Personalized Drug Therapy: Innovative Concept Guided With Proteoformics.

Personalized medicine can reduce adverse effects, enhance drug efficacy, and optimize treatment outcomes, which represents the essence of personalized medicine in the pharmacy field. Protein drugs are crucial in the field of personalized drug therapy and are currently the mainstay, which possess higher target specificity and biological activity than small-molecule chemical drugs, making them efficient in regulating disease-related biological processes, and have significant potential in the development of personalized drugs. Currently, protein drugs are designed and developed for specific protein targets based on patient-specific protein data. However, due to the rapid development of two-dimensional gel electrophoresis and mass spectrometry, it is now widely recognized that a canonical protein actually includes multiple proteoforms, and the differences between these proteoforms will result in varying responses to drugs. The variation in the effects of different proteoforms can be significant and the impact can even alter the intended benefit of a drug, potentially making it harmful instead of lifesaving. As a result, we propose that protein drugs should shift from being targeted through the lens of protein (proteomics) to being targeted through the lens of proteoform (proteoformics). This will enable the development of personalized protein drugs that are better equipped to meet patients' specific needs and disease characteristics. With further development in the field of proteoformics, individualized drug therapy, especially personalized protein drugs aimed at proteoforms as a drug target, will improve the understanding of disease mechanisms, discovery of new drug targets and signaling pathways, provide a theoretical basis for the development of new drugs, aid doctors in conducting health risk assessments and making more cost-effective targeted prevention strategies conducted by artificial intelligence/machine learning, promote technological innovation, and provide more convenient treatment tailored to individualized patient profile, which will benefit the affected individuals and society at large.

Estimating perceptions of the relative COVID risk of different social-distancing behaviors from respondents' pairwise assessments.

How do people compare the effectiveness of different social-distancing behaviors in avoiding the spread of viral infection? During the COVID pandemic, we showed 676 online respondents in the United States, United Kingdom, and Israel 30 pairs of brief videos of acquaintances meeting. We asked respondents to indicate which video from each pair depicted greater risk of COVID infection. Their choices imply that on average, respondents considered talking 14 min longer to be as risky as standing 1 foot closer, being indoors as standing 3 feet closer, being exposed to coughs or sneezes as 3 to 4 ft closer, greeting with a hug as 7 ft closer, and with a handshake as 5 ft closer. Respondents considered properly masking as protecting the wearer and interlocutor equally, removing the mask entirely or only when talking as standing 4 to 5 ft closer but wearing it under the nose as only 1 to 2 ft closer. We provide weaker evidence on beliefs about the interaction effects of different behaviors. In a more limited, ex post analysis, we find little evidence of differences in beliefs across subpopulations.

Predicting the in vivo developmental toxicity of fenarimol from in vitro toxicity data using PBTK modelling-facilitated reverse dosimetry approach.

In vitro methods are widely used in modern toxicological testing; however, the data cannot be directly employed for risk assessment. In vivo toxicity of chemicals can be predicted from in vitro data using physiologically based toxicokinetic (PBTK) modelling-facilitated reverse dosimetry (PBTK-RD). In this study, a minimal-PBTK model was constructed to predict the in-vivo kinetic profile of fenarimol (FNL) in rats and humans. The model was verified by comparing the observed and predicted pharmacokinetics of FNL for rats (calibrator) and further applied to humans. Using the PBTK-RD approach, the reported in vitro developmental toxicity data for FNL was translated to in vivo dose-response data to predict the assay equivalent oral dose in rats and humans. The predicted assay equivalent rat oral dose (36.46 mg/kg) was comparable to the literature reported in vivo BMD10 value (22.8 mg/kg). The model was also employed to derive the chemical-specific adjustment factor (CSAF) for interspecies toxicokinetics variability of FNL. Further, Monte Carlo simulations were performed to predict the population variability in the plasma concentration of FNL and to derive CSAF for intersubject human kinetic differences. The comparison of CSAF values for interspecies and intersubject toxicokinetic variability with their respective default values revealed that the applied uncertainty factors were adequately protective.

Relative associations of behavioral and physiological risks for cardiometabolic disease with cognition in bipolar disorder during mid and later-life: findings from the UK biobank.

BACKGROUND: Cardiometabolic disease risk factors are disproportionately prevalent in bipolar disorder (BD) and are associated with cognitive impairment. It is, however, unknown which health risk factors for cardiometabolic disease are relevant to cognition in BD. This study aimed to identify the cardiometabolic disease risk factors that are the most important correlates of cognitive impairment in BD; and to examine whether the nature of the relationships vary between mid and later life. METHODS: Data from the UK Biobank were available for 966 participants with BD, aged between 40 and 69 years. Individual cardiometabolic disease risk factors were initially regressed onto a global cognition score in separate models for the following risk factor domains; (1) health risk behaviors (physical activity, sedentary behavior, smoking, and sleep) and (2) physiological risk factors, stratified into (2a) anthropometric and clinical risk (handgrip strength, body composition, and blood pressure), and (2b) cardiometabolic disease risk biomarkers (CRP, lipid profile, and HbA1c). A final combined multivariate regression model for global cognition was then fitted, including only the predictor variables that were significantly associated with cognition in the previous models. RESULTS: In the final combined model, lower mentally active and higher passive sedentary behavior, higher levels of physical activity, inadequate sleep duration, higher systolic and lower diastolic blood pressure, and lower handgrip strength were associated with worse global cognition. CONCLUSIONS: Health risk behaviors, as well as blood pressure and muscular strength, are associated with cognitive function in BD, whereas other traditional physiological cardiometabolic disease risk factors are not.

A screening-level human health risk assessment of dietary intake of pesticide residues in produce as compared to consumer guide recommendations.

Consumers are confronted with conflicting information regarding the safety of specific foods. For example, the Environmental Working Group (EWG) publishes an annual consumer guide in which they rank the pesticide contamination of 46 popular fruits and vegetables, which includes designating the 12 with the greatest pesticide contamination as the "Dirty Dozen," to help consumers reduce exposures to toxic pesticides. However, consumer guides like EWG's only incorporate some hazard assessment principles and do not reflect a dietary risk assessment. Therefore, the purpose of this study is to apply risk assessment techniques to EWG's Dirty Dozen list using a uniform screening-level approach to estimate pesticide exposures for U.S. consumers and to characterize the associated chronic human health risks. The most commonly detected pesticide and its representative residue concentrations were identified for each produce type on the 2022 Dirty Dozen list using the USDA Pesticide Data Program database. Estimates of mean dietary consumption in the U.S. were used to calculate dietary exposure to each pesticide-produce combination for adults and children. Pesticide-specific U.S. EPA dietary health-based guidance values (HBGVs) were then used as benchmarks to evaluate the chronic human health risk of consuming each produce type. Overall, the estimated daily exposure for each pesticide-produce combination was below the corresponding HBGV for all exposure scenarios. The current analysis demonstrates that excessive produce-specific pesticide exposure is unexpected as the amount of produce that would need to be consumed on a chronic basis, even among children, far exceeds typical dietary intake. Future research is necessary to assess acute dietary exposure scenarios and to consider cumulative risk.

Data derived extrapolation factors (DDEFs) for rat to human interspecies extrapolation for the HPPD inhibitor mesotrione.

In the risk assessment of agrochemicals, there has been a historical paucity of using data to refine the default adjustment factors, even though large datasets are available to support this. The current state of the science for addressing uncertainty regarding animal to human extrapolation (AFA) is to develop a "data-derived" adjustment factor (DDEF) to quantify such differences, if data are available. Toxicokinetic (TK) and toxicodynamic (TD) differences between species can be utilized for the DDEF, with human datasets being ideal yet rare. We identified a case for a currently registered herbicide, mesotrione, in which human TK and TD are available. This case study outlines an approach for the development of DDEFs using comparative human and animal data and based on an adverse outcome pathway (AOP) for inhibition of 4-hydroxyphenol pyruvate dioxygenase (HHPD). The calculated DDEF for rat to human extrapolation (AFA) for kinetics (AFAK = 2.5) was multiplied by the AFA for dynamics (AFAD = 0.3) resulting in a composite DDEF of ∼1 (AFA = 0.75). This reflects the AOP and available scientific evidence that humans are less sensitive than rats to the effects of HPPD inhibitors. Further analyses were conducted utilizing in vitro datasets from hepatocytes and liver cytosols and extrapolated to whole animal using in vitro to in vivo extrapolation (IVIVE) to support toxicodynamic extrapolation. The in vitro datasets resulted in the same AFAD as derived for in vivo data (AFAD = 0.3). These analyses demonstrate that a majority of the species differences are related to toxicodynamics. Future work with additional in vitro/in vivo datasets for other HPPD inhibitors and cell types will further support this result. This work demonstrates utilization of all available toxicokinetic and toxicodynamic data to replace default uncertainty factors for agrochemical human health risk assessment.

Sleep should not be this difficult: An interpretive descriptive study of older adults' perspectives on behaviour change elements in Sleepwell and experiences with benzodiazepine discontinuation.

Benzodiazepine receptor agonists are often used for insomnia in older adults contrary to current evidence. The harms outweigh the benefits, which are limited. Cognitive behavioural therapy for insomnia is the first-line recommended treatment. Sleepwell was created as a repository of evidence-based resources to promote cognitive behavioural therapy for insomnia and limit benzodiazepine receptor agonist use. This qualitative study uses an interpretive description design and reflexive thematic analysis to explore older adults' perspectives on behavioural change techniques used in Sleepwell resources. It also explores challenges and opportunities towards benzodiazepine receptor agonist discontinuation and cognitive behavioural therapy for insomnia use. Participants were recruited from the Sleepwell arm of a randomized controlled trial. Data were collected from 15 older adults using semi-structured interviews. Two main themes were developed: (1) sleep should not be this difficult; and (2) whether you know it, or learn it, drugs are bad. Two sub-themes were created within the first theme: (1) justification of benzodiazepine receptor agonist use to achieve sleep goals; (2) efforts of committing to cognitive behavioural therapy for insomnia. Several behavioural change techniques (e.g. information about consequences, anticipated regret, salience of consequences) were enablers of benzodiazepine receptor agonist-related behaviour change. For committing to cognitive behavioural therapy for insomnia, several behavioural change techniques (e.g. self-monitoring of behaviour, distraction, stimulus substitution) were beneficial, but social support, which was perceived as useful, was absent. Older adults experienced tension with benzodiazepine receptor agonist use and deprescribing, despite knowing or learning the potential consequences of benzodiazepine receptor agonists. Cognitive behavioural therapy for insomnia implementation was challenging. Embedded behavioural change techniques in the Sleepwell booklets were identified as helpful, but more (e.g. social support) are needed to optimize cognitive behavioural therapy for insomnia use.

Investigation of hydrochemical characteristic, water quality and associated health risks of metals and metalloids in water resources in the vicinity of Akamkpa quarry district, southeastern, Nigeria.

Quarrying of rock aggregates generates produced water that, if not handled properly will be a source of pollution for nearby water bodies, thus affecting the chemistry of the water. This study examined the chemistry, impact of quarrying activities on water resources and the health consequences/risks posed by ingestion of the water by humans in the Akamkpa quarry region in southeastern Nigeria. Thirty (30) water samples consisting of pond water, stream water, hand dug wells, and borehole samples were collected and analyzed for their physicochemical parameters using standard methods. The results obtained from the analyses indicated that the water was moderately acidic, fresh, and not salty, with many parameters below the recommended standards with Ca2+, and HCO3- being the dominant ions present in the water resources. Rock weathering processes including silicate weathering as illustrated by hydrochemical facies, cross plots, and Gibbs diagrams are the dominant mechanisms influencing the quality and major ions chemistry of the water resources with minor contributions from dissolution, anthropogenic activities, and ion exchange. Ca-Mg-SO4-Cl and Na-K-HCO3- are the most important water types. Although the water quality index shows that the water is suitable for human use and irrigation, the mean values of As, Cd, Pb, and Se are above the acceptable limits. Additionally, the calculated contamination factor revealed the water resources are moderate to highly contaminated by As, Cd, Cr, Mo, Pb, Sb, and Se, and are therefore unsuitable for consumption with regards to these parameters. However, the residual sodium carbonate and water hazard index (WHI) values showed that 38% to 90% of sites in the quarry area were unsuitable for cultivation, 10-30% were in the low to medium impact category, and 60% were classified as risky and are from high to very high impact category. A non-cancer study of inhabitants living in the vicinity of the quarry area indicated that 6.7% of the sites have values greater than one, indicating that it may endanger the health of the people. Therefore, constant monitoring of the water quality is recommended as long-term use of contaminated water can harm humans, plants, and soils.

Paenalcaligenes faecalis sp. nov., a novel species of the family Alcaligenaceae isolated from chicken faeces.

A Gram-negative, motile, rod-shaped aerobic and alkalogenic bacterium, designated as strain YLCF04T, was isolated from chicken faeces. Its growth was optimal at 28 °C (range, 10-40 °C), pH 8 (range, pH 6-9) and in 1 % (w/v) NaCl (range, 0-10 %). It was classified to the genus Paenalcaligenes and was most closely related to Paenalcaligenes hominis CCUG 53761AT (97.5 % similarity) based on 16S rRNA gene sequence analysis. Average nucleotide identity and digital DNA-DNA hybridization values between YLCF04T and P. hominis CCUG 53761AT were 76.3 and 18.2 %, respectively. Strain YLCF04T has a genome size of 2.7 Mb with DNA G+C content of 46.3 mol%. Based on its phylogenetic, genomic, phenotypic and biochemical characteristics, strain YLCF04T represents a novel species of the genus Paenalcaligenes, for which the name Paenalcaligenes faecalis sp. nov. is proposed. The type strain is YLCF04T (=CCTCC AB 2022359T= KCTC 92789T).

Clustering of health risk behaviors in pregnant individuals: Data from the Brazilian risk factor surveillance system for non-communicable chronic diseases.

OBJECTIVE: To investigate the clustering of health risk behaviors (HRB) and its association with demographics, physical exercise, overweight, perception of health, and diseases in Brazilian pregnant people. STUDY DESIGN: This is a cross-sectional study using data from the Risk Factor Surveillance System for Non-communicable Chronic Diseases by Telephone Survey (VIGITEL), the main health survey in Brazil. METHODS: We used data on fruit and vegetable consumption, TV time, tobacco, and alcohol abuse in individuals who reported being pregnant (n = 4553). We used latent class analysis to identify optimal HRB clustering among participants. Multinomial regression (odds ratio [OR] and 95% confidence intervals [95%CI]) was applied to identify factors associated with HRB cluster. RESULTS: Three clustering classes were identified: "without HRB cluster" (i.e., least unhealthy behaviors) (n = 2402, 52,8%), "moderate HRB cluster" (n = 1983, 43,5%), and "high HRB cluster" (i.e., most unhealthy behaviors) (n = 168, 3,7%). Pregnant people aged 35-50 years (OR = 1.89, 95%CI = 1.01; 3.52) who did not practice physical exercise (OR = 1.94, 95%CI 1.11; 3.39) were more likely to be classified as "high HRB cluster". Participants with 9-11 years (OR = 0.11, 95%CI = 0.07; 0.17) and ≥ 12 (OR = 0.05, 95%CI = 0.02; 0.11) years of education had a lower likelihood of being in the "high HRB cluster". CONCLUSION: Three HRB clustering patterns were found in this study. Greater maternal age, low education, and absence of physical exercises increased the chances of being in the high HRB cluster group. Participants with higher educational levels were less likely to be in the High HRB cluster.

Self-Reported PrEP Use and Risk of Bacterial STIs Among Ontarian Men Who Are Gay or Bisexual or Have Sex With Men.

PURPOSE: HIV pre-exposure prophylaxis (PrEP) may increase rates of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM) through risk compensation (eg, an increase in condomless sex or number of partners); however, longitudinal studies exploring the time-dependent nature of PrEP uptake and bacterial STIs are limited. We used marginal structural models to estimate the effect of PrEP uptake on STI incidence. METHODS: We analyzed data from the iCruise study, an online longitudinal study of 535 Ontarian GBM from July 2017 to April 2018, to estimate the effects of PrEP uptake on incidence of self-reported bacterial STIs (chlamydia, gonorrhea, and syphilis) collected with 12 weekly diaries. The incidence rate was calculated as the number of infections per 100 person-months, with evaluation of the STIs overall and individually. We used marginal structural models to account for time-varying confounding and quantitative bias analysis to evaluate the sensitivity of estimates to nondifferential outcome misclassification. RESULTS: Participating GBM were followed up for a total of 1,623.5 person-months. Overall, 70 participants (13.1%) took PrEP during the study period. Relative to no uptake, PrEP uptake was associated with an increased incidence rate of gonorrhea (incidence rate ratio = 4.00; 95% CI, 1.67-9.58), but not of chlamydia or syphilis, and not of any bacterial STI overall. Accounting for misclassification, the median incidence rate ratio for gonorrhea was 2.36 (95% simulation interval, 1.08-5.06). CONCLUSIONS: We observed an increased incidence rate of gonorrhea associated with PrEP uptake among Ontarian GBM that was robust to misclassification. Although our findings support current guidelines for integrating gonorrhea screening with PrEP services, additional research should consider the long-term impact of PrEP among this population.Annals Early Access article.

School Dropout, Absenteeism and Coverage of Sexual and Reproductive Health Services in South Africa: Are Those Most at Risk Reached?

School attendance or completion is important for adolescents' development. Adolescents who drop out or are regularly absent from school are at higher risk of adverse sexual and reproductive health (SRH) outcomes. However, there is little evidence evaluating SRH service coverage among adolescents in and out of school. In the context of a large-scale combination HIV and pregnancy prevention intervention funded by the Global Fund, we compared the SRH intervention coverage and SRH risks among adolescent girls who dropped out of school with those who were still in school or who had completed grade 12 in South Africa. Among those still in school, we compared the SRH intervention coverage and SRH risk profiles of those with high versus low or no absenteeism. In 2017 to 2018, we conducted a household survey of adolescent girls aged 15 to 19 years in six of the ten combination intervention districts. Of 2515 participants, 7.6% had dropped out of school. Among the 1864 participants still in school, 10.8% had high absenteeism. Ever having had sex, and condomless sex were more prevalent among dropouts compared with non-dropouts. Dropouts were more likely to access SRH services such as condoms and contraceptives, except the combination prevention intervention services which were more likely to reach those who had not dropped out and were equally likely to reach those in school with high versus low/no absenteeism. Combination SRH prevention programmes can improve the accessibility of SRH services for adolescents in school/who complete school.

Mechanisms of Uptake and Translocation of Thallium in Brassica Vegetables: An X-ray Fluorescence Microspectroscopic Investigation.

Most nonoccupational human exposure to thallium (Tl) occurs via consumption of contaminated food crops. Brassica cultivars are common crops that can accumulate more than 500 µg Tl g-1. Knowledge of Tl uptake and translocation mechanisms in Brassica cultivars is fundamental to developing methods to inhibit Tl uptake or conversely for potential use in phytoremediation of polluted soils. Brassica cultivars (25 in total) were subjected to Tl dosing to screen for Tl accumulation. Seven high Tl-accumulating varieties were selected for follow-up Tl dosing experiments. The highest Tl accumulating Brassica cultivars were analyzed by synchrotron-based micro-X-ray fluorescence to investigate the Tl distribution and synchrotron-based X-ray absorption near-edge structure spectroscopy (XANES) to unravel Tl chemical speciation. The cultivars exhibited different Tl tolerance and accumulation patterns with some reaching up to 8300 µg Tl g-1. The translocation factors for all the cultivars were >1 with Brassica oleracea var. acephala (kale) having the highest translocation factor of 167. In this cultivar, Tl is preferentially localized in the venules toward the apex and along the foliar margins and in minute hot spots in the leaf blade. This study revealed through scanning electron microscopy and X-ray fluorescence analysis that highly Tl-enriched crystals occur in the stoma openings of the leaves. The finding is further validated by XANES spectra that show that Tl(I) dominates in the aqueous as well as in the solid form. The high accumulation of Tl in these Brassica crops has important implications for food safety and results of this study help to understand the mechanisms of Tl uptake and translocation in these crops.

Probabilistic Estimation of Airborne Micro- and Nanoplastic Intake in Humans.

Little research exists on the magnitude, variability, and uncertainty of human exposure to airborne micro- and nanoplastics (AMNPs), despite their critical role in human exposure to MNPs. We probabilistically estimate the global intake of AMNPs through three main pathways: indoor inhalation, outdoor inhalation, and ingestion during indoor meals, for both children and adults. The median inhalation of AMPs is 1,207.7 (90% CI, 42.5-8.48 × 104) and 1,354.7 (90% CI, 47.4-9.55 × 104) N/capita/day for children and adults, respectively. The annual intake of AMPs is 13.18 mg/capita/a for children and 19.10 mg/capita/a for adults, which is approximately one-fifth and one-third of the mass of a standard stamp, assuming a consistent daily intake of medians. The majority of AMP number intake occurs through inhalation, while the ingestion of deposited AMPs during meals contributes the most in terms of mass. Furthermore, the median ANP intake through outdoor inhalation is 9,638.1 N/day (8.23 × 10-6 µg/d) and 5,410.6 N/day (4.62 × 10-6 µg/d) for children and adults, respectively, compared to 5.30 × 105 N/day (5.79 × 10-4 µg/d) and 6.00 × 105 N/day (6.55 × 10-4 µg/d) via indoor inhalation. Considering the increased toxicity of smaller MNPs, the significant number of ANPs inhaled warrants great attention. Collaborative efforts are imperative to further elucidate and combat the current MPN risks.

Lithium Pollution and Its Associated Health Risks in the Largest Lithium Extraction Industrial Area in China.

Lithium (Li) is an important resource that drives sustainable mobility and renewable energy. Its demand is projected to continue to increase in the coming decades. However, the risk of Li pollution has also emerged as a global concern. Here, we investigated the pollution characteristics, sources, exposure levels, and associated health risks of Li in the Jinjiang River basin, the largest area for Li2CO3 production in China. Our results revealed the dominant role of Li extraction activities in the pollution of the river, with over 95% of dissolved Li in downstream river water being emitted from this source. Moreover, the Li concentration in aquatic plants (i.e., water hyacinth) and animals (i.e., fish) significantly increased from upstream to downstream areas, indicating a significant risk to local aquatic ecosystems. More importantly, our study found that local residents were suffering potential chronic noncarcinogenic health risks primarily from consuming contaminated water and vegetables. We also investigated the pollution characteristics of associated elements present in Li ores (e.g., Rb, Cs, Ni, and F-). By uncovering the remarkable impact of Li extraction activities on the Li content in ecosystems for the first time, our study emphasizes the importance of evaluating Li pollution from Li-related industrial activities, including mining, extraction, and recovery.

Cadmium in Market Pork Kidneys: A Study on Cadmium Bioavailability and the Health Effects Based on Mouse Models.

Edible offal of farmed animals can accumulate cadmium (Cd). However, no studies have investigated Cd bioavailability and its health effects. Here, based on mouse models, market pork kidney samples exhibited high Cd relative bioavailability of 74.5 ± 11.2% (n = 26), close to 83.8 ± 7.80% in Cd-rice (n = 5). This was mainly due to high vitamin D3 content in pork kidney, causing 1.7-2.3-fold up-regulated expression of duodenal Ca transporter genes in mice fed pork kidney compared to mice fed Cd-rice, favoring Cd intestinal absorption via Ca transporters. However, although pork kidney was high in Cd bioavailability, subchronic low-dose (5% in diet) consumption of two pork kidney samples having 0.48 and 0.97 µg Cd g-1 dw over 35 d did not lead to significant Cd accumulation in the tissue of mice fed Cd-free rice but instead remarkably decreased Cd accumulation in the tissue of mice fed Cd-rice (0.48 µg Cd g-1) by ∼50% and increased abundance of gut probiotics (Faecalibaculum and Lactobacillus). Overall, this study contributed to our understanding of the bioavailability and health effects associated with Cd in edible offal, providing mechanistic insights into pork kidney consumption safety based on Cd bioavailability.

Mitochondrial DNA Stress-Mediated Health Risk to Dibutyl Phthalate Contamination on Zebrafish (Danio rerio) at Early Life Stage.

Plastics contaminations are found globally and fit the exposure profile of the planetary boundary threat. The plasticizer of dibutyl phthalate (DBP) leaching has occurred and poses a great threat to human health and the ecosystem for decades, and its toxic mechanism needs further comprehensive elucidation. In this study, environmentally relevant levels of DBP were used for exposure, and the developmental process, oxidative stress, mitochondrial ultrastructure and function, mitochondrial DNA (mtDNA) instability and release, and mtDNA-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway with inflammatory responses were measured in zebrafish at early life stage. Results showed that DBP exposure caused developmental impairments of heart rate, hatching rate, body length, and mortality in zebrafish embryo. Additionally, the elevated oxidative stress damaged mitochondrial ultrastructure and function and induced oxidative damage to the mtDNA with mutations and instability of replication, transcription, and DNA methylation. The stressed mtDNA leaked into the cytosol and activated the cGAS-STING signaling pathway and inflammation, which were ameliorated by co-treatment with DBP and mitochondrial reactive oxygen species (ROS) scavenger, inhibitors of cGAS or STING. Furthermore, the larval results suggest that DBP-induced mitochondrial toxicity of energy disorder and inflammation were involved in the developmental defects of impaired swimming capability. These results enhance the interpretation of mtDNA stress-mediated health risk to environmental contaminants and contribute to the scrutiny of mitochondrial toxicants.

Nonalcoholic Fatty Liver Disease Development in Male Mice upon Exposure to Flubendiamide.

Flubendiamide (FLU), a widely used diamide insecticide, has been observed to potentiate adipogenesis in 3T3-L1 preadipocytes in vitro. Whether exposure to FLU disrupts hepatic lipid homeostasis in mammals and induces visceral obesity, however, remains unclear. The aim of this study was to assess the effects of FLU when administered orally to male C57BL/6J mice under normal diet (ND) and high-fat diet (HFD) conditions. FLU accumulated at higher levels in the tissues of the HFD group than those of the ND group, indicating that an HFD contributed to the accumulation of lipophilic pesticides in vivo. Notably, FLU (logP = 4.14) is highly lipophilic and easily accumulates in fat. Exposure to FLU had opposing effects on the lipid metabolism of the liver in the ND and HFD groups. Liver triacylglycerol levels in the ND group were reduced, while those in the HFD group were increased, resulting in more severe hepatic steatosis. More lipid accumulation was also observed in HepG2 cells exposed to FLU. Changes in hepatic lipid deposition in vivo occurred as the enhanced transcriptional regulation of the genes involved in lipid uptake, de novo lipogenesis, and fatty acid ß-oxidation (FAO). Moreover, an excessive increase in FAO caused oxidative stress, which in turn exacerbated the inflammation of the liver. This study revealed the disruptive effect of FLU exposure on hepatic lipid homeostasis, which may facilitate the triggering of nonalcoholic fatty liver disease in HFD-fed mice.

Unequal Health Risks and Attributable Mortality Burden of Source-Specific PM2.5 in China.

Anthropogenic emissions, originating from human activities, stand as the primary contributors to PM2.5, which is recognized as a global health threat. The disease burden associated with PM2.5 has been extensively documented. However, the prevailing estimations have predominantly relied on PM2.5 exposure-response functions, neglecting the distinct risks posed by PM2.5 from various sources. China has experienced a significant reduction in the PM2.5 concentration due to stringent emission controls. With diverse sources and abundant mortality data, this situation provides a unique opportunity to estimate short-term source-specific attributable mortality. Our approach involves an integrated unequal health risk-oriented modeling in China, incorporating a source-oriented Community Multiscale Air Quality model, an adjustment and downscaling method for exposure measurement, a generalized linear model with random-effects meta-analysis, and premature mortality estimation. Adhering to the unequal health risk concept, we calculated the attributable mortality of multiple PM2.5 sources by determining the source risk-adjusted factor. In this study, we observed varying excess risks associated with multiple PM2.5 sources, with transportation-related PM2.5 exhibiting the most substantial association. An interquartile range increase (7.65 µg/m3) was linked to a 1.98% higher daily nonaccidental mortality. Residential use- and transportation-related PM2.5 emerged as the two principal sources of premature mortality. In 2018, a remarkable 53,381 avoiding deaths were estimated compared to 2013, and over 67% of these were attributed to reductions in coal-dependent sources. Notably, transportation-related PM2.5 emerged as the largest contributor to premature mortality in 2018. This study underscores the significance of a new source-oriented health risk assessment to support actions aimed at reducing air pollution. It strongly advocates for heightened attention to PM2.5 reductions in the transportation sector in China.

Sewage Sludge Promotes the Accumulation of Antibiotic Resistance Genes in Tomato Xylem.

Xylem serves as a conduit linking soil to the aboveground plant parts and facilitating the upward movement of microbes into leaves and fruits. Despite this potential, the composition of the xylem microbiome and its associated risks, including antibiotic resistance, are understudied. Here, we cultivated tomatoes and analyzed their xylem sap to assess the microbiome and antibiotic resistance profiles following treatment with sewage sludge. Our findings show that xylem microbes primarily originate from soil, albeit with reduced diversity in comparison to those of their soil microbiomes. Using single-cell Raman spectroscopy coupled with D2O labeling, we detected significantly higher metabolic activity in xylem microbes than in rhizosphere soil, with 87% of xylem microbes active compared to just 36% in the soil. Additionally, xylem was pinpointed as a reservoir for antibiotic resistance genes (ARGs), with their abundance being 2.4-6.9 times higher than in rhizosphere soil. Sludge addition dramatically increased the abundance of ARGs in xylem and also increased their mobility and host pathogenicity. Xylem represents a distinct ecological niche for microbes and is a significant reservoir for ARGs. These results could be used to manage the resistome in crops and improve food safety.