck Dinko in Ho, Ghana) that is adapted to culture, we will fully test drug susceptibility, and genetically characterise them using genome sequencing. In gene-editing experiments we will then directly measure the impact of each candidate gene variant in both established laboratory lines and in our new cultures from UK and Ghanaian patients; any variant proven to generate a drug susceptibility phenotype may therefore be contributing to changing patterns of drug susceptibility, and could be developed as a surveillance marker for use in malaria endemic areas. Our work will thus assist our understanding of resistance to our current combination drugs, and help us to devise strategies for deploying these drugs carefully in both the UK and Africa, to maximise their useful life in curing malaria patients.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. 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