Development and application of a catchment scale pesticide fate and transport model for use in drinking water risk assessment

This paper describes the development and application of IMPT (Integrated Model for Pesticide Transport), a parameter-efficient tool for predicting diffuse-source pesticide concentrations in surface waters used for drinking water supply. The model was applied to a small UK headwater catchment with high frequency (8 h) pesticide monitoring data and to five larger catchments (479–1653 km2) with sampling approximately every 14 days. Model performance was good for predictions of both flow (Nash Sutcliffe Efficiency generally > 0.59 and PBIAS < 10%) and pesticide concentrations, although low sampling frequency in the larger catchments is likely to mask the true episodic nature of exposure. The computational efficiency of the model, along with the fact that most of its parameters can be derived from existing national soil property data mean that it can be used to rapidly predict pesticide exposure in multiple surface water resources to support operational and strategic risk assessments

Effect of temperature anisotropy on the dynamics of geodesic acoustic modes

In this work, we revisit the linear gyro-kinetic theory of geodesic acoustic modes (GAMs) and derive a general dispersion relation for an arbitrary equilibrium distribution function of ions. A bi-Maxwellian distribution of ions is then used to study the effects of ion temperature anisotropy on GAM frequency and growth rate. We find that ion temperature anisotropy yields sensible modifications to both the GAM frequency and growth rate as both tend to increase with anisotropy and these results are strongly affected by the electron to ion temperature ratio

Nonlinear interaction of Alfv\'enic instabilities and turbulence via the modification of the equilibrium profiles

Nonlinear simulations of Alfv\'en modes (AM) driven by energetic particles (EP) in the presence of turbulence are performed with the gyrokinetic particle-in-cell code ORB5. The AMs carry a heat flux, and consequently they nonlinearly modify the plasma temperature profiles. The isolated effect of this modification on the dynamics of turbulence is studied, by means of electrostatic simulations. We find that turbulence is reduced when the profiles relaxed by the AM are used, with respect to the simulation where the unperturbed profiles are used. This is an example of indirect interaction of EPs and turbulence. First, an analytic magnetic equilibrium with circular concentric flux surfaces is considered as a simplified example for this study. Then, an application to an experimentally relevant case of ASDEX Upgrade is discussed

GSK3β-SCFFBXW7α mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover

IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilised protein that accumulates at target promoters but fails to induce RNA-Pol-II elongation and subsequent transcription of target genes. Consequently, the anti-proliferative activity of IRF1 is lost in cell lines expressing T181A mutant. Further, cell lines with dysfunctional Fbxw7 are less sensitive to IRF1 overexpression, suggesting an important co-activator function for this ligase complex. As T181 phosphorylation requires both DNA binding and RNA-Pol-II elongation, we propose that this event acts to clear " spent " molecules of IRF1 from transcriptionally engaged target promoters

Numerical tools for burning plasmas

The software stack under development within a European coordinated effort on tools for burning plasma modelling is presented. The project is organised as a Task (TSVV Task 10) under the new E-TASC initiative (Litaudon et al 2022 Plasma Phys. Control. Fusion 64 034005). This is a continued effort within the EUROfusion inheriting from the earlier European coordination projects as well as research projects based at various European laboratories. The ongoing work of the TSVV Tasks is supported by the Advanced Computing Hubs. Major projects requiring the high performance computing (HPC) resources are global gyrokinetic codes and global hybrid particle-magnetohydrodynamics (MHD) codes. Also applications using the integrated modelling tools, such as the Energetic-Particle Workflow, based on the ITER Integrated Modelling & Analysis Suite (IMAS), or the code package for modelling radio-frequency heating and fast-ion generation may require intensive computation and a substantial memory footprint. The continual development of these codes both on the physics side and on the HPC side allows us to tackle frontier problems, such as the interaction of turbulence with MHD-type modes in the presence of fast particles. One of the important mandated outcomes of the E-TASC project is the IMAS-enabling of EUROfusion codes and release of the software stack to the EUROfusion community

Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study

Background Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection. Objectives To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme. Design Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later. Setting Thirty-one UK hospitals. Participants Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis. Interventions An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy. Main outcome Identifying ulcerative colitis patients with neoplasia. Results Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09). Limitations Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed. Conclusions Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes. Trial registration Current Controlled Trials ISRCTN81826545. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information