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Abstract Hepatitis B virus is a globally distributed pathogen and the history of HBV infection in humans predates 10000 years. However, long-term evolutionary history of HBV in Eastern Eurasia remains elusive. We present 34 ancient HBV genomes dating between approximately 5000 to 400 years ago sourced from 17 sites across Eastern Eurasia. Ten sequences have full coverage, and only two sequences have less than 50% coverage. Our results suggest a potential origin of genotypes B and D in Eastern Asia. We observed a higher level of HBV diversity within Eastern Eurasia compared to Western Eurasia between 5000 and 3000 years ago, characterized by the presence of five different genotypes (A, B, C, D, WENBA), underscoring the significance of human migrations and interactions in the spread of HBV. Our results suggest the possibility of a transition from non-recombinant subgenotypes (B1, B5) to recombinant subgenotypes (B2 - B4). This suggests a shift in epidemiological dynamics within Eastern Eurasia over time. Here, our study elucidates the regional origins of prevalent genotypes and shifts in viral subgenotypes over centuries.

Background: Stroke is the second leading cause of death for all human beings and poses a serious threat to human health. Environmental exposure to a mixture of metals may be associated with the occurrence and development of stroke, but the evidence in the Chinese population is not yet conclusive. Objectives: This study evaluated the association between stroke risk and 13 metals Methods: Metal concentrations in whole blood samples from 100 stroke cases and 100 controls were measured by ICP-MS. The cumulative impact of mixed metal on stroke risk was investigated by using three statistical models, BKMR, WQS and QGC. Results: The case group had higher concentrations of Mg, Mn, Zn, Se, Sn, and Pb than the control group (p

Abstract The evolution of pathway enzymes enhances the biosynthesis of high‐value chemicals, crucial for pharmaceutical, and agrochemical applications. However, unpredictable evolutionary landscapes of pathway genes often hinder successful evolution. Here, the presence of complex epistasis is identifued within the representative naringenin biosynthetic pathway enzymes, hampering straightforward directed evolution. Subsequently, a biofoundry‐assisted strategy is developed for pathway bottlenecking and debottlenecking, enabling the parallel evolution of all pathway enzymes along a predictable evolutionary trajectory in six weeks. This study then utilizes a machine learning model, ProEnsemble, to further balance the pathway by optimizing the transcription of individual genes. The broad applicability of this strategy is demonstrated by constructing an Escherichia coli chassis with evolved and balanced pathway genes, resulting in 3.65 g L−1 naringenin. The optimized naringenin chassis also demonstrates enhanced production of other flavonoids. This approach can be readily adapted for any given number of enzymes in the specific metabolic pathway, paving the way for automated chassis construction in contemporary biofoundries.

Inorganic arsenic (iAs) contamination in drinking water is a global public health problem, and exposure to iAs is a known risk factor for bladder cancer. Perturbation of urinary microbiome and metabolome induced by iAs exposure may have a more direct effect on the development of bladder cancer. The aim of this study was to determine the impact of iAs exposure on urinary microbiome and metabolome, and to identify microbiota and metabolic signatures that are associated with iAs-induced bladder lesions. We evaluated and quantified the pathological changes of bladder, and performed 16S rDNA sequencing and mass spectrometry-based metabolomics profiling on urine samples from rats exposed to low (30 mg/L NaAsO2) or high (100 mg/L NaAsO2) iAs from early life (in utero and childhood) to puberty. Our results showed that iAs induced pathological bladder lesions, and more severe effects were noticed in the high-iAs group and male rats. Furthermore, six and seven featured urinary bacteria genera were identified in female and male offspring rats, respectively. Several characteristic urinary metabolites, including Menadione, Pilocarpine, N-Acetylornithine, Prostaglandin B1, Deoxyinosine, Biopterin, and 1-Methyluric acid, were identified significantly higher in the high-iAs groups. In addition, the correlation analysis demonstrated that the differential bacteria genera were highly correlated with the featured urinary metabolites. Collectively, these results suggest that exposure to iAs in early life not only causes bladder lesions, but also perturbs urinary microbiome composition and associated metabolic profiles, which shows a strong correlation. Those differential urinary genera and metabolites may contribute to bladder lesions, suggesting a potential for development of urinary biomarkers for iAs-induced bladder cancer.

Ingestion of arsenic interferes with spermatogenesis and increases the risk of male infertility, but the underlying mechanism remines unclear. In this study, we investigated spermatogenic injury with a focus on blood-testis barrier (BTB) disruption by administrating 5 mg/L and 15 mg/L arsenic orally to adult male mice for 60 d. Our results showed that arsenic exposure reduced sperm quality, altered testicular architecture, and impaired Sertoli cell junctions at the BTB. Analysis of BTB junctional proteins revealed that arsenic intake downregulated Claudin-11 expression and increased protein levels of β-catenin, N-cadherin, and Connexin-43. Aberrant localization of these membrane proteins was also observed in arsenic-treated mice. Meanwhile, arsenic exposure altered the components of Rictor/mTORC2 pathway in mouse testis, including inhibition of Rictor expression, reduced phosphorylation of protein kinase Cα (PKCα) and protein kinase B (PKB), and elevated matrix metalloproteinase-9 (MMP-9) levels. Furthermore, arsenic also induced testicular lipid peroxidative damage, inhibited antioxidant enzyme (T-SOD) activity, and caused glutathione (GSH) depletion. Our findings suggest that disruption of BTB integrity is one of the main factors responsible for the decline in sperm quality caused by arsenic. PKCα-mediated rearrangement of actin filaments and PKB/MMP-9-increased barrier permeability jointly contribute to arsenic-induced BTB disruption.

Co-contamination of arsenic and fluoride is widely distributed in groundwater. However, little is known about the interactively influence of arsenic and fluoride, especially the combined mechanism in cardiotoxicity. Cellular and animal models exposure to arsenic and fluoride were established to assess the oxidative stress and autophagy mechanism of cardiotoxic damage using the factorial design, a widely used statistical method for assessing two factor interventions. In vivo, combined exposure to high arsenic (50 mg/L) and high fluoride (100 mg/L) induced myocardial injury. The damage is accompanied by accumulation of myocardial enzyme, mitochondrial disorder, and excessive oxidative stress. Further experiment identified that arsenic and fluoride induced the accumulation of autophagosome and increased expression level of autophagy related genes during the cardiotoxicity process. These findings were further demonstrated through the in vitro model of arsenic and fluoride-treated the H9c2 cells. Additionally, combined of arsenic-fluoride exposure possesses the interactively influence on oxidative stress and autophagy, contributing to the myocardial cell toxicity. In conclusion, our data suggest that oxidative stress and autophagy are involved in the process of cardiotoxic injury, and that these indicators showed interaction effect in response to the combined exposure of arsenic and fluoride.

Objective: The evidence for the beneficial effects of physical activity (PA) and potentially detrimental effects of long-term exposure to fine particulate matter (PM2.5) on neurodegeneration diseases is accumulating. However, their joint effects remain unclear. We evaluated joint associations of habitual PA and PM2.5 exposure with incident dementia in a longitudinal elderly cohort in Hong Kong. Methods: A total of 57,775 elderly participants (≥65 years) without dementia were enrolled during 1998–2001 and followed up till 2011. Their information on PA and other relevant covariates were collected at baseline (1998–2001) by a standard self-administered questionnaire, including PA volumes (high, moderate, low, and inactive) and types (aerobic exercise, traditional Chinese exercise, stretching exercise, walking slowly, and no exercise). Their annual mean PM2.5 exposures at the residential address were estimated using a satellite-based spatiotemporal model. We then adopted the Cox proportional hazards model to examine the joint associations with the incidence of all-cause dementia, Alzheimer’s diseases, and vascular dementia on additive and multiplicative scales. Results: During the follow-up period, we identified 1,157 incident cases of dementia, including 642 cases of Alzheimer’s disease and 324 cases of vascular dementia. A higher PA level was associated with a lower risk of incident all-cause dementia (hazard ratio (HR) for the high-PA volume was 0.59 (95% CI, 0.47, 0.75), as compared with the inactive-PA), whereas a high level of PM2.5 was related to the higher risk with an HR of 1.15 (95%CI: 1.00, 1.33) compared with the low-level of PM2.5. No clear evidence was observed of interaction between habitual PA (volume and type) and PM2.5 inhalation to incident dementia on either additive or multiplicative scale. Conclusion: Habitual PA and long-term PM2.5 exposure were oppositely related to incident dementia in the Hong Kong aged population. The benefits of PA remain in people irrespective of exposure to air pollution.

While numerous studies have shown that fluoride or arsenic exposure may damage the reproductive system, there are few reports of co-exposure to fluoride and arsenic. In addition, the literature on autophagy and intestinal flora composition in reproductive toxicity studies of co-exposure to fluoride and arsenic is insufficient. In this study, we developed a rat model of fluoride and arsenic exposure via drinking water from pre-pregnancy to 90 days postnatal. Sprague-Dawley rats were randomly divided into sterile water control group, fluoride group (100 mg/L NaF), arsenic group (50 mg/L NaAsO2) and combined exposure group (100 mg/L NaF+50 mg/L NaAsO2). Our results showed that fluoride and arsenic exposure caused a reduction in testicular weight and significant pathological damage to tissue. We found that the levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were reduced to varying degrees. Meanwhile experiments showed that fluoride and arsenic exposure can modulate autophagic flux, causing increased levels of Beclin1 and LC3 expression and decreased p62 expression. Analogously, by performing 16S sequencing of rat feces, we found 24 enterobacterial genera that differed significantly among the groups. Furthermore, the flora associated with testicular injury were identified by correlation analysis of hormonal indices and autophagy alterations with intestinal flora composition at the genus level, respectively. In summary, our study shows that fluoride and arsenic co-exposure alters autophagic flux in the testis, causes testicular injury, and reveals an association between altered intestinal flora composition and testicular injury.

The regulation of mitochondrial function, which is dominated by oxidative phosphorylation (OXPHOs), is important in fluoride induced cardiovascular disease. Based on the previous study of fluoride-induced mitochondrial structure and membrane potential abnormalities, this study integrated ITRAQ protein quantification and RNA-Seq methods to analyze the sequencing data of rat myocardial tissue under fluoride exposure (0, 30, 60 and 90 mg/L). A total of 22 differentially expressed genes associated with the OXPHOs pathway were screened by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) co-enrichment analysis, and were localizated by Interaction Network and calculated inter-genes and inter-omics correlations by Pearson correlation. In general, fluoride exposure can down-regulate genes related OXPHOs, particularly affecting the assembly of the complex I including Ndufa10, resulting in abnormal mitochondrial ATP synthesis and reduced myocardial energy supply. Most importantly, this study shows that the enriched information from the proteomics can explain the change process of energy production, but the specific molecules involved in energy supply cannot be obtained via transcriptomics information alone. Based on the results of transcriptional and protein analysis, our findings contribute to an innovative understanding of the pathways and molecular changes of myocardial injury induced by fluorosis.

Nationwide mass social unrest has emerged in the US since May 25 and raised broad concerns about its impacts on the local COVID-19 epidemics. We compared the COVID-19 transmissibility between May 19–May 25 and May 29–June 4 for each state of the US. We found that social unrest is likely associated with the rebound of the COVID-19 transmissibility, which might raise difficulties in the pandemic control.

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30–35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6–8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8–10 mg/kg every 24 h was optimal under 30–35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin.

In this study, we conducted an ecological study to examine their effects in the early phase of the pandemic (from December 2019 to February 2020) in China. We found that the associations between the average concentrations of NO2, SO2, and CO and the COVID-19 transmissibility are not statistically clear.

Many “hot spot” geographic areas across the world with drinking water co-contaminated with inorganic arsenic (iAs) and fluoride (F-), two of the most common natural contaminants in drinking water. Both iAs and F- are known neurotoxins and affect neurodevelopment of children. However, very few studies have investigated the neurodevelopmental effects of concurrent exposure to iAs and F-, which could potentially pose a greater risk than iAs or F- exposure alone. Further, perturbations of gut microbiota, which plays a regulatory role in neurodevelopment, resulting from iAs and F- exposure has been reported in numerous studies. There is lacking of information regarding to the relationship among concurrent iAs and F- exposure, microbiome disruption, and neurodevelopmental impacts. To fill these gaps, we treated offspring rats to iAs (50 mg/L NaAsO2) and F- (100 mg/L NaF), alone or combined from early life (in utero and childhood) to puberty. We applied Morris water maze test to assess spatial learning and memory of these rats and generated gut microbiome profiles using 16S rRNA gene sequencing. We showed that concurrent iAs and F- exposure caused more prominent neurodevelopmental effects in rats than either iAs or F- exposure alone. Moreover, Unsupervised Principal Coordinates Analysis (PCoA) and Linear Discriminant Analysis Effect Size (LEfSe) analysis of gut microbiome sequencing results separated concurrent exposure group from others, indicating a more sophisticated change of gut microbial communities occurred under the concurrent exposure condition. Further, a correlation analysis between indices of the water maze test and microbial composition at the genus level identified featured genera that were clearly associated with neurobehavioral performance of rats. 75% (9 out of 12) genera, which had a remarkable difference in relative abundance between the control and combined iAs and F- exposure groups, showed significantly strong correlations (r = 0.70–0.90) with the water maze performance indicators. Collectively, these results suggest that concurrent iAs and F- exposure led to more prominent effects on neurodevelopment and gut microbiome composition structures in rats, and the strong correlation between them indicates a high potential for the development of novel microbiome-based biomarkers of iAs and/or F- associated neurodevelopmental deficits.

Background: Mast cells participate in immune responses by releasing potent immune system modifiers via degranulation. Due to currently reported controversial roles of mast cells in Streptococcus pneumoniae infections, this study aimed to determine the role and mechanism of mast cells in clearing S. pneumoniae in mice. Methods: In vivo mouse model of mast cell degranulation established by administration of C48/80 was evaluated for the influences of mast cell degranulation on bacterial colonization and inflammation. In vitro model was established to observe the influences of mast cell degranulation on phagocytic and bactericidal functions of neutrophils and macrophages. IL-6 null and TNF-α null mice on the C57BL/6 background were used to investigate the effects of inflammatory factors released by mast cell degranulation on bacterial clearance. Results: Mast cell degranulation increased IL-6 and TNF-α levels and immune cell numbers in nasal lavage fluid, and inhibited the bactericidal function of macrophages and neutrophils in vitro. It decreased the number of neutrophils and macrophages recruited to respiratory tract after S. pneumoniae challenge and inhibited the clearance of S. pneumoniae in mice. After pretreatment with C48/80, S. pneumoniae loads were significantly lower in IL-6 null mice than in wild type mice, while no differences were observed between TNF-α null and wild type mice. Conclusions: Mast cell degranulation can cause inflammation and impair immune cell recruitment to respiratory tract after S. pneumoniae challenge. Products of mast cell degranulation including IL-6 decreased the bactericidal function of neutrophils and macrophages. Through these mechanisms, mast cell degranulation inhibited clearance of S. pneumoniae in mice. Keywords: Degranulation, Inflammatory response, Mast cell, Streptococcus pneumoniae

Streptococcus pneumoniae is a major pathogen leading to substantial morbidity and mortality in children under 5 years of age. Vaccination is an effective strategy to prevent S. pneumoniae infection. SPY1 is a pneumococcal vaccine candidate strain obtained in our previous study. To improve its stability and immunogencity, in this study, we constructed the SPY1ΔlytA strain that lacks autolysin activity and was coated with an artificial exterior surface calcium phosphate shell by in situ mineralization. The resulting strain SPY1ΔlytACaPi displayed enhanced thermal stability enabling storage at 37°C for 1 week. Furthermore, mucosal and subcutaneous immunization with the SPY1ΔlytACaPi strain induced better protective effects than SPY1ΔlytA in anti-colonization after challenging with 19F and anti-invasion by D39 in mice. Subcutaneous immunization with SPY1ΔlytACaPi elicited higher IgG level while mucosal immunization primarily elicited an immune response which is supposed to be related to Th17 cells. Taken together, the mineralized strain may be a promising candidate for an attenuated S. pneumoniae vaccine.

This research investigated the relationship between the levels of reactive oxygen species (ROS), mitochondrial membrane potentials, and apoptosis in MC3T3-E1 osteoblasts (OB) by administering varying concentrations of the fluoride ion. Sodium fluoride (NaF), at concentrations of 0, 1, 5, 10, and 30 mg/L, was administered to cultured OB. Hematoxylin and eosin (HE) and 4',6-diamidino-2-phenylindole (DAPI) staining were used to observe the effects of fluoride on OB apoptosis. In addition, the ROS levels and the mitochondrial membrane potentials of the OB were analyzed with a Fluorescence Activated Cell Sorter (FACS) using labeling probes DCFH-DA and JC-1 after fluoride treatment for 72 hr. There were pronounced negative effects on OB survival from long-term NaF treatment. These negative effects included apoptosis, increased ROS levels, and decreased mitochondrial membrane potentials. Our results demonstrated that fluoride-induced OB apoptosis is mediated by the direct effects of fluoride on ROS levels and mitochondrial membrane potentials. [ABSTRACT FROM AUTHOR]

In humans, arsenic is primarily metabolized by arsenic (þ3 oxidation state) methyltransferase (As3MT) to yield both trivalent and pentavalent methylated metabolites. We recently reported that the putative N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) can biotransform monomethylarsonous acid (MMAIII) to dimethylarsinic acid, conferring resistance of human cells to arsenic exposure. To further decipher the role of N6AMT1 and its interaction with As3MT in arsenic biomethylation, we examined the relative contribution of N6AMT1 and As3MT in metabolizing arsenic using several newly modified UROtsa human urothelial cells, ie, UROtsa cells with either a constant level of N6AMT1 or As3MT in combination with an inducible level of As3MT or N6AMT1, respectively. Our analysis confirmed the involvement of N6AMT1 in MMAIII biomethylation but not for inorganic arsenic. In a comparable level of N6AMT1 and As3MT, the effect of N6AMT1 mediated MMAIII biomethylation was obscured by the action of As3MT. Furthermore, we showed that the levels of N6AMT1 and As3MT proteins varied among and within human normal and cancerous tissues. Overall, the data showed that N6AMT1 has a role in MMAIII biomethylation, but its effect is relatively minor and limited compared with As3MT. In addition, the varied levels and distributions of N6AMT1 and As3MT among human tissues may potentially contribute to the tissue specificity and susceptibility to arsenic toxicity and carcinogenicity. [ABSTRACT FROM AUTHOR]

Background: Unintentional injury remains the leading cause of morbidity and mortality among children worldwide. The aims of this study were to assess a baseline level of first aid knowledge and overall attitudes regarding first aid among staff members in Shanghai preschools. Methods: A cross-sectional study was carried out among the staff members at selected preschools. A stratified random sampling method was first used to identify suitable subjects. Data were obtained using a multiple-choice questionnaire. A standardized collection of demographics was performed and participants were given the aforementioned questionnaire to indicate knowledge of and attitudes toward first aid. Results: 1067 subjects completed the questionnaire. None of the surveyed employees answered all questions correctly; only 39 individuals (3.7%) achieved passing scores. The relative number of correct answers to specific questions ranged from 16.5% to 90.2%. In particular, subjects lacked knowledge regarding first aid for convulsive seizures (only 16.5% answered correctly), chemical injuries to the eye (23%), inhaled poison (27.6%), and choking and coughing (30.1%). A multiple linear regression analysis showed scores were significantly higher among staff members with more education, those who had received first aid training before or were already healthcare providers, younger employees, and staff members from rural districts. Most employees agreed that giving first aid was helpful; the vast majority felt that it was important and useful for them to learn pediatric first aid. Conclusions: The level of first-aid knowledge among preschool staffs in Shanghai was low. There is an urgent need to educate staff members regarding first aid practices and the various risk factors relating to specific injuries. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigates the association of genetic polymorphisms, messenger ribonucleic acid (RNA) expression of p53 and p21 with chronic benzene poisoning in Chinese workers. The study employs polymerase chain reaction (PCR)-restriction fragment length polymorphism technique to determine polymorphisms of p53 and p21. It concludes that the results indicate that polymorphisms in p21 can protect against the risk of chronic benzene poisoning.