Translesion synthesis DNA polymerases contribute to DNA damage tolerance by mediating replication of damaged templates. Due to the low fidelity of these enzymes, lesion bypass is often mutagenic. We have previously shown that, in Saccharomyces cerevisiae, the contribution of the error-prone DNA polymerase z (Polz) to replication and mutagenesis is greatly enhanced if the normal replisome is defective due to mutations in replication genes. Here we present evidence that this defective-replisome-induced mutagenesis (DRIM) results from the participation of Polz in the copying of undamaged DNA rather than from mutagenic lesion bypass. First, DRIM is not elevated in strains that have a high level of endogenous DNA lesions due to defects in nucleotide excision repair or base excision repair pathways. Second, DRIM remains unchanged when the level of endogenous oxidative DNA damage is decreased by using anaerobic growth conditions. Third, analysis of the spectrum of mutations occurring during DRIM reveals the characteristic error signature seen during replication of undamaged DNA by Polz in vitro. These results extend earlier findings in Escherichia coli indicating that Y-family DNA polymerases can contribute to the copying of undamaged DNA. We also show that exposure of wild-type yeast cells to the replication inhibitor hydroxyurea causes a Polz-dependent increase in mutagenesis. This suggests that DRIM represents a response to replication impediment per se rather than to specific defects in the replisome components.

Microbial ecology provides insights into the ecological and evolutionary dynamics of microbial communities underpinning every ecosystem on Earth. Microbial communities can now be investigated in unprecedented detail, although there is still a wealth of open questions to be tackled. Here we identify 50 research questions of fundamental importance to the science or application of microbial ecology, with the intention of summarising the field and bringing focus to new research avenues. Questions are categorised into seven themes: host-microbiome interactions; health and infectious diseases; human health and food security; microbial ecology in a changing world; environmental processes; functional diversity; and evolutionary processes. Many questions recognise that microbes provide an extraordinary array of functional diversity that can be harnessed to solve real-world problems. Our limited knowledge of spatial and temporal variation in microbial diversity and function is also reflected, as is the need to integrate micro- and macro-ecological concepts, and knowledge derived from studies with humans and other diverse organisms. Although not exhaustive, the questions presented are intended to stimulate discussion and provide focus for researchers, funders and policy makers, informing the future research agenda in microbial ecology.

The wine yeast, Saccharomyces cerevisiae, is the best understood microbial eukaryote at the molecular and cellular level, yet its natural geographic distribution is unknown. Here we report the results of a field survey for S. cerevisiae,S. paradoxus and other budding yeast on oak trees in Europe. We show that yeast species differ in their geographic distributions, and investigated which ecological variables can predict the isolation rate of S. paradoxus, the most abundant species. We find a positive association between trunk girth and S. paradoxus abundance suggesting that older trees harbor more yeast. S. paradoxus isolation frequency is also associated with summer temperature, showing highest isolation rates at intermediate temperatures. Using our statistical model, we estimated a range of summer temperatures at which we expect high S. paradoxus isolation rates, and show that the geographic distribution predicted by this optimum temperature range is consistent with the worldwide distribution of sites where S. paradoxus has been isolated. Using laboratory estimates of optimal growth temperatures for S. cerevisiae relative to S. paradoxus, we also estimated an optimum range of summer temperatures for S. cerevisiae. The geographic distribution of these optimum temperatures is consistent with the locations where wild S. cerevisiae have been reported, and can explain why only human‐associated S. cerevisiae strains are isolated at northernmost latitudes. Our results provide a starting point for targeted isolation of S. cerevisiae from natural habitats, which could lead to a better understanding of climate associations and natural history in this important model microbe.

(2018) Adiposity-mortality relationships in type 2 diabetes, coronary heart disease and cancer subgroups in the UK Biobank, and their modification by smoking. Diabetes Care, (doi:10.2337/dc17-2508).There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/165359/ ObjectiveThe obesity paradox, in which overweight/obesity is associated with mortality benefits, is believed to be explained by confounding and reverse causality, rather than a genuine clinical benefit of excess body weight. We aimed to gain deeper insights in the paradox through:analysing mortality relationships with several adiposity measures; assessing subgroups with type 2 diabetes, coronary heart disease (CHD) and smokers and by adjusting for several confounders. Research design and methodsWe studied the general UK Biobank population (n=502,631), along with 3 subgroups: individuals with a) type 2 diabetes (n=23,842); CHD (n=24,268) and c) cancer (n=45790) at baseline. A range of adiposity exposures were considered, including BMI (continuous and categorical), waist circumference, body fat percentage and waist-to-hip ratio, and the outcome was all-cause mortality. We used Cox regression models adjusted for age, smoking status, deprivation, education and disease history. ResultsFor BMI, the obesity paradox was observed among people with type 2 diabetes (adjusted HR: obese vs. normal BMI: 0.78, 95% CI: 0.65,0.95), but not among those with CHD (HR:1.00: 0.86,1.17). The obesity paradox was pronounced in current smokers, absent in never -3 -smokers, and more pronounced in men than women. For other adiposity measures, there was less evidence for an obesity paradox, yet smoking status consistently modified the adiposity-mortality relationships. ConclusionsThe obesity paradox was observed in people with type 2 diabetes and is heavily modified by smoking status. The results of sub-group analyses and statistical adjustments are consistent with reverse causality and confounding.

ObjectivesA rapid growth in the reported rates of acute kidney injury (AKI) has led to calls for greater attention and greater resources for improving care. However, the reported incidence of AKI also varies more than tenfold between previous studies. Some of this variation is likely to stem from methodological heterogeneity. This study explores the extent of cross-population variation in AKI incidence after minimising heterogeneity.DesignPopulation-based cohort study analysing data from electronic health records from three regions in the UK through shared analysis code and harmonised methodology.SettingThree populations from Scotland, Wales and England covering three time periods: Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012.ParticipantsAll residents in each region, aged 15 years or older.Main outcome measuresPopulation incidence of AKI and AKI phenotype (severity, recovery, recurrence). Determined using shared biochemistry-based AKI episode code and standardised by age and sex.ResultsRespectively, crude AKI rates (per 10 000/year) were 131, 138, 139, 151 and 124 (p=0.095), and after standardisation for age and sex: 147, 151, 146, 146 and 142 (p=0.257) for Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012. The pattern of variation in crude rates was robust to any modifications of the AKI definition. Across all populations and time periods, AKI rates increased substantially with age from ~20 to ~550 per 10 000/year among those aged <40 and ≥70 years.ConclusionWhen harmonised methods are used and age and sex differences are accounted for, a similar high burden of AKI is consistently observed across different populations and time periods (~150 per 10 000/year). There are particularly high rates of AKI among older people. Policy-makers should be careful not draw simplistic assumptions about variation in AKI rates based on comparisons that are not rigorous in methodological terms.

Children's body mass index (BMI) growth trajectories are associated with adult health outcomes, and vary by geography and epoch. Understanding these trajectories could help to identify high risk children and thus support improved health outcomes. In this review, we compare and quantitatively analyse BMI level and trajectory data published since 2010. We characterise recent growth in children aged 4–11 years, an age range most frequently targeted for BMI intervention, yet less studied than young childhood or infancy. Through searches in OVID, we identified 54 relevant texts which describe either post-2000 summary BMI values by age and gender in cohorts with sample sizes of over 1000 children, or the results of latent class analyses of BMI trajectories within the 4–11 year age range. Population level median growth curves were projected and visualised as weighted means. These BMI curves, based on data from 729,692 children, can be visually clustered into ‘high’ and ‘low’ charting groups with extreme outlying values. Within populations, latent class analyses converge on 3–4 individual child trajectories, two of which predispose adult overweight. These growth pathways diverge early in childhood, yet are not effectively distinguished via isolated BMI measurements taken between 4 and 11 years, meaning some high risk children may currently be poorly identified.

Background This study aimed to determine the impact of preoperative exposure to intravenous contrast for CT and the risk of developing postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. Methods This prospective, multicentre cohort study included adults undergoing gastrointestinal resection, stoma reversal or liver resection. Both elective and emergency procedures were included. Preoperative exposure to intravenous contrast was defined as exposure to contrast administered for the purposes of CT up to 7 days before surgery. The primary endpoint was the rate of AKI within 7 days. Propensity score‐matched models were adjusted for patient, disease and operative variables. In a sensitivity analysis, a propensity score‐matched model explored the association between preoperative exposure to contrast and AKI in the first 48 h after surgery. Results A total of 5378 patients were included across 173 centres. Overall, 1249 patients (23·2 per cent) received intravenous contrast. The overall rate of AKI within 7 days of surgery was 13·4 per cent (718 of 5378). In the propensity score‐matched model, preoperative exposure to contrast was not associated with AKI within 7 days (odds ratio (OR) 0·95, 95 per cent c.i. 0·73 to 1·21; P = 0·669). The sensitivity analysis showed no association between preoperative contrast administration and AKI within 48 h after operation (OR 1·09, 0·84 to 1·41; P = 0·498). Conclusion There was no association between preoperative intravenous contrast administered for CT up to 7 days before surgery and postoperative AKI. Risk of contrast‐induced nephropathy should not be used as a reason to avoid contrast‐enhanced CT.

The peri-operative use of angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri-operative period. This study aimed to investigate if withholding angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers peri-operatively reduces the risk of acute kidney injury following major non-cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi-level models were used to account for centre-level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers withheld during the peri-operative period. One hundred and seventy-five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58-1.34); p = 0.567).