A large proportion of nutrients and sediment is mobilised in catchments during storm events. Therefore understanding a catchment's hydrological behaviour during storms and how this acts to mobilise ...and transport nutrients and sediment to nearby watercourses is extremely important for effective catchment management. The expansion of available in-situ sensors is allowing a wider range of water quality parameters to be monitored and at higher temporal resolution, meaning that the investigation of hydrochemical behaviours during storms is increasingly feasible. Studying the relationship between discharge and water quality parameters in storm events can provide a valuable research tool to infer the likely source areas and flow pathways contributing to nutrient and sediment transport. Therefore, this paper uses 2years of high temporal resolution (15/30min) discharge and water quality (nitrate-N, total phosphorus (TP) and turbidity) data to examine hysteretic behaviour during storm events in two contrasting catchments, in the Hampshire Avon catchment, UK. This paper provides one of the first examples of a study which comprehensively examines storm behaviours for up to 76 storm events and three water quality parameters. It also examines the observational uncertainties using a non-parametric approach. A range of metrics was used, such as loop direction, loop area and a hysteresis index (HI) to characterise and quantify the storm behaviour. With two years of high resolution information it was possible to see how transport mechanisms varied between parameters and through time. This study has also clearly shown the different transport regimes operating between a groundwater dominated chalk catchment versus a surface-water dominated clay catchment. This information, set within an uncertainty framework, means that confidence can be derived that the patterns and relationships thus identified are statistically robust. These insights can thus be used to provide information regarding transport processes and biogeochemical processing within river catchments.
Display omitted
•Hysteretic storm behaviour was analysed in 3 water quality parameters at 2 sites•Storms were analysed within an observational uncertainty framework•Range of metrics were used, including a new index, to quantify storm hysteresis•Differences in transport mechanisms shown between nitrate and TP in chalk system.•Behaviour was complex but provides insight into catchment processes in landscapes.
Understanding many processes, e.g., fusion experiments, planetary interiors, and dwarf stars, depends strongly on microscopic physics modeling of warm dense matter and hot dense plasma. This complex ...state of matter consists of a transient mixture of degenerate and nearly free electrons, molecules, and ions. This regime challenges both experiment and analytical modeling, necessitating predictive ab initio atomistic computation, typically based on quantum mechanical Kohn-Sham density functional theory (KS-DFT). However, cubic computational scaling with temperature and system size prohibits the use of DFT through much of the warm dense matter regime. A recently developed stochastic approach to KS-DFT can be used at high temperatures, with the exact same accuracy as the deterministic approach, but the stochastic error can converge slowly and it remains expensive for intermediate temperatures ( < 50 eV ). We have developed a universal mixed stochastic-deterministic algorithm for DFT at any temperature. This approach leverages the physics of KS-DFT to seamlessly integrate the best aspects of these different approaches. We demonstrate that this method significantly accelerated self-consistent field calculations for temperatures from 3 to 50 eV, while producing stable molecular dynamics and accurate diffusion coefficients.
Full text
Available for:
CMK, CTK, FMFMET, NUK, UL
The mitigation of diffuse sediment pollution requires reliable provenance information so that measures can be targeted. Sediment source fingerprinting represents one approach for supporting these ...needs, but recent methodological developments have resulted in an increasing complexity of data processing methods rendering the approach less accessible to non-specialists. A comprehensive new software programme (SIFT; SedIment Fingerprinting Tool) has therefore been developed which guides the user through critical data analysis decisions and automates all calculations. Multiple source group configurations and composite fingerprints are identified and tested using multiple methods of uncertainty analysis. This aims to explore the sediment provenance information provided by the tracers more comprehensively than a single model, and allows for model configurations with high uncertainties to be rejected. This paper provides an overview of its application to an agricultural catchment in the UK to determine if the approach used can provide a reduction in uncertainty and increase in precision. Five source group classifications were used; three formed using a k-means cluster analysis containing 2, 3 and 4 clusters, and two a-priori groups based upon catchment geology. Three different composite fingerprints were used for each classification and bi-plots, range tests, tracer variability ratios and virtual mixtures tested the reliability of each model configuration. Some model configurations performed poorly when apportioning the composition of virtual mixtures, and different model configurations could produce different sediment provenance results despite using composite fingerprints able to discriminate robustly between the source groups. Despite this uncertainty, dominant sediment sources were identified, and those in close proximity to each sediment sampling location were found to be of greatest importance. This new software, by integrating recent methodological developments in tracer data processing, guides users through key steps. Critically, by applying multiple model configurations and uncertainty assessment, it delivers more robust solutions for informing catchment management of the sediment problem than many previously used approaches.
Display omitted
•Sediment source fingerprinting methods have become complex and inaccessible.•SIFT is comprehensive, user-friendly and free sediment fingerprinting software.•Multiple source group classifications and composite fingerprints are used.•Different methods of uncertainty analysis are used to validate each model.•Localised sources were identified to contribute to channel bed sedimentation.
Sediment fingerprinting techniques provide a means of assembling valuable reliable information on the principal sources of sediment problems at catchment scale. However, there is a need to refine ...existing approaches to take account of a variety of sources of uncertainty and to incorporate prior information. To address this need, a modified mass balance model incorporating a Monte Carlo approach for representing the uncertainty surrounding source and sediment sampling, as well as weightings to take account of the within-source variability and discriminatory power of individual tracer properties and prior information on bank erosion, was used to apportion recent sediment sources in sub-catchments of the Somerset Levels, south west UK. Sensitivity tests confirmed that the precision of source apportionment was improved by incorporating the weightings and prior information into the mixing model. Estimates of the overall mean contributions from individual source types, bounded by 95% confidence limits, were assessed to be 42
±
2% (pasture topsoils), 22
±
2% (cultivated topsoils), 22
±
1% (channel banks/subsurface sources), 12
±
2% (damaged road verges) and 2
±
1% (STWs). Respective estimates of net sediment delivery to watercourses, provided by integrating the source ascription results with estimated sediment yield ranges and sub-catchment or land use areas, ranged between 33–829
kg
ha
−
1
yr
−
1
, 30–1995
kg
ha
−
1
yr
−
1
, 2–315
kg
ha
−
1
yr
−
1
, 0–217
kg
ha
−
1
yr
−
1
, and 0–28
kg
ha
−
1
yr
−
1
. Sediment fingerprinting should always include uncertainty analysis but on the understanding that the latter will be conditional on the assumptions used.
Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of ...healthcare resources.
To provide a comprehensive and critical review of the epidemiological literature on ALS.
MEDLINE and EMBASE (1995-2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods and incidence and/or prevalence rates. Medians and interquartile ranges (IQRs) were calculated, and ALS case estimates were derived using 2010 population estimates.
In all, 37 articles met the inclusion criteria. In Europe, the median incidence rate (/100,000 population) was 2.08 (IQR 1.47-2.43), corresponding to an estimated 15,355 (10,852-17,938) cases. Median prevalence (/100,000 population) was 5.40 (IQR 4.06-7.89), or 39,863 (29,971-58,244) prevalent cases.
Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics such as age and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS.
The growing awareness of the environmental significance of fine-grained sediment fluxes through catchment systems continues to underscore the need for reliable information on the principal sources of ...this material. Source estimates are difficult to obtain using traditional monitoring techniques, but sediment source fingerprinting or tracing procedures, have emerged as a potentially valuable alternative. Despite the rapidly increasing numbers of studies reporting the use of sediment source fingerprinting, several key challenges and uncertainties continue to hamper consensus among the international scientific community on key components of the existing methodological procedures. Accordingly, this contribution reviews and presents recent developments for several key aspects of fingerprinting, namely: sediment source classification, catchment source and target sediment sampling, tracer selection, grain size issues, tracer conservatism, source apportionment modelling, and assessment of source predictions using artificial mixtures. Finally, a decision-tree representing the current state of knowledge is presented, to guide end-users in applying the fingerprinting approach.
•Key methodological issues hamper widespread uptake of sediment fingerprinting.•Recent key developments are reviewed.•A decision-tree for the current state of knowledge is presented to guide end-users.
Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes. ...However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino (BCAAs) and keto-acids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
Therapeutics such as lapatinib that target ERBB2 often provide initial clinical benefit but resistance frequently develops. Adaptive responses leading to lapatinib resistance involve reprogramming of ...the kinome through reactivation of ERBB2/ERBB3 signaling and transcriptional upregulation and activation of multiple tyrosine kinases. The heterogeneity of induced kinases prevents their targeting by a single kinase inhibitor, underscoring the challenge of predicting effective kinase inhibitor combination therapies. We hypothesized that to make the tumor response to single kinase inhibitors durable, the adaptive kinome response itself must be inhibited. Genetic and chemical inhibition of BET bromodomain chromatin readers suppresses transcription of many lapatinib-induced kinases involved in resistance including ERBB3, IGF1R, DDR1, MET, and FGFRs, preventing downstream SRC/FAK signaling and AKT reactivation. Combining inhibitors of kinases and chromatin readers prevents kinome adaptation by blocking transcription, generating a durable response to lapatinib and overcoming the dilemma of heterogeneity in the adaptive response.
Display omitted
Lapatinib induces heterogeneous RTK-based kinome adaptation in ERBB2+ cellsMultiple unrelated kinases contribute to cell growth in the presence of lapatinibBET bromodomain inhibition suppresses expression of lapatinib-induced kinasesTargeting kinome adaptation makes kinase inhibition durable
Nitrate is necessary for agricultural productivity, but can cause considerable problems if released into aquatic systems. Agricultural land is the major source of nitrates in UK groundwater. Due to ...the long time-lag in the groundwater system, it could take decades for leached nitrate from the soil to discharge into freshwaters. However, this nitrate time-lag has rarely been considered in environmental water management. Against this background, this paper presents an approach to modelling groundwater nitrate at the national scale, to simulate the impacts of historical nitrate loading from agricultural land on the evolution of groundwater nitrate concentrations. An additional process-based component was constructed for the saturated zone of significant aquifers in England and Wales. This uses a simple flow model which requires modelled recharge values, together with published aquifer properties and thickness data. A spatially distributed and temporally variable nitrate input function was also introduced. The sensitivity of parameters was analysed using Monte Carlo simulations. The model was calibrated using national nitrate monitoring data. Time series of annual average nitrate concentrations along with annual spatially distributed nitrate concentration maps from 1925 to 2150 were generated for 28 selected aquifer zones. The results show that 16 aquifer zones have an increasing trend in nitrate concentration, while average nitrate concentrations in the remaining 12 are declining. The results are also indicative of the trend in the flux of groundwater nitrate entering rivers through baseflow. The model thus enables the magnitude and timescale of groundwater nitrate response to be factored into source apportionment tools and to be taken into account alongside current planning of land-management options for reducing nitrate losses.
Display omitted
•An approach to modelling groundwater nitrate at the national scale is presented.•The long time-lag for nitrate in the groundwater system is considered.•The impact of historical nitrate loading on groundwater quality is better understood.•Areas of high groundwater nitrate input to surface water are delineated.•The method is transferable and requires a modest parameterisation.
Analysis of hydrochemical behaviour during storm events can provide new insights into the process controls on nutrient transport in catchments. The examination of storm behaviours using hysteresis ...analysis has increased in recent years, partly due to the increased availability of high temporal resolution data sets for discharge and water quality parameters. A number of these analyses involve the use of an index to describe the characteristics of a hysteresis loop in order to compare storm behaviours both within and between catchments. This technical note reviews the methods for calculation of the hysteresis index (HI) and explores a new more effective methodology. Each method is systematically tested and the impact of the chosen calculation on the results is examined. Recommendations are made regarding the most effective method of calculating a HI which can be used for comparing data between storms and between different water quality parameters and catchments.
PDF
