Typhoid fever is an infectious disease caused by Salmonella Typhi resulting in 14 million cases, 140,000 deaths and 8 million daily-adjusted life years lost to ill health per annum. The problem is exacerbated by antimicrobial-resistance and poor diagnostics due to a lack of suitable biomarkers. We must advance understanding of typhoid to accelerate development of therapeutic interventions, which represent priorities for the WHO and UN Sustainable Development Goals. S.Typhi lives inside our gut cells before infecting the bloodstream (bacteraemia) and spreading to different organs in the body resulting in typhoid fever. My UKRI FLF was awarded upon our discovery that S.Typhi causes premature ageing in human cells by releasing a toxin. The typhoid toxin causes DNA damage in our cells, in much the same way as UV light, and this elicits an ageing-like process in cells called acute senescence. Ageing comes with increased susceptibility to infection. Thus, we initially hypothesised that the toxin causes senescence to make human cells more vulnerable to infection. To our surprise, discoveries during my FLF indicate the opposite may be true and that acute senescence is a novel immune defence pathway, which can attack S.Typhi through antimicrobial activities and help prevent typhoid. This is unexpected yet, in early life, acute senescence is known to prevent cancer, thus, we hypothesise that acute senescence may have co-evolved to counteract infectious diseases such as typhoid. The FLF renewal aims to lead a new area of research investigating Acute Senescence Antimicrobial Responses (ASAR). Our experiments with cultured cells and clinical samples indicate that when typhoid toxin causes DNA damage, cells signal their distress by (i) entering into a senescent state through the human gene p21, and by (ii) secreting antimicrobial proteins into the extracellular environment. In cancerous cells, p21 stops the cells from growing into tumours and secrete proteins that attracts immune cells to destroy the cancer cells. Thus, we will determine whether p21 launches ASAR: (i) by suppressing the growth of S.Typhi living inside senescent cells, and (ii) by suppressing the growth of extracellular S.Typhi via secretion of antimicrobials and immune cell attractants. This is how we will investigate ASAR: Objective 1: Advance discovery of antimicrobials secreted in human participants with typhoid. A clinical study revealed that the duration of bacteraemia in human participants with typhoid was shorter with wild-type (WT) S.Typhi carrying typhoid toxin than toxin-negative (TN) S.Typhi (WT 48 hours; TN 96 hours). This indicates that unknown factors are attacking WT but not TN S.Typhi. Thus, we will determine whether clinical samples from participants infected with WT contain antimicrobial biomarkers released in response to typhoid toxin. Objective 2: Determine whether antimicrobial responses are regulated by senescence. We will validate whether antimicrobial biomarkers identified through objective 1 rely upon p21-mediated senescence. This will be achieved by examining Salmonella-infected cells undergoing senescence in human tissue culture experiments and infected mice Objective 3: Establish antimicrobial activities of the Acute Senescence Antimicrobial Response We will progress from objective 2 by elucidating whether secreted senescent-associated antimicrobial biomarkers attack extracellular S.Typhi and whether p21 in the infected senescent cells suppress infection by activating intracellular defences against S.Typhi. By revealing ASAR as a novel innate defence suppressing Salmonella infection, my team will discover a new immune pathway that combats typhoid fever, which will be significant during infections by related pathogens of global importance. By leading a new area of research on ASAR, the renewal will facilitate ways to enhance ASAR and discover of translatable antimicrobial biomarkers with diagnostic potential.

The northern coast of Peru has been experiencing anomalously warm (4-5C) sea surface temperatures (SST). These high SSTs have produced intense and prolonged rainfall that has resulted in extensive flooding, and on the 26th March 2017, the Rio Piura in northern Peru burst its banks leading to loss of life, displacement of people and damaged infrastructure. Peru is intimately linked to the El Niño-Southern Oscillation (ENSO): fishermen first identified El Niño in the late 19th Century off the north coast of Peru. The phenomenon driving this current acute rainfall event has been dubbed 'El Niño Costero' or Coastal El Niño, but is not El Niño per se as it is not being driven by anomalous SSTs in the central Pacific (Niño 3.4), which generally defines the onset of El Niño. Rather it represents more local (Niño1+2) El Niño-like conditions last known to have occurred in 1925, which is considered the most intense flooding of the 20th Century. Despite Peru's preparedness for the global El Niño in 2016, the country appears to be overwhelmed by the sudden shift from La Niña drought to the intense rainfall of El Niño Costero, suggesting this type of locally driven El Niño event has hitherto been overlooked. It is essential to establish a record of El Niño Costero alongside ENSO, especially as the 1925 event was the most extreme on record. If local SSTs cause El Niño-like conditions and play an important part in climate dynamics in northern Peru, but have so far been overlooked, then we don't have a full understanding of tropical Pacific climate change. Critical to understanding equatorial Pacific climate change are records of extreme flood events that reflect El Niño-type behavior, and in particular how El Niño Costero fits within the wider climate picture. This proposal is based on a unique opportunity to quantify and determine the dynamics and evolution of a large magnitude flood, and to use its sedimentary signature, coupled to climatological data over the last 120 years, to unequivocally fingerprint and calibrate past El Niño-type events in recent lake sediments. We will (a) undertake a geophysical survey of lakes in the Rio Piura catchment that act as repositories of flood-waters and sediments, and we will identify modern flood sediments and determine their depth and extent; (b) recover and survey surface sediments related to flooding to characterize their flood signature using grain size, geochemistry and mineral magnetics; (c) recover and date short sediment cores from our survey lakes and directly compare the flood signature of the 2017 El Niño Costero to the 1925 event, as well as putting it in the context of 20th Century ENSO variability. Our study will provide a framework for reconstructing El Niño-related flood events from lake sediments over the recent past in northern Peru, but has the potential to establish a much longer-term (Holocene and older) history of all El Niño variability in the region.

The Fellowship will pioneer the concept of integrated numerical modelling for coastal defence design by combining two different classes of numerical model for wave transformation in the coastal zone and wave-structure interaction.This will enable simultaneous investigation of those physical processes that act at very different spatial scales and influence wave propagation and the performance of coastal structures during extreme storms and flooding. The Fellowship is motivated by the pressing need for the coastal research community to provide for advanced design tools that can help designers and coastal communities in optimizing the resources needed for designing, building and maintaining coastal defences.The Fellow will lead a research team that will develop these tools using an open source platform. A modular approach will be pursued so that at the end of each task of the project a self-standing, well-tested numerical tool can be delivered. The research will then focus on the most challenging task: interfacing a coastal model with one model able to investigate the local-scale processes that act in the near field of coastal structures and thereby to determine their performance. Additionally, a large-scale wave generation and a surge models will be interface with the coastal model. This integrated model will be first built for one-dimensional wave propagation and therefore the fully two-dimensional case. This model will have the remarkable capability of describing the features of the wave propagation and describe the three-dimensional nature of the flow in the near field of structures of interest. In order to be efficient and to benefit coastal designers, this interfacing should be possible both for non-breaking waves and breaking wave conditions. This is particularly challenging since it will require that the two-dimensional coastal model be equipped with an accurate sub-model to describe the turbulence transport due to wave breaking. The research team will also establish a methodology able to measure the uncertainty of the prediction of the numerical model at hand.The research objectives will be measured by the accuracy of the simulations of selected test cases found in literature. The project will culminate in the analysis of a test case, involving a realistic scenario of coastal flooding in the presence of defence structures, which will measure the benefits of the use of an integrated modelling approach with respect to the state of the art in coastal design.

People with schizophrenia suffer from a range of symptoms including hallucinations (such as hearing voices), delusions (false beliefs) and thought disorder (thoughts not flowing in a logical way), as well as 'negative symptoms' such as a lack of motivation and withdrawal from social contact. Currently, antipsychotic medication is the mainstay of treatment of schizophrenia and all existing antipsychotic medications are thought to work by acting to reduce transmission of a brain chemical called dopamine. However, even after attempts to treat the disorder with two different antipsychotics, around 30% of patients still fail to improve. When this happens, the medical guidelines recommend treatment with a different drug called clozapine. However clozapine has several side effects and requires regular blood tests, so people do not like taking it. It is also ineffective in some patients. The result is that a large number of patients spend too long on ineffective drugs which impact greatly on their mental health, well-being and quality of life whilst the costs of ineffective treatment is a huge financial burden to the NHS, consuming 25-50% of the total national mental health budget. This set of studies aims to build on new evidence from neuroimaging and genetics studies suggesting that those who do not respond may actually have a completely different neurochemical abnormality causing their symptoms, involving a different chemical called glutamate. There are some new medicines under development that we hope will help people whose illness has not responded to standard medicines acting on dopamine. We aim to develop a method to predict, ultimately as early as first admission, which patients will respond to standard dopamine drugs, and which people are instead more likely to respond to the new glutamate drugs. This will allow people to receive the medicines they need straight away, without having to try ineffective drugs first. The proposed research programme is broken down into several parts. The first set of studies will use cutting edge brain scans to confirm that those patients who don't respond to standard treatments have higher glutamate levels, but normal dopamine levels. We will then develop tests, using genetic markers and other information, to identify in advance which people will respond to which medication types. If this is successful, we will then conduct a clinical trial to see whether prescribing medicines according to the test results gives better outcomes for patients than the 'trial and error' method by which we prescribe medicines at present. Lastly we will investigate economic benefits and, with Service User groups, investigate the acceptability of an early identification tool from the patient perspective.

The NDECA project aims to extend the applicability of fracture mechanics methods for predicting the behaviour of structures/components containing non-sharp flaws. Many defects formed during manufacture or in service (e.g. porosity, dents or corrosion pits, weld defects, etc.) and certain design features (e.g. crevices in partial penetration welds) are not sharp i.e, have non-zero crack tip radius. Common structural integrity assessment procedures- such as R6 [1] and BS7910 [2]- use fracture mechanics principles for the assessment of flaws that are assumed to be infinitely sharp. While this approach is appropriate for planar (2D) flaws, such as fatigue cracks, it can be excessively conservative for non-sharp defects, leading to erroneous decisions (replace/repair/re-inspect), thus reducing assets cost-effectiveness (through increasing operating costs and/or reducing service life). Several assessment methods have been proposed in the literature to quantify the additional margins of safety of non-sharps defects compared to the margins that would be calculated if the defects were assumed to be sharp cracks. Unfortunately, the validation and application of these methods is currently limited by the lack of both credible non-destructive evaluation (NDE) techniques to distinguish between sharp and non-sharp flaws and; representative and reproducible effective fracture toughness testing procedures. Therefore, this proposal will focus in the: -Development and validation of novel NDE methodologies for accurate notch-tip acuity characterisation; -Development of recommendations for future fracture mechanics-based test methods to account for the defect topology on the resistance to failure. This multidisciplinary effort - it cuts across multiple academic fields, i.e. ultrasonics and NDT, mathematical modelling, engineering structural integrity, finite element analysis, and engineering design - will produce a step change improvement in damage tolerance methods for the next generation of design (by analysis) and structural integrity procedures of high integrity structures, allowing enhanced efficiency of assets. The project is supported by TWI, Wood, RCNDE, University of Cantabria and BP. NDECA takes advantage of the UK's leadership and experience on the development of structural integrity assessment procedures (TWI, Wood, BP), the application of NDE methods for defect characterisation (University of Bristol Ultrasonics and NDT group, TWI and RCNDE members) and experience with FEA damage simulation and testing of non-sharp defects (Larrosa [PI], Wood, University of Cantabria). The timeliness and critical needs for this project are reflected in requirement for more precise methods in life extension programmes for in-service nuclear power plants and Oil and Gas high integrity assets which are currently at (or close to) the end of the design life. References 1. R6 - Revision 4, Assessment of the Integrity of Structures Containing Defects, Latest Updates: March 2015. EDF Energy, Gloucester, UK. 2. BS7910: 2013+A1:2015, incorporating Corrigenda Nos.1 and 2, 2016. Guide to Methods for Assessing the Acceptability of Flaws in MetalliMetallic Structures. British Standards Institution, London.