Particulate polycyclic aromatic hydrocarbons and metals, DNA methylation and DNA methyltransferase among middle-school students in China.

The main components of particulate matter (PM) had been reported to change DNA methylation levels. However, the mixed effect of PM and its constituents on DNA methylation and the underlying mechanism in children has not been well characterized. To investigate the association between single or mixture exposures and global DNA methylation or DNA methyltransferases (DNMTs), 273 children were recruited (110 in low-exposed area and 163 in high-exposed area) in China. Serum benzo[a]pyridin-7,8-dihydroglycol-9, 10-epoxide (BPDE)-albumin adduct and urinary metals were determined as exposure markers. The global DNA methylation (% 5mC) and the mRNA expression of DNMT1, and DNMT3A were measured. The linear regression, quantile-based g-computation (QGC), and mediation analyses were performed to investigate the effects of individual and mixture exposure. We found that significantly lower levels of % 5mC (P < 0.001) and the mRNA expression of DNMT3A in high-PM exposed group (P = 0.031). After adjustment for age, gender, BMI z-score, detecting status of urinary cotinine, serum folate, and white blood cells, urinary arsenic (As) was negatively correlated with the % 5mC. One IQR increase in urinary As (19.97 µmol/mol creatinine) was associated with a 11.06 % decrease in % 5mC (P = 0.026). Serum BPDE-albumin adduct and urinary cadmium (Cd) were negatively correlated with the levels of DNMT1 and DNMT3A (P < 0.05). Mixture exposure was negatively associated with expression of DNMT3A in QGC analysis (ß: -0.19, P < 0.001). Mixture exposure was significantly associated with decreased % 5mC in the children with non-detected cotinine or normal serum folate (P < 0.05), which the most contributors were PAHs and As. The mediated effect of hypomethylation through DNMT1 or DNMT3A pathway was not observed. Our findings indicated that individual and mixture exposure PAHs and metal components had negative associations with global DNA methylation and decreased DNMT3A expression significantly in school-age individuals.

Identification of sensitive endpoints for the assessment of phthalates-induced reproductive and developmental toxicity: A literature mining study.

Dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP), two common types of phthalates, are known to cause reproductive and developmental toxicity in animals and humans. The reference doses (RfD) of DBP and DEHP should be determined by sensitive endpoints. We here aimed to identify sensitive endpoints for DBP- and DEHP-induced such toxicity using published literatures. By examining the impacts of maternal exposure to DBP or DEHP on anogenital distance (AGD) and semen quality of offspring, we discovered that DBP or DEHP caused AGD decline in boys but increase in girls with DBP being more potent and the first 14weeks of pregnancy being more susceptible, suggesting a chemical- and time-dependent phenomenon. We also identified AGD shortening and total sperm count reduction as two sensitive endpoints for DBP- or DEHP-induced reproductive and developmental toxicity, respectively. Based upon these two endpoints and the employment of the Bayesian benchmark dose approach with an uncertainty factor of 3,000, we estimated the RfD values of DBP and DEHP were 15 µg/kg/day and 36 µg/kg/day, respectively. Thus, we uncover previously unrecognized phenomena of DBP- or DEHP-induced reproductive and developmental toxicity and establish new and comparable or more conservative RfDs for the risk assessment of phthalates exposure in humans.

Unveiling the mechanisms of trichloroethylene hypersensitivity syndrome: Exploring the role of connexin 43 gap junctions in severe skin damage.

Trichloroethylene (TCE), extensively used as an organic solvent in various industrial applications, has been identified as a causative factor in inducing hypersensitivity syndrome (THS). Currently, there is no specific treatment for THS, and most patients experience serious adverse outcomes due to extensive skin damage leading to severe infection. However, the pathogenesis of THS-associated skin damage remains unclear. This study aims to elucidate the mechanism underlying skin damage from the perspective of intercellular communication and gap junctions in THS. Our results verified that hyperactivation of connexin43 gap junctions, caused by the aberrantly elevated expression of connexin43, triggers a bystander effect that promotes apoptosis and inflammation in THS via the TNF-TNFRSF1B and mitochondria-associated pathways. Additionally, we identified the gap junction inhibitor Carbenoxolone disodium (CBX) as a promising agent for the treatment of skin damage in THS. CBX protects against inflammatory cell infiltration in the skin and decreases immune cell imbalance in the peripheral blood of THS mice. Furthermore, CBX reduces connexin43 expression, apoptosis and inflammation in THS mice. The study reveals new insights into the mechanisms underlying TCE-induced skin damage, offering a potential treatment strategy for the development of effective therapies targeting severe dermatitis induced by chemical exposure.

Granulysin-mediated reduction of PDZRN3 induces Cx43 gap junctions activity exacerbating skin damage in trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE)-induced hypersensitivity syndrome (THS) has been a concern for many researchers in the field of environmental and occupational health. Currently, there is no specific treatment for THS, leaving patients to contend with severe infections arising from extensive skin lesions, consequently leading to serious adverse effects. However, the pathogenesis of severe skin damage in THS remains unclear. This study aims to investigate the specific danger signals and mechanisms underlying skin damage in THS through in vivo and in vitro experiments. We identified that cell supernatant containing 15 kDa granulysin (GNLY), released from activated CD3-CD56+NK cells or CD3+CD56+NKT cells in PBMC induced by TCE or its metabolite, promoted apoptosis in HaCaT cells. The apoptosis level decreased upon neutralization of GNLY in the supernatant by a GNLY-neutralizing antibody in HaCaT cells. Subcutaneous injection of recombinant 15 kDa GNLY exacerbated skin damage in the THS mouse model and better mimicked patients' disease states. Recombinant 15 kDa GNLY could directly induce cellular communication disorders, inflammation, and apoptosis in HaCaT cells. In addition to its cytotoxic effects, GNLY released from TCE-activated NK cells and NKT cells or synthesized GNLY alone could induce aberrant expression of the E3 ubiquitin ligase PDZRN3, causing dysregulation of the ubiquitination of the cell itself. Consequently, this resulted in the persistent opening of gap junctions composed of connexin43, thereby intensifying cellular inflammation and apoptosis through the "bystander effect". This study provides experimental evidence elucidating the mechanisms of THS skin damage and offers a novel theoretical foundation for the development of effective therapies targeting severe dermatitis induced by chemicals or drugs.

Association between blood metals mixture and chronic kidney disease in adults: NHANES 2013-2016.

BACKGROUND: The association between single metal exposure and chronic kidney disease (CKD) has been established. However, there is limited research on the effects of multi-metal mixtures and their potential age-specific associations with kidney injury. This study aimed to examine the relationship between metal mixtures and kidney function in adults, while also exploring the modifying effects of age. METHODS: We included a subset (n = 4250) of a nationally representative adult population in the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Kidney function was assessed using the glomerular filtration rate (eGFR) and creatinine albumin ratio (ACR). The individual and combined effects of lead (Pb), cadmium (Cd), mercury, and manganese on kidney injury and the risk of CKD were evaluated. RESULTS: Pb and Cd were found to be positively associated with decreased kidney function. For a one Ln-unit increase in lead and cadmium, the adjusted ORs of CKD were 1.60 (95% CI: 1.35, 1.90) and 1.41 (95% CI:1.12, 1.77), respectively. We also observed an interaction between lead and cadmium for ACR. We also observed the joint effect between Pb and Cd on eGFR, ACR and CKD. Stratified analysis found a higher risk of decreased kidney function among older individuals. The quantile-g calculation model further showed that metal mixture was associated with decreased kidney function and the risk of CKD (OR = 1.53, 95% CI: 1.22, 1.90). And lead and cadmium were the main contributors. And Pb and Cd were the major components that increased the risk of CKD. CONCLUSION: Co-exposure to metal mixture were associated with reduced kidney function in adults, especially in older. Our findings support co-exposure to lead and cadmium as risk factors of CKD in adults.

Herpesvirus activated NF-κB-mediated antigen processing and presentation to aggravate trichloroethylene-induced hypersensitivity dermatitis.

Trichloroethylene-induced hypersensitivity dermatitis (TIHD) is a delayed hypersensitivity response that is affected by genetic and environmental factors. Occupational exposure to trichloroethylene (TCE) enhances antigen presentation, leading to hypersensitivity in workers with the HLA-B* 13:01 allele. Several studies have observed the activation of herpesviruses, such as EpsteinBarr virus (EBV), in TIHD patients. However, the underlying mechanisms remain unclear. Toll-like receptors (TLRs) play a pivotal role in the pathogenesis of herpesvirus infection. This study aimed to explore whether TLRs serve as a shared mechanism for both herpesvirus and allergenic chemicals. In this study, HLA-B* 13:01-transfected Hmy2. A C1R cell model was constructed, and cells were treated with TCOH and EBV to explore the possible mechanisms. We established a mouse model of dermatitis and used a TLR4 agonist to verify the effect of herpesvirus on TIHD. The results showed that EBV and TCOH synergistically enhance antigen processing and presentation via the TLR2/NF-κB axis. Furthermore, TLR4 agonist further aggravated skin lesions and liver damage in TCE-sensitized mice through TLR4/NF-κB axis-mediated antigen processing and presentation. Together, this study indicates that viral infection further aggravates the inflammatory response in TIHD based on environment-gene interactions.

Urinary Amino-PAHs in relation to diesel engine emissions and urinary mutagenicity.

Diesel exhaust has long been of health concern due to established toxicity including carcinogenicity in humans. However, the precise components of diesel engine emissions that drive carcinogenesis are still unclear. Limited work has suggested that nitrated polycyclic aromatic hydrocarbons (NPAHs) such as 1-nitropyrene and 2-nitrofluorene may be more abundant in diesel exhaust. The present study aimed to examine whether urinary amino metabolites of these NPAHs were associated with high levels of diesel engine emissions and urinary mutagenicity in a group of highly exposed workers including both smokers and nonsmokers. Spot urine samples were collected immediately following a standard work shift from each of the 54 diesel engine testers and 55 non-tester controls for the analysis of five amino metabolites of NPAHs, and cotinine (a biomarker of tobacco smoke exposure) using liquid chromatography-mass spectrometry. An overnight urine sample was collected in a subgroup of non-smoking participants for mutagenicity analysis using strain YG1041 in the Salmonella (Ames) mutagenicity assay. Personal exposure to fine particles (PM2.5) and more-diesel-specific constituents (elemental carbon and soot) was assessed for the engine testers by measuring breathing-zone concentrations repeatedly over several full work shifts. Results showed that it was 12.8 times more likely to detect 1-aminopyrene and 2.9 times more likely to detect 2-aminofluorene in the engine testers than in unexposed controls. Urinary concentrations of 1-aminopyrene were significantly higher in engine testers (p < 0.001), and strongly correlated with soot and elemental carbon exposure as well as mutagenicity tested in strain YG1041 with metabolic activation (p < 0.001). Smoking did not affect 1-aminopyrene concentrations and 1-aminopyrene relationships with diesel exposure. In contrast, both engine emissions and smoking affected 2-aminofluorene concentrations. The results confirm that urinary 1-aminopyrene may serve as an exposure biomarker for diesel engine emissions and associated mutagenicity.

Inhalable mixture of polycyclic aromatic hydrocarbons and metals, DNA oxidative stress and nasal ribosomal DNA copy number amplification: Direct and indirect effect analyses among population.

The ribosomal DNA (rDNA) plays a crucial role in maintaining genome stability. So far, alterations of rDNA from airborne pollutants exposure remain unclear. Nasal epithelial cells are the earliest respiratory barrier, which has an accessible surrogate for evaluating respiratory impairment. We developed a mixture-centered biomarkers study integrated epidemiological and biological evidence among 768 subjects, a mixture of polycyclic aromatic hydrocarbons (PAHs) and metals. We identified the mixed exposure of PAHs and metals by environmental and biological monitoring, selected urinary 8-hydroxy-2'-deoxyguanosine as DNA oxidative stress marker, and measured their rDNA copy number (rDNA CN) in nasal epithelial cells. We performed linear regression, adaptive elastic net regression, BKMR, and mediation analyses to assess the direct and indirect effects. We found a 10% elevation in urinary 1-hydroxypyrene was correlated with a separate 0.31% and 0.82% amplification of nasal 5S and 45S rDNA CN, respectively (all P < 0.05). A 10% increment of urine nickel was associated with a separate 0.37% and 1.18% elevation of nasal 5S and 45S rDNA CN, respectively (all P < 0.05). BKMR results also confirmed our findings of PAHs and nickel. Our findings suggested that DNA oxidative stress might trigger rDNA instability induced by inhaled PAHs and metals.

Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans.

Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.

Alterations to biomarkers related to long-term exposure to diesel exhaust at concentrations below occupational exposure limits in the European Union and the USA.

BACKGROUND: We previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear. METHODS: In a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (<106 µg/m3), below the European Union (EU) OEL (<50 µg/m3) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (<20 µg/m3). RESULTS: Below the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1ß (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (ptrend=0.01, FDR=0.19) and gene expression (ptrend=0.02, FDR=0.19). CONCLUSIONS: DEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response.

Occupational exposure to diesel engine exhaust and serum levels of microRNAs in a cross-sectional molecular epidemiology study in China.

Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel-induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross-sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two-stage study, first measuring 405 miRNAs in a pilot study of six DEE-exposed workers exposed and six controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range: 47.7, 6.1-79.7 µg/m3 ) and 46 controls. The relationship between exposure to DEE and EC with miRNA levels was analyzed using linear regression adjusted for potential confounders. Serum levels of four miRNAs were significantly lower (miR-191-5p, miR-93-5p, miR-423-3p, miR-122-5p) and one miRNA was significantly higher (miR-92a-3p) in DEE exposed workers compared to controls. Of these miRNAs, miR-191-5p (ptrend  = .001, FDR = 0.04) and miR-93-5p (ptrend  = .009, FDR = 0.18) showed evidence of an inverse exposure-response with increasing EC levels. Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function.

Effect of trichloroethanol on TLR2 and TLR4/NF-κB-mediated antigen processing and presentation in HLA-B* 13:01-transfected antigen-presenting cells.

Trichloroethanol (TCOH), as a metabolite of trichloroethylene, has sensitization in the pathogenesis of trichloroethylene-induced hypersensitivity dermatitis (TIHD) which the human leukocyte antigen (HLA)-B∗13:01 gene is strongly associated with it. However, it is still obscure how TCOH participates in the pathogenesis of TIHD. Here, we demonstrate that TLR2 and TLR4 signaling through MyD88 and TRAF6-dependent pathway could activate NF-κB by promoting degradation of the inhibitor IκB-α to stimulate the process of NF-κB nuclear translocation. Besides, the crucial molecules of antigen processing and presentation, including TAP1, LMP2, LMP7, and HLA-B* 13:01, were all enhanced and the abundance of HLA-B* 13:01 on the surface of CIR-B* 13:01 cells was also up-regulated with the TCOH concentration increasing. Notably, we used 50 µM pyrrolidinedithiocarbamate (ammonium) to effectively inhibit the activation of NF-κB, which could effectively reverse the stimulation of antigen processing and presentation in TCOH-treated CIR-B* 13:01 cells. Taken together, we speculated that TCOH could promote the abundance of HLA complex on the antigen-presenting cells via TLR2 and TLR4/NF-κB to induce the severe reactivation of T lymphocytes, leading to the extreme immune response.

Association between diesel exhaust exposure and mitochondrial DNA methylation.

OBJECTIVES: Diesel exhaust is an established human carcinogen, however the mechanisms by which it leads to cancer development are not fully understood. Mitochondrial dysfunction is an established contributor to carcinogenesis. Recent studies have improved our understanding of the role played by epigenetic modifications in the mitochondrial genome on tumorigenesis. In this study, we aim to evaluate the association between diesel engine exhaust (DEE) exposure with mitochondrial DNA (mtDNA) methylation levels in workers exposed to DEE. METHODS: The study population consisted of 53 male workers employed at a diesel engine manufacturing facility in Northern China who were routinely exposed to diesel exhaust in their occupational setting, as well as 55 unexposed male control workers from other unrelated factories in the same geographic area. Exposure to DEE, elemental carbon, organic carbon, and particulate matter (PM2.5) were assessed. mtDNA methylation for CpG sites (CpGs) from seven mitochondrial genes (D-Loop, MT-RNR1, MT-CO2, MT-CO3, MT-ATP6, MT-ATP8, MT-ND5) was measured in blood samples. Linear regression models were used to estimate the associations between DEE, elemental carbon, organic carbon and PM2.5 exposures with mtDNA methylation levels, adjusting for potential confounders. RESULTS: DEE exposure was associated with decreased MT-ATP6 (difference = -35.6%, P-value = 0.019) and MT-ATP8 methylation (difference = -30%, P-value = 0.029) compared to unexposed controls. Exposures to elemental carbon, organic carbon, and PM2.5 were also significantly and inversely associated with methylation in MT-ATP6 and MT-ATP8 genes (all P-values < 0.05). CONCLUSIONS: Our findings suggest that DEE exposure perturbs mtDNA methylation, which may be of importance for tumorigenesis.

Occupational health effect of TCE exposure: Experiment evidence of gene-environment interaction in hypersensitivity reaction.

BACKGROUND: Recently, Trichloroethylene (TCE) induced TCE hypersensitivity syndrome (THS) has attracted the attention of many researchers in the field of environmental and occupational health. Studies have revealed that Human leukocyte antigen (HLA) polymorphisms were the important genetic determinants of the diseases, but the potential molecular mechanism remains unclear. OBJECTIVE: This study aimed to investigate the association between THS and HLA at the molecular level. METHOD: We chose the human B-lymphoblastoid cell line Hmy2.C1R transfected with cDNA of HLA-B*13:01 and HLA-B*13:02 to analyze the characteristics of HLA-B-binding peptides and investigate the effect of TCE on the binding affinity of peptides to the HLA-B molecules. Further, the mathematical model was used to identify the possible interaction between TCE and HLA-B*13:01 or HLA-B*13:02 molecule. RESULTS: 54 HLA-B*13:01-binding peptides and 85 HLA-B*13:02-binding peptides were identified. Comparing the protein sequences of HLA-B*13:01 and HLA-B*13:02, amino acids were different at positions 94, 95 and 97. The results of the binding affinity of self-peptides to HLA molecules in the presence of TCE showed that TCE significantly decreased the binding affinity of peptides to HLA-B*13:01 only, but did not affect that of HLA-B*13:02. Molecular docking model showed that there was a unique high-affinity binding mode between TCE and HLA-B*13:01 (but not HLA-B*13:02), and the binding site located in the region of F pocket, suggesting that the unique structure of the F pocket of HLA-B*13:01 might provide the possibility of binding TCE. The pathogenesis of interaction between HLA-B*13:01 and TCE might belong to the model of the alteration of the HLA-presented self-peptide repertoire. DISCUSSION: This study explored the molecular mechanism of the association between THS and HLA-B*13:01, and had important implications for understanding the role of gene-environment interaction in the development of complex environment-related diseases.

Exposure to diesel engine exhaust and alterations to the Cys34/Lys525 adductome of human serum albumin.

We investigated whether exposure to carcinogenic diesel engine exhaust (DEE) was associated with altered adduct levels in human serum albumin (HSA) residues. Nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS) was used to measure adducts of Cys34 and Lys525 residues in plasma samples from 54 diesel engine factory workers and 55 unexposed controls. An untargeted adductomics and bioinformatics pipeline was used to find signatures of Cys34/Lys525 adductome modifications. To identify adducts that were altered between DEE-exposed and unexposed participants, we used an ensemble feature selection approach that ranks and combines findings from linear regression and penalized logistic regression, then aggregates the important findings with those determined by random forest. We detected 40 Cys34 and 9 Lys525 adducts. Among these findings, we found evidence that 6 Cys34 adducts were altered between DEE-exposed and unexposed participants (i.e., 841.75, 851.76, 856.10, 860.77, 870.43, and 913.45). These adducts were biologically related to antioxidant activity.

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity.

BACKGROUND: Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B*13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. However, HLA-B*13:01-DDS-TCR immune synapse that plays role in drug-induced hypersensitivity syndrome (DIHS) associated T cells activation remains uncharacterized. METHODS: To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of Dapsone-induced drug hypersensitivity (DDS-DIHS), we performed crystallization and expanded drug-specific CTLs to analyze the pathological role of DDS-DIHS. RESULTS: Results showed the crystal structure of HLA-B*13:01-beta-2-microglobulin (ß2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DDS-DIHS. CONCLUSION: Our study identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DDS-DIHS.

Total pancreatectomy and islet cell autotransplantation: a 10-year update on outcomes and assessment of long-term durability.

BACKGROUND: Total pancreatectomy and islet cell autotransplantation (TPIAT) offers an effective, lasting solution for the management of chronic pancreatitis up to 5-years post-operatively. Our aim was to assess durability of TPIAT at 10-years. METHODS: Patients undergoing TPIAT for chronic pancreatitis eligible for 10-year follow-up were included. Primary outcomes, including endocrine function and narcotic requirements, were reported at 5-, 7.5-, and 10-years post-operatively. RESULTS: Of the 231 patients who underwent TPIAT, 142 met inclusion criteria. All patients underwent successful TPIAT with an average of 5680.3 islet equivalents per body weight. While insulin independence tended to decrease over time (25.7% vs. 16.0% vs. 10.9%, p = 0.11) with an increase in HbA1C (7.6% vs. 8.2% vs. 8.4%, p = 0.09), partial islet function persisted (64.9% vs. 68.0% vs. 67.4%, p = 0.93). Opioid independence was achieved and remained durable in the majority (73.3% vs. 72.2% vs. 75.5%, p = 0.93). Quality of life improvements persisted, with 85% reporting improvement from baseline at 10-years. Estimated median overall survival was 202.7 months. CONCLUSION: This study represents one of the largest series reporting on long-term outcomes after TPIAT, demonstrating excellent long-term pain control and durable improvements in quality of life. Islet cell function declines over time however stable glycemic control is maintained.

Aberrant mitochondrial DNA methylation and declined pulmonary function in a population with polycyclic aromatic hydrocarbon composition in particulate matter.

Air pollution exposure has been found to be associated with epigenetic modification of the mitochondrial genome, which could subsequently induce adverse health outcomes. However, very limited studies exist regarding the association between fine particulate matter (PM2.5) exposure and pulmonary function at the molecular level of mitochondrial epigenetic changes. This study aimed to investigate the association of platelet mitochondrial DNA (mtDNA) methylation with occupational PM2.5 exposure and pulmonary function. First, 768 participants were occupationally exposed to polycyclic aromatic hydrocarbon (PAH)-enriched PM2.5 in a coke-oven plant in East China. The levels of PM2.5, PAH components bound to PM2.5, and urinary PAH metabolites in the workplace environment were measured as an internal dose, respectively. mtDNA methylation was measured by bisulfite pyrosequencing of two genes of ATP synthase (MT-ATP6 and MT-ATP8). Mediation analysis was conducted to evaluate the role of mtDNA methylation in pulmonary alteration induced by PAH. A decreasing trend of platelet mtDNA methylation was observed with increase in PM2.5 exposure across all participants. As an important PAH metabolite in urine, 1-hydroxypyrene (1-OHP) was significantly negatively associated with FEV1/FVC (Forced Expiratory Volume in 1s/Forced Vital Capacity) ratio. The participants with high serum folate levels (≥10 nmol/L) showed positive association between MT-ATP6 methylation and FEV1/FVC ratio. Mediation analysis suggested that MT-ATP6 methylation mediated the significant association of urinary 1-OHP with FEV1/FVC. Our findings suggested the methylation of platelet mitochondrial gene MT-ATP6 and FEV1/FVC to be negatively associated with PM exposure. Platelet mtDNA methylation acted as an intermediary between PAH exposure and lung function decline. The mitochondrial epigenetic regulation in platelets, in response to PM exposure, might be involved in subsequent progress of abnormal pulmonary function.

High genetic differentiation of Indo-Pacific humpback dolphins (Sousa chinensis) along the Asian Coast of the Pacific Ocean.

The Indo-Pacific humpback dolphin (Sousa chinensis) is a vulnerable marine mammal species that inhabits shallow, coastal waters from Southeast China, southward throughout Southeast Asia, and westward around the Bay of Bengal to eastern India. Polymorphic microsatellites are useful for elucidating ecological and population genetics-related questions. Here, 18 new polymorphic microsatellites were developed from S. chinensis genomic DNA by Illumina MiSeq sequencing. Population genetic analyses were conducted on 42 S. chinensis individuals from three geographic locations, including the Xiamen Bay of China, the Western Gulf of Thailand, and Andaman Sea. Our microsatellite data revealed a strong and significant population structure among the three sampling regions (overall F ST = 0.371, p = .001). Pairwise mutual information index also demonstrated high levels of genetic differentiation between different region pairs (values range from 0.272 to 0.339, p < .001). Moreover, Structure analysis inferred three genetic clusters, with the high assignment probabilities of 95.92%, 99.47%, and 99.68%, respectively. Principal coordinate analysis plots of individuals divided entire genotypes into three clusters, indicating high level of genetic differentiation. Our results indicated the strong genetic structure in S. chinensis populations is a result of geographic distances. Other factors such as environmental variables, anthropogenic interference, and social behavior may also have contributed to population differentiation.

The prevalence and potential implications of microplastic contamination in marine fishes from Xiamen Bay, China.

The wide presence of microplastics (MPs) in the ocean leads their exposure on marine fish. MP contamination was reported for the gastrointestinal tracts and gills of 117 marine fishes attributed to nine species from Xiamen Bay, a special economic zone in China. Among species, MP abundance ranged from 1.07 items individual-1 to 8.00 items individual -1. Fibers dominated MP shapes, accounting for 59.03% of all MPs. Polymer composition was dominated by polyamide (26.97%) and rayon (17.56%). MPs were most commonly (55.22%) transparent, and most (77.61%) were < 1 mm in size. Our report represents the first of MP contamination in wild marine fish from Xiamen Bay, which we determine to be at an intermediate to slightly higher level compared with levels reported elsewhere, and provides further insights into potential risks of MPs pose to fish and human health.