Smc5/6: a link between DNA repair and unidirectional replication?

Of the three structural maintenance of chromosome (SMC) complexes, two directly regulate chromosome dynamics. The third, Smc5/6, functions mainly in homologous recombination and in completing DNA replication. The literature suggests that Smc5/6 coordinates DNA repair, in part through post-translational modification of uncharacterized target proteins that can dictate their subcellular localization, and that Smc5/6 also functions to establish DNA-damage-dependent cohesion. A nucleolar-specific Smc5/6 function has been proposed because Smc5/6 yeast mutants display penetrant phenotypes of ribosomal DNA (rDNA) instability. rDNA repeats are replicated unidirectionally. Here, we propose that unidirectional replication, combined with global Smc5/6 functions, can explain the apparent rDNA specificity

Cardiorespiratory fitness predicts clustered cardiometabolic risk in 10-11.9 year olds

The aim of this study was to investigate levels of clustered cardiometabolic risk and the odds of being ‘at risk’ according to cardiorespiratory fitness status in children. Data from 88 10–11.9-year-old children (mean age 11.05 ± 0.51 years), who participated in either the REACH Year 6 or the Benefits of Fitness Circuits for Primary School Populations studies were combined. Waist circumference, systolic blood pressure, diastolic blood pressure, glucose, triglycerides, high-density lipoprotein cholesterol, adiponectin and C-reactive protein were assessed and used to estimate clustered cardiometabolic risk. Participants were classified as ‘fit’ or ‘unfit’ using recently published definitions (46.6 and 41.9 mL/kg/min for boys and girls, respectively), and continuous clustered risk scores between fitness groups were assessed. Participants were subsequently assigned to a ‘normal’ or ‘high’ clustered cardiometabolic risk group based on risk scores, and logistic regression analysis assessed the odds of belonging to the increased cardiometabolic risk group according to fitness. The unfit group exhibited significantly higher clustered cardiometabolic risk scores (p < 0.001) than the fit group. A clear association between fitness group and being at increased cardiometabolic risk (B = 2.509, p = 0.001) was also identified, and participants classed as being unfit were found to have odds of being classified as ‘at risk’ of 12.30 (95 % CI = 2.64–57.33).\ud \ud Conclusion Assessing cardiorespiratory fitness is a valid method of identifying children most at risk of cardiometabolic pathologies. The ROC thresholds could be used to identify populations of children most at risk and may therefore be used to effectively target a cardiometabolic risk-reducing public health intervention

A radiomics-based decision support tool improves lung cancer diagnosis in combination with the Herder score in large lung nodules

Background: Large lung nodules (≥15 mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk. Methods: 502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores. Findings: 499 patients had technically evaluable scans (mean age 69 ± 11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77–0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70–0.81], DeLong p = 0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80–0.93) compared to 0.67 (95% CI 0.55–0.76, DeLong p = 0.002) for the Brock score and 0.83 (95% CI 0.75–0.90, DeLong p = 0.4) for the Herder score. In the international external test set (n = 151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63–0.85). 18 out of 22 (82%) malignant nodules in the Herder 10–70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earlier intervention. Interpretation: The model accurately segments and classifies large lung nodules, and may improve upon existing clinical models. Funding This project represents independent research funded by: 1) Royal Marsden Partners Cancer Alliance, 2) the Royal Marsden Cancer Charity, 3) the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London, 5) Cancer Research UK (C309/A31316)

Utility of three anthropometric indices in assessing the cardiometabolic risk profile in children

Objectives: To evaluate the ability of BMI, WC and WHtR to identify increased cardiometabolic risk in pre-adolescents. Methods: This is a cross-sectional study involving 192 children (10.92 ± 0.58 years, 56% female) from the United Kingdom between 2010 and 2013. Receiver operating characteristic curves determined the discriminatory ability of BMI, WC and WHtR to identify individuals with increased cardiometabolic risk (increased clustered triglycerides, HDL-cholesterol, systolic blood pressure, cardiorespiratory fitness and glucose). Results: A WHtR ≥ 0.5 increased the odds by 5.2 (95% confidence interval 2.6, 10.3) of having increased cardiometabolic risk. Similar associations were observed for BMI and WC. Both BMI-z and WHtR were fair predictors of increased cardiometabolic risk although BMI-z demonstrated the best trade-off between sensitivity and specificity, 76.1% and 63.6%, compared to 68.1% and 65.5% for WHtR. Cross-validation analysis revealed that BMI-z and WHtR correctly classified 84% of individuals (kappa score = 0.671, 95% CI 0.55, 0.79). The sensitivity of the cut-points suggests that 89.3% of individuals were correctly classified as being at risk with only 10.7% misdiagnosed whereas the specificity of the cut-points indicated that 77.8% of individuals were correctly identified as being healthy with 22.2% of individuals incorrectly diagnosed as being at risk. Conclusions: Findings suggest that WHtR provides similar cardiometabolic risk estimates to age and sex adjusted BMI

SUMO-Targeted Ubiquitin Ligase, Rad60, and Nse2 SUMO Ligase Suppress Spontaneous Top1–Mediated DNA Damage and Genome Instability

Through as yet undefined proteins and pathways, the SUMO-targeted ubiquitin ligase (STUbL) suppresses genomic instability by ubiquitinating SUMO conjugated proteins and driving their proteasomal destruction. Here, we identify a critical function for fission yeast STUbL in suppressing spontaneous and chemically induced topoisomerase I (Top1)–mediated DNA damage. Strikingly, cells with reduced STUbL activity are dependent on tyrosyl–DNA phosphodiesterase 1 (Tdp1). This is notable, as cells lacking Tdp1 are largely aphenotypic in the vegetative cell cycle due to the existence of alternative pathways for the removal of covalent Top1–DNA adducts (Top1cc). We further identify Rad60, a SUMO mimetic and STUbL-interacting protein, and the SUMO E3 ligase Nse2 as critical Top1cc repair factors in cells lacking Tdp1. Detection of Top1ccs using chromatin immunoprecipitation and quantitative PCR shows that they are elevated in cells lacking Tdp1 and STUbL, Rad60, or Nse2 SUMO ligase activity. These unrepaired Top1ccs are shown to cause DNA damage, hyper-recombination, and checkpoint-mediated cell cycle arrest. We further determine that Tdp1 and the nucleotide excision repair endonuclease Rad16-Swi10 initiate the major Top1cc repair pathways of fission yeast. Tdp1-based repair is the predominant activity outside S phase, likely acting on transcription-coupled Top1cc. Epistasis analyses suggest that STUbL, Rad60, and Nse2 facilitate the Rad16-Swi10 pathway, parallel to Tdp1. Collectively, these results reveal a unified role for STUbL, Rad60, and Nse2 in protecting genome stability against spontaneous Top1-mediated DNA damage

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30