Explore the vast range of titles available.

Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N -glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of Pngl in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of Pngl mutants rescued their developmental delay but not lethality. However, raising Pngl mutants on isocaloric, fat-rich diets partially rescued lethality. Our data indicate that Pngl functions in Drosophila larvae to establish the gut barrier, and that the lethality caused by loss of Pngl is primarily mediated through non-bacterial induction of immune and metabolic abnormalities. NGLY1 mutations cause a multisystem developmental disorder. Here they show that this enzyme is required for normal gut barrier function, and when mutated, causes immune and metabolic abnormalities, contributing to lethality.

Gene knock outs (KOs) are efficiently engineered through CRISPR–Cas9-induced frameshift mutations. While the efficiency of DNA editing is readily verified by DNA sequencing, a systematic understanding of the efficiency of protein elimination has been lacking. Here we devised an experimental strategy combining RNA sequencing and triple-stage mass spectrometry to characterize 193 genetically verified deletions targeting 136 distinct genes generated by CRISPR-induced frameshifts in HAP1 cells. We observed residual protein expression for about one third of the quantified targets, at variable levels from low to original, and identified two causal mechanisms, translation reinitiation leading to N-terminally truncated target proteins or skipping of the edited exon leading to protein isoforms with internal sequence deletions. Detailed analysis of three truncated targets, BRD4, DNMT1 and NGLY1, revealed partial preservation of protein function. Our results imply that systematic characterization of residual protein expression or function in CRISPR–Cas9-generated KO lines is necessary for phenotype interpretation.

BackgroundConcern remains about how occupational SARS-CoV-2 risk has evolved during the COVID-19 pandemic. We aimed to ascertain occupations with the greatest risk of SARS-CoV-2 infection and explore how relative differences varied over the pandemic.MethodsAnalysis of cohort data from the UK Office of National Statistics COVID-19 Infection Survey from April 2020 to November 2021. This survey is designed to be representative of the UK population and uses regular PCR testing. Cox and multilevel logistic regression were used to compare SARS-CoV-2 infection between occupational/sector groups, overall and by four time periods with interactions, adjusted for age, sex, ethnicity, deprivation, region, household size, urban/rural neighbourhood and current health conditions.ResultsBased on 3 910 311 observations (visits) from 312 304 working age adults, elevated risks of infection can be seen overall for social care (HR 1.14; 95% CI 1.04 to 1.24), education (HR 1.31; 95% CI 1.23 to 1.39), bus and coach drivers (1.43; 95% CI 1.03 to 1.97) and police and protective services (HR 1.45; 95% CI 1.29 to 1.62) when compared with non-essential workers. By time period, relative differences were more pronounced early in the pandemic. For healthcare elevated odds in the early waves switched to a reduction in the later stages. Education saw raises after the initial lockdown and this has persisted. Adjustment for covariates made very little difference to effect estimates.ConclusionsElevated risks among healthcare workers have diminished over time but education workers have had persistently higher risks. Long-term mitigation measures in certain workplaces may be warranted.

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN–PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN–PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets. Hebrok and colleagues use mouse models to demonstrate that loss of the chromatin modifier Brg1 cooperates with oncogenic KRas to form lesions resembling intraductal papillary mucinous neoplasia that progress to pancreatic adenocarcinoma.

The effectiveness of respiratory protection is dependent on many factors, including the duration and times during the day when it is worn. To date, these factors could only be assessed by direct observation of the respirator user. We describe the novel use of a data-logging temperature and humidity sensor (iButton Hygrochron) located inside a facemask to quantify respirator wear-time through supervised experiments (Phase 1) and an unsupervised wearing trial (Phase 2). Additionally, in Phase 1 the in-mask temperature was compared with measurements of exhaled breath temperature. We found humidity responds more rapidly than temperature to donning a mask, so it was considered a more sensitive measure of wear-time, particularly for short durations. Supervised tests showed that this method can provide accurate and precise estimates of wear-time, although the approach may be unsuitable for use in situations where there is high ambient humidity. In-mask temperature is closely associated with exhaled breath temperature, which is linked to lung inflammation. This technique could provide a useful way of evaluating the effectiveness of respirators in protecting health in real-life situations.

Populations consuming saline drinking water are at greater risk of high blood pressure and potentially other adverse health outcomes. We modelled data and used available datasets to identify countries of higher vulnerability to future saltwater intrusion associated with climate change in 2050 under Representative Concentration Pathways (RCP)4.5 and RCP8.5. We developed three vulnerability criteria to capture geographies with: (1) any coastal areas with projected inland saltwater intrusion of ≥ 1 km inland, (2) > 50% of the population in coastal secondary administrative areas with reliance on groundwater for drinking water, and 3) high national average sodium urinary excretion (i.e., > 3 g/day). We identified 41 nations across all continents (except Antarctica) with ≥ 1 km of inland saltwater intrusion by 2050. Seven low- and middle-income countries of higher vulnerability were all concentrated in South/Southeast Asia. Based on these initial findings, future research should study geological nuances at the local level in higher-risk areas and co-produce with local communities contextually appropriate solutions to secure equitable access to clean drinking water.

Objective This study aimed to understand whether the proportionate mortality of COVID-19 for various occupational groups has varied over the pandemic. Methods We used the Office for National Statistics (ONS) mortality data for England and Wales. The deaths (20-64 years) were classified as either COVID-19-related using ICD-10 codes (U07.1, U07.2), or from other causes. Occupational data recorded at the time of death was coded using the SOC10 coding system into 13 groups. Three time periods (TP) were used: (i) January 2020 to September 2020; (ii) October 2020-May 2021; and (iii) June 2021-October 2021. We analyzed the data with logistic regression and compared odds of death by COVID-19 to other causes, adjusting for age, sex, deprivation, region, urban/rural and population density. Results Healthcare professionals and associates had a higher proportionate odds of COVID-19 death in TP1 compared to non-essential workers but were not observed to have increased odds thereafter. Medical support staff had increased odds of death from COVID-19 during both TP1 and TP2, but this had reduced by TP3. This latter pattern was also seen for social care, food retail and distribution, and bus and coach drivers. Taxi and cab drivers were the only group that had higher odds of death from COVID-19 compared to other causes throughout the whole period under study [TP1: odds ratio (OR) 2.42, 95% confidence interval (CI) 1.99-2.93; TP2: OR 3.15, 95% CI 2.63-3.78; TP3: OR 1.7, 95% CI 1.26-2.29]. Conclusion Differences in the odds of death from COVID-19 between occupational groups has declined over the course of the pandemic, although some occupations have remained relatively high throughout.

Particulate air pollution causes a spectrum of adverse health effects affecting the respiratory, cardiovascular, neurological, and metabolic systems that are hypothesised to be driven by inflammation and oxidative stress. Millions of premature deaths each year are attributed to exposure to ambient particulate matter (PM). We quantified health and economic impacts from long-term exposure to ambient PM 2.5 in the population of Thailand for 2016. We collected data on ambient PM 2.5 concentrations from automatic monitoring stations across Thailand over 1996–2016. We used historic exposure to PM 2.5 to estimate the mortality in each province from lower respiratory infections (LRIs), stroke, chronic obstructive pulmonary disease, lung cancer, and ischaemic heart disease, and also assessed diabetes mortality, as well as incident cases of dementia and Parkinson’s disease, in supplementary analyses. We applied risk estimates from the Global Exposure Mortality Model to calculate attributable mortality and quantify disability-adjusted life years (DALYs); we based economic costs on the value of a statistical life (VSL). We calculated 50 019 (95% confidence interval [CI]: 42 189–57 849) deaths and 508 918 (95% CI: 438 345–579 492) DALYs in 2016 attributed to long-term PM 2.5 exposure in Thailand. Population attributable fractions ranged from 20% (95% CI: 10% to 29%) for stroke to 48% (95% CI: 27% to 63%) for LRIs. Based on the VSL, we calculated a cost of US $ 60.9 billion (95% CI: US$51.3–70.4 billion), which represents nearly 15% of Thailand’s gross domestic product in 2016. While progress has been made to reduce exposure to ambient PM 2.5 in Thailand, continued reductions based on stricter regulatory limits for PM 2.5 and other air pollutants would help prolong life, and delay, or prevent, onset of cardiorespiratory and other diseases.

Purpose of Review A large body of epidemiological evidence demonstrates that exposure to particulate matter (PM) is associated with increased morbidity and mortality. Many epidemiology studies have investigated the health effects of PM in Europe and North America and focussed on traffic derived PM. However, elevated levels of PM are a global problem and the impacts of other sources of PM on health should be assessed. Biomass burning can increase PM levels in urban and rural indoor and outdoor environments in developed and developing countries. We aim to identify whether the health effects of traffic and biomass burning derived PM are similar by performing a narrative literature review. We focus on Thailand as haze episodes from agricultural biomass burning can substantially increase PM levels. Recent Findings Existing epidemiology, in vitro and in vivo studies suggest that biomass burning derived PM elicits toxicity via stimulation of oxidative stress, inflammation and genotoxicity. Thus, it is likely to cause similar adverse health outcomes to traffic PM, which causes toxicity via similar mechanisms. However, there is conflicting evidence regarding whether traffic or biomass burning derived PM is most hazardous. Also, there is evidence that PM released from different biomass sources varies in its toxic potency. Summary We recommend that epidemiology studies are performed in Thailand to better understand the impacts of PM emitted from specific biomass sources (e.g. agricultural burning). Further, experimental studies should assess the toxicity of PM emitted from more diverse biomass sources. This will fill knowledge gaps and inform evidence-based interventions that protect human health.