Biological-physical interactions are fundamental to understanding and managing coastal dynamics.

There is an urgent need to address coastal dynamics as a fundamental interaction between physical and biological processes, particularly when trying to predict future biological-physical linkages under anticipated changes in environmental forcing. More integrated modelling, support for observational networks and the use of management interventions as controlled experimental exercises should now be vigorously pursued.

Novel luminescence diagnosis of storm deposition across intertidal environments.

Salt marshes provide valuable nature-based, low-cost defences protecting against coastal flooding and erosion. Storm sedimentation can improve the resilience of salt marshes to accelerating rates of sea-level rise, which poses a threat to salt marsh survival worldwide. It is therefore important to be able to accurately detect the frequency of storm activity in longer-term sediment records to quantify how storms contribute to salt marsh resilience. Luminescence is able to infer how long mineral grains were exposed to sunlight prior to burial (e.g., the presence or absence of sediment processing). This study used sediment cores collected from the Ribble Estuary, North West England, to show that luminescence properties of sand-sized K-feldspar grains can diagnose the differential modes of deposition across intertidal settings (i.e., sandflat, mudflat and salt marsh) in longer-term sediment records by detecting the variability in sediment bleaching potential between settings (i.e., sediment exposure to sunlight), thus establishing a framework for the interpretation of luminescence properties of intertidal sediments. It then used modern sediment samples collected before and after a storm event to show how such properties can diagnose changes in sediment processing (i.e., bleaching potential) of mudflat sediments caused by storm activity, despite no changes in sediment composition being recorded by geochemical and particle size distribution analyses. This new luminescence approach can be applied to longer-term sediment records to reveal (and date) changes in the environment of deposition and/or depositional dynamics where there is no obvious stratigraphic evidence of such.

Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention.

We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial drug-like compounds (MMV019721 and MMV084978) selects for mutations in PfAcAS. Metabolic profiling of compound-treated parasites reveals changes in acetyl-CoA levels for both compounds. Genome editing confirms that mutations in PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate that PfAcAS is essential for asexual growth, and partial knockdown induces hypersensitivity to both compounds. In vitro biochemical assays using recombinantly expressed PfAcAS validates that MMV019721 and MMV084978 directly inhibit the enzyme by preventing CoA and acetate binding, respectively. Immunolocalization studies reveal that PfAcAS is primarily localized to the nucleus. Functional studies demonstrate inhibition of histone acetylation in compound-treated wild-type, but not in resistant parasites. Our findings identify and validate PfAcAS as an essential, druggable target involved in the epigenetic regulation of gene expression.

Prioritization of Molecular Targets for Antimalarial Drug Discovery.

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in Plasmodium species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery. We describe the analysis of a number of drug targets in the Malaria Drug Accelerator (MalDA) pipeline, which has allowed us to prioritize targets that are ready to enter the drug discovery process. This selection process has also highlighted where additional data are required to inform target progression or deprioritization of other targets. Finally, we comment on how additional drug targets may be identified.

Uncertainty in estuarine extreme water level predictions due to surge-tide interaction.

Storm surge is often the greatest threat to life and critical infrastructures during hurricanes and violent storms. Millions of people living in low-lying coastal zones and critical infrastructure within this zone rely on accurate storm surge forecast for disaster prevention and flood hazard mitigation. However, variability in residual sea level up-estuary, defined here as observed sea level minus predicted tide, can enhance total water levels; variability in the surge thus needs to be captured accurately to reduce uncertainty in site specific hazard assessment. Delft3D-FLOW is used to investigate surge variability, and the influence of storm surge timing on barotropic tide-surge propagation in a tide-dominant estuary using the Severn Estuary, south-west England, as an example. Model results show maximum surge elevation increases exponentially up-estuary and, for a range of surge timings consistently occurs on the flood tide. In the Severn Estuary, over a distance of 40 km from the most upstream tide gauge at Oldbury, the maximum surge elevation increases by 255%. Up-estuary locations experience short duration, high magnitude surge elevations and greater variability due to shallow-water effects and channel convergence. The results show that surge predictions from forecasting systems at tide gauge locations could under-predict the magnitude and duration of surge contribution to up-estuary water levels. Due to the large tidal range and dynamic nature of hyper-tidal estuaries, local forecasting systems should consider changes in surge elevation and shape with distance up-estuary from nearby tide gauge sites to minimize uncertainties in flood hazard assessment.

An HTRF® Assay for the Protein Kinase ATM.

Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase that plays a key role in the regulation of DNA damage pathways and checkpoint arrest. In recent years, there has been growing interest in ATM as a therapeutic target due to its association with cancer cell survival following genotoxic stress such as radio- and chemotherapy. Large-scale targeted drug screening campaigns have been hampered, however, by technical issues associated with the production of sufficient quantities of purified ATM and the availability of a suitable high-throughput assay. Using a purified, functionally active recombinant ATM and one of its physiological substrates, p53, we have developed an in vitro FRET-based activity assay that is suitable for high-throughput drug screening.

The effectiveness of beach mega-nourishment, assessed over three management epochs.

Resilient coastal protection requires adaptive management strategies that build with nature to maintain long-term sustainability. With increasing pressures on shorelines from urbanisation, industrial growth, sea-level rise and changing storm climates soft approaches to coastal management are implemented to support natural habitats and maintain healthy coastal ecosystems. The impact of a beach mega-nourishment along a frontage of interactive natural and engineered systems that incorporate soft and hard defences is explored. A coastal evolution model is applied to simulate the impact of different hypothetical mega-nourishment interventions to assess their impacts' over 3 shoreline management planning epochs: present-day (0-20 years), medium-term (20-50 years) and long-term (50-100 years). The impacts of the smaller interventions when appropriately positioned are found to be as effective as larger schemes, thus making them more cost-effective for present-day management. Over time the benefit from larger interventions becomes more noticeable, with multi-location schemes requiring a smaller initial nourishment to achieve at least the same benefit as that of a single-location scheme. While the longer-term impact of larger schemes reduces erosion across a frontage the short-term impact down drift of the scheme can lead to an increase in erosion as the natural sediment drift becomes interrupted. This research presents a transferable modelling tool to assess the impact of nourishment schemes for a variety of sedimentary shorelines and highlights both the positive and negative impact of beach mega-nourishment.

Physical and economic impacts of sea-level rise and low probability flooding events on coastal communities.

Conventionally flood mapping typically includes only a static water level (e.g. peak of a storm tide) in coastal flood inundation events. Additional factors become increasingly important when increased water-level thresholds are met during the combination of a storm tide and increased mean sea level. This research incorporates factors such as wave overtopping and river flow in a range of flood inundation scenarios of future sea-level projections for a UK case study of Fleetwood, northwest England. With increasing mean sea level it is shown that wave overtopping and river forcing have an important bearing on the cost of coastal flood events. The method presented converts inundation maps into monetary cost. This research demonstrates that under scenarios of joint extreme surge-wave-river events the cost of flooding can be increased by up to a factor of 8 compared with an increase in extent of up to a factor of 3 relative to "surge alone" event. This is due to different areas being exposed to different flood hazards and areas with common hazard where flood waters combine non-linearly. This shows that relying simply on flood extent and volume can under-predict the actual economic impact felt by a coastal community. Additionally, the scenario inundation depths have been presented as "brick course" maps, which represent a new way of interpreting flood maps. This is primarily aimed at stakeholders to increase levels of engagement within the coastal community.

Denudation of the continental shelf between Britain and France at the glacial-interglacial timescale.

The erosional morphology preserved at the sea bed in the eastern English Channel dominantly records denudation of the continental shelf by fluvial processes over multiple glacial-interglacial sea-level cycles rather than by catastrophic flooding through the Straits of Dover during the mid-Quaternary. Here, through the integration of multibeam bathymetry and shallow sub-bottom 2D seismic reflection profiles calibrated with vibrocore records, the first stratigraphic model of erosion and deposition on the eastern English Channel continental shelf is presented. Published Optical Stimulated Luminescence (OSL) and 14C ages were used to chronometrically constrain the stratigraphy and allow correlation of the continental shelf record with major climatic/sea-level periods. Five major erosion surfaces overlain by discrete sediment packages have been identified. The continental shelf in the eastern English Channel preserves a record of processes operating from Marine Isotope Stage (MIS) 6 to MIS 1. Planar and channelised erosion surfaces were formed by fluvial incision during lowstands or relative sea-level fall. The depth and lateral extent of incision was partly conditioned by underlying geology (rock type and tectonic structure), climatic conditions and changes in water and sediment discharge coupled to ice sheet dynamics and the drainage configuration of major rivers in Northwest Europe. Evidence for major erosion during or prior to MIS 6 is preserved. Fluvial sediments of MIS 2 age were identified within the Northern Palaeovalley, providing insights into the scale of erosion by normal fluvial regimes. Seismic and sedimentary facies indicate that deposition predominantly occurred during transgression when accommodation was created in palaeovalleys to allow discrete sediment bodies to form. Sediment reworking over multiple sea-level cycles (Saalian-Eemian-early Weichselian) by fluvial, coastal and marine processes created a multi-lateral, multi-storey succession of palaeovalley-fills that are preserved as a strath terrace. The data presented here reveal a composite erosional and depositional record that has undergone a high degree of reworking over multiple sea-level cycles leading to the preferential preservation of sediments associated with the most recent glacial-interglacial period.