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Studies on associations of erythrocytes parameters with hypertension risk are scarce. We aimed to examine associations of the erythrocytes parameters with the hypertension risk and potential effect modification by gender using data from the China Health and Nutrition Survey.A total of 5419 eligible participants (2468 men, 45.5%) without hypertension at baseline in 2009 were included and followed for a median of 6.1 years. Parameters of erythrocytes and hemoglobin were measured at baseline. Multivariable Cox proportional hazards models were used to estimate the hazard ratio for the associations between these parameters and hypertension risk. Data were collected from 2009 to 2015 and analyzed in 2021.A total of 1178 incident cases of hypertension were identified during the follow-up. In women, erythrocytes and hemoglobin were positively associated with risk of hypertension, yielding the highest hazard ratio in the third quartile of 1.59 (95% confidence interval, 1.28-1.97, P trend0.001) for erythrocytes and in the fourth quartile of 1.64 (95% confidence interval, 1.23-2.17, P trend0.001) for hemoglobin compared with their first quartile, respectively. In addition, quartiles of erythrocytes and hemoglobin were not associated with risk of hypertension in men ( P trend0.050).Erythrocytes and hemoglobin were associated with an increased risk of hypertension in women, but not in men. Our findings suggest that special attention for the prevention of hypertension should be given to those women with the moderate to high level of circulating erythrocytes and higher level of hemoglobin.

Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic.Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software.We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders.Our findings provide new insights into possible mechanisms underlying optimism and health.

We aimed to explore the associations of self-reported sleep-disordered breathing (SDB) and insomnia with hypertension based on a community-based survey among adults in Suzhou, Eastern China.The Suzhou Food Consumption and Health Survey was conducted from 2018 to 2019. A multistage random sampling method was used to recruit potential participants. Associations of SDB and insomnia with hypertension were examined by multivariable logistic regression models with adjustment for covariates. In addition, sensitivity analysis was used to reinforce our findings.A total of 2728 participants were included in the final analysis. SDB (OR, 1.83; 95% CI, 1.44-2.34; P0.001) and insomnia (OR, 1.31; 95% CI, 1.04-1.65; P0.001) were significantly associated with prevalent hypertension after multivariable adjustments. In the subgroup analysis by age groups and sex, the association between SDB and hypertension persisted in all groups, whereas the association between insomnia and hypertension remained significant in males and different age groups. In addition, SDB was positively correlated with DBP. Notably, participants with comorbid SDB and insomnia had the highest risk for hypertension (OR, 1.95; 95% CI, 1.40-2.72; P0.001).Both SDB and insomnia were associated with the prevalence of hypertension among the Chinese adults, whereas the comorbid conditions conveyed the highest risk for hypertension. Our findings provide a new insight for the potential pathogenesis of hypertension and a prevention strategy of hypertension among community adults.

Background Several studies have shown that preoperative blood transfusion is associated with postoperative venous thromboembolism (VTE). In this study, a meta-analysis was performed to explore the relationship between preoperative blood transfusion and postoperative VTE. Methods Published articles were identified through a comprehensive review of PubMed and EMBASE. Data from studies reporting relative risks, odds ratios, or hazard ratios comparing the risk of postoperative VTE among participants who had preoperative blood transfusion versus those without preoperative blood transfusion were analyzed. A random-effect model was used to calculate pooled odds ratios and 95% confident intervals (CIs). Results Eight studies, which included 3,504,778 participants, aligned with our inclusion criteria and were included in the meta-analysis. Pooled analysis showed an association between preoperative blood transfusion and postoperative VTE, with an odds ratio of 2.95 (95% CI: 1.65–5.30; I2 = 89.1%). In subgroup analyses, the positive association between preoperative blood transfusion and postoperative VTE was still exist in studies with confounders adjustment. Sensitivity analysis by one-study-removed analysis confirmed the robustness of our results. Conclusions Our study indicated that preoperative blood transfusion was associated with higher odds of postoperative VTE. Further large-scale prospective cohort studies are needed to investigate the causality between preoperative blood transfusion and postoperative VTE.

Objective: Optimal dosing regimens for achieving a positive clinical outcome were simulated for seven antibiotics commonly used to treat bloodstream infections (BSIs) in adults. Methods and Results...

Targeting of PP2A suggests a close link to tau-related cognitive and functional declines. However, little is known about how the expression of PP2A subunits and PP2A activity are dysregulated in the course of AD, precluding any specific targeting strategy for restoring PP2A in AD patients. Although the PP2A heterotrimer containing the regulatory subunit PR55/Bα (encoded by the PPP2R2A gene) is the major tau phosphatase, the involvement of other brain-specific PP2A regulatory subunits in tau dephosphorylation remains unknown. PR55/Bγ (encoded by the PPP2R2C gene) is a pivotal phosphatase in the brain, and single-nucleotide polymorphisms (SNPs) of PPP2R2C are involved in several mental disorders. By measuring the differential spatiotemporal expression patterns of PPP2R2C in Wt and transgenic AD mice, we revealed that PPP2R2C expression is downregulated in the aged AD mouse brain as compared to the Wt mouse brain. In cultured cells, PPP2R2C expression regulates PP2A activity and tau dephosphorylation. These results suggest that dysregulation of PPP2R2C expression may be involved in the onset of AD and that specifically targeting PPP2R2C expression or activity is a promising strategy against brain dementia disorders, including AD and other tauopathies.

Background Comorbidities, any other coexisting diseases in patients with a particular index disease, are known to increase the mortality of a stroke. However, the association of pre-existing comorbidities with stroke risk has not been fully studied. Methods This study included 16,246 adults from a prospective community-based cohort with a baseline survey conducted in 2013 in China. Participants were followed up with hospitalization records and the Cause of Death Registry. The association of eight pre-existing comorbidities (coronary heart disease, hyperlipidemia, hypertension, diabetes, previous stroke, chronic obstructive pulmonary disease, nephropathy, and cancer) with stroke risk was analyzed using the Cox proportional hazard model in 2020. Results At a median follow-up of 5.5 years, a total of 449 participants (206 men and 243 women) developed a stroke. Four pre-existing comorbidities (hypertension, congenital heart disease, previous stroke, and diabetes) were independently and positively associated with the risk for all types of stroke. The adjusted hazard ratios for participants with only 1 and ≥ 2 pre-existing comorbidities compared with those without pre-existing conditions were 1.96 (95% CI: 1.44, 2.67; P P Conclusions The number of pre-existing comorbidities was independently associated with an increased risk of stroke. There was a synergic effect between increased age and a higher number of pre-existing comorbidities on stroke occurrence. Our novel findings emphasize the importance and potential application of pre-existing comorbidities as a risk indicator in stroke prevention.

Background:Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously, we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al., 2020). Here, we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).Methods:We used data from the Dunedin Study 1972–1973 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.Results:DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.Conclusions:DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.Funding:This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

It is indicated that lipids profiles are associated with carotid plaque and Atherosclerosis. However, studies about the relationship between serum lipid profiles and carotid plaque composition in Chinese Population is limited. We conducted a cross-sectional study among 3,214 participants between January 2015 and December 2017 in China, to investigate the association between various lipid profiles and the prevalence of carotid plaque. Logistic regression model was used to investigate the association between plasma lipid profiles and odds of carotid plaque. Analysis of covariance (ANCOVA) was used to compare the mean plasma lipid profiles among different number and composition of carotid artery plaques. HDL-C, Non-HDL-C levels, TC/HDL-C, LDL-C/HDL-C were significantly associated with the presence of carotid plaque; HDL-C, LDL-C, Non-HDL-C levels, TC/HDL-C, LDL-C/HDL-C were significantly associated with the presence of common carotid artery (CCA) plaque. Compare with participants without carotid plaque, increased level of LDL-C/HDL-C was found in those with echolucent/polytype plaque. Similarly, compared with participants without CCA plaque, increased level of LDL-C/HDL-C was found in those with echolucent plaque. In conclusion, we found that serum HDL-C, Non-HDLc level, TC/HDLc, and LDLc/HDLc were all associated with the prevalence of carotid plaque, and LDL-C/HDL-C differed among different group of carotid plaque composition.

Bundling, as a common selling strategy, is often used along with a price discount. However, relatively little is known about the neural correlates of discount framing effect in the bundling context. In the current study, we recorded event-related potentials while participants were performing a virtual shopping task in which they had to decide whether or not to buy bundles. Each bundle consisted of a relatively high-priced product and a relatively low-priced product, and three discount frames with practically identical total prices were devised for each bundle. The price reduction was described either as a discount on the individual component [discount on the high-priced product (DH); discount on the low-priced product (DL)] or on the overall bundle (DB). Behavioral data showed that DH and DB led to higher purchase rate than DL. Electrophysiological data revealed increased P300 amplitudes for DH and DB relative to DL, which was suggestive of the cognitive process of evaluative categorization. In addition, attenuated LPP amplitudes were observed for DH and DL compared with DB, indicating higher cognitive load for DH and DL. Overall, these results demonstrate the discount framing effect in the purchase of bundles and the potential neural correlates of this effect.

BackgroundA ‘mortality risk score’ (MS) based on ten prominent mortality-related cytosine-phosphate-guanine (CpG) sites was previously associated with all-cause mortality, but has not been verified externally. We aimed to validate the association of MS with mortality and to compare MS with three aging biomarkers: telomere length (TL), DNA methylation age (DNAmAge) and phenotypic age (DNAmPhenoAge) to explore whether MS can serve as a reliable measure of biological aging and mortality.MethodsAmong 534 males aged 55–85 years from the US Normative Aging Study, the MS, DNAmAge and DNAmPhenoAge were derived from blood DNA methylation profiles from the Illumina HumanMethylation450 BeadChip, and TL was measured by quantitative real-time polymerase chain reaction (qRT-PCR).ResultsA total of 147 participants died during a median follow-up of 9.4 years. The MS showed strong associations with all-cause, cardiovascular disease (CVD) and cancer mortality. After controlling for all potential covariates, participants with high MS (>5 CpG sites with aberrant methylation) had almost 4-fold all-cause mortality (hazard ratio: 3.84, 95% confidence interval: 1.92–7.67) compared with participants with a low MS (0–1 CpG site with aberrant methylation). Similar patterns were observed with respect to CVD and cancer mortality. MS was associated with TL and DNAmPhenoAge acceleration but not with DNAmAge acceleration. Although the MS and DNAmPhenoAge acceleration were independently associated with all-cause mortality, the former exhibited a higher predictive accuracy of mortality than the latter.ConclusionsMS has the potential to be a prominent predictor of mortality that could enhance survival prediction in clinical settings.

Background and aims: Studies on associations of apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I) and the ApoB/ApoA-I ratio with stroke risk are scarce. We aimed to prospectively examine the associations of the ApoB/ApoA-I ratio and other lipid profiles with the risk of stroke using data from the China Health and Nutrition Survey (CHNS). Methods and results: A total of 7318 participants without stroke at baseline in 2009 were included in the final analysis and followed for a median of 6.1 years. The serum lipid profiles including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), ApoA-I, and ApoB were measured at baseline. Multivariable Cox proportional hazards models were used to evaluate the associations between these parameters and stroke risk. The ApoB/ApoA-I ratio was positively associated with incident stroke, yielding adjusted hazard ratio (HR) of 1.32 (95% CI: 1.09 – 1.59, P = 0.004). In comparison, ratio of ApoB and ApoA-I containing lipoproteins, the non-HDL-C/HDL-C ratio, possessed relatively weaker association with incident stroke (HR: 1.24, 95% CI: 1.01 – 1.52, P = 0.036). Furthermore, the risk associations for the ApoB/ApoA-I and non-HDL-C/HDL-C ratios were prominent among those participants aged > 51, body mass index ≤ 23, or female. There were no significant associations of other lipids and their ratios with the stroke risk. Conclusions: Higher ApoB/ApoA-I ratio was associated with an increased risk of stroke. Our findings suggest that the ApoB/ApoA-I ratio may serve as a better risk indicator of stroke than other lipid profiles and their ratios.

Background DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. Methods We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. Findings The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. Interpretation From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. Funding National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.

BACKGROUND: The metabolomic signatures of short- and long-term exposure to PM(2.5) have been reported and linked to inflammation and oxidative stress. However, little is known about the relative contribution of the specific PM(2.5) species (hence sources) that drive these metabolomic signatures. OBJECTIVES: We aimed to determine the relative contribution of the different species of PM(2.5) exposure to the perturbed metabolic pathways related to changes in the plasma metabolome. METHODS: We performed mass-spectrometry based metabolomic profiling of plasma samples among men from the Normative Aging Study to identify metabolic pathways associated with PM(2.5) species. The exposure windows included short-term (one, seven-, and thirty-day moving average) and long-term (one year moving average). We used linear mixed-effect regression with subject-specific intercepts while simultaneously adjusting for PM(2.5), NO(2), O(3), temperature, relative humidity, and covariates and correcting for multiple testing. We also used independent component analysis (ICA) to examine the relative contribution of patterns of PM(2.5) species. RESULTS: Between 2000 and 2016, 456 men provided 648 blood samples, in which 1,158 metabolites were quantified. We chose 305 metabolites for the short-term and 288 metabolites for the long-term exposure in this analysis that were significantly associated (p-value

One-carbon metabolism is an important contributor to aging-related diseases; nevertheless, relationships of one-carbon metabolites with novel DNA methylation-based measures of biological aging remain poorly characterized. We examined relationships of one-carbon metabolites with 3 DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. We measured plasma levels of 4 common one-carbon metabolites (vitamin B6, vitamin B12, folate, and homocysteine) in 715 VA Normative Aging Study participants with at least 1 visit between 1999 and 2008 (observations = 1153). DNA methylation age metrics were calculated using the HumanMethylation450 BeadChip. We utilized Bayesian Kernel Machine Regression models adjusted for chronological age, lifestyle factors, age-related diseases, and study visits to determine metabolites important to the aging outcomes. Bayesian Kernel Machine Regression models allowed for the estimation of the relationships of single metabolites and the cumulative metabolite mixture with methylation age. Log vitamin B6 was selected as important to PhenoAge (β = −1.62 years, 95% CI: −2.28, −0.96). Log folate was selected as important to GrimAge (β = 0.75 years, 95% CI: 0.41, 1.09) and PhenoAge (β = 1.62 years, 95% CI: 0.95, 2.29). Compared to a model where each metabolite in the mixture is set to its 50th percentile, the log cumulative mixture with each metabolite at its 30th (β = −0.13 years, 95% CI: −0.26, −0.005) and 40th percentile (β = −0.06 years, 95% CI: −0.11, −0.005) was associated with decreased GrimAge. Our results provide novel characterizations of the relationships between one-carbon metabolites and DNA methylation age in a human population study. Further research is required to confirm these findings and establish their generalizability.

Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.

Background Waardenburg syndrome (WS) is a highly clinically and genetically heterogeneous disease. The core disease phenotypes of WS are sensorineuronal hearing loss and pigmentary disturbance, which are usually caused by the absence of neural crest cell‐derived melanocytes. At present, four subtypes of WS have been defined, which are caused by seven genes. Waardenburg syndrome type 2 (WS2) is one of the most common forms. Two genes, MITF and SOX10, have been found to be responsible for majority of WS2. Methods In this study, we performed a clinical longitudinal follow‐up and mutation screening for a Chinese family with Waardenburg syndrome type II. Results A diversity of clinical manifestations was observed in this WS2 family. In addition to the congenital hearing loss of most affected family members, progressive hearing loss was also found in some WS2 patients. A nonsense mutation of c.328C>T (p.R110X) in MITF was identified in all affected family members. This mutation results in a truncated MITF protein, which is considered to be a disease‐causing mutation. Conclusion These findings offer a better understanding of the spectrum of MITF mutations and highlight the necessity of continuous hearing assessment in WS patients., The present study describes a large Chinese WS2 family with a highly clinical heterogeneity. Clinical longitudinal follow‐up revealed progressive hearing loss in some patients. A nonsense mutation of c.328C>T (p.R110X) in MITF was identified.

Both native language background and second-language proficiency may shape brain responses to a second language. Using cross-modal mismatch negativity (MMN) (pre-attentive processing) and audiovisual P300 (attentive processing) paradigms, this study examined how native Chinese speakers with various second-language proficiency responded to English letter-sound integration and what role visual attention may play in this process. The results indicated that native Chinese speakers failed to integrate letters and sounds in pre-attentive stage of reading, regardless of their English proficiency level, in contrast to the successful letter-sound integration shown by native English speakers. With more explicit visual attention resources, native Chinese speakers integrated English letters and sounds just as successfully as native English speakers did. These findings suggest that native language background may exert profound constraints on automatic brain responses to a second language, and attention may help the brain overcome these constraints and respond as required by the second language.

Objective Nitidine chloride (NC), a natural small molecular compound from traditional Chinese herbal medicine zanthoxylum nitidum, has been shown to exhibit anti-tumor effect. However, its role in autoimmune diseases such as rheumatoid arthritis (RA) is unknown. Here, we investigate the effect of NC in controlling fibroblast-like synoviocytes (FLS)-mediated synovial inflammation and joint destruction in RA and further explore its underlying mechanism(s). Methods FLSs were separated from synovial tissues obtained from patients with RA. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression was measured using quantitative RT-PCR. ELISA was used to measure the levels of cytokines and MMPs. Cell proliferation was detected using EdU incorporation. Migration and invasion were evaluated by Boyden chamber assay. RNA sequencing analysis was used to identify the target of NC. Collagen-induced arthritis (CIA) model was used to evaluate the in vivo effect of NC. Results NC treatment reduced the proliferation, migration, invasion, and lamellipodia formation but not apoptosis of RA FLSs. We also demonstrated the inhibitory effect of NC on TNF-α-induced expression and secretion of IL-6, IL-8, CCL-2, MMP-1 and MMP-13. Furthermore, we identified KCNH1, a gene that encodes ether-a-go-go-1 channel, as a novel targeting gene of NC in RA FLSs. KCNH1 expression was increased in FLSs and synovial tissues from patients with RA compared to healthy controls. KCNH1 knockdown or NC treatment decreased the TNF-α-induced phosphorylation of AKT. Interestingly, NC treatment ameliorated the severity of arthritis and reduced synovial KCNH1 expression in mice with CIA. Conclusions Our data demonstrate that NC treatment inhibits aggressive and inflammatory actions of RA FLSs by targeting KCNH1 and sequential inhibition of AKT phosphorylation. Our findings suggest that NC might control FLS-mediated rheumatoid synovial inflammation and joint destruction, and be a novel therapeutic agent for RA.

Background Epidemiological studies have shown the associations of ambient temperature and particulate matter (PM) air pollution with respiratory morbidity and mortality. However, the underlying mechanisms have not been well characterized. The aim of this study is to investigate the associations of temperature and fine and coarse PM with fractional exhaled nitric oxide (FeNO), a well-established biomarker of respiratory inflammation. Methods We conducted a longitudinal panel study involving six repeated FeNO tests among 33 type 2 diabetes mellitus patients from April to June 2013 in Shanghai, China. Hourly temperature and PM concentrations were obtained from a nearby fixed-site monitoring station. We then explored the associations between temperature, PM, and FeNO using linear mixed-effect models incorporated with distributed lag nonlinear models for the lagged and nonlinear associations. The interactions between temperature and PM were evaluated using stratification analyses. Results We found that both low and high temperature, as well as increased fine and coarse PM, were significantly associated with FeNO. The cumulative relative risk of FeNO was 1.75% (95% confidence interval [CI], 1.04–2.94) comparing 15 °C to the referent temperature (24 °C) over lags 0–9 days. A 10 μg/m3 increase in fine and coarse PM concentrations were associated with 1.18% (95% CI, 0.18–2.20) and 1.85% (95% CI, 0.62–3.09) FeNO in lag 0–1 days, respectively. PM had stronger effects on cool days than on warm days. Conclusions This study suggested low ambient temperature, fine PM, and coarse PM might elevate the levels of respiratory inflammation. Our findings may help understand the epidemiological evidence linking temperature, particulate air pollution, and respiratory health., Highlights • Both low and high temperatures were significantly associated with FeNO. • The increases of fine and coarse PM concentrations were associated with FeNO. • Both fine and coarse PM had stronger effects in cool days.

Air pollution may increase cardiovascular and respiratory risk through inflammatory pathways, but evidence for acute effects has been weak and indirect. Between December 2014 and July 2015, we enrolled 36 healthy, nonsmoking college students for a panel study in Shanghai, China, a city with highly variable levels of air pollution. We measured personal exposure to particulate matter with an aerodynamic diameter less than or equal to 2.5 μm (PM2.5) continuously for 72 hours preceding each of 4 clinical visits that included phlebotomy. We measured 4 inflammation proteins and DNA methylation at nearby regulatory cytosine-phosphate-guanine (CpG) loci. We applied linear mixed-effect models to examine associations over various lag times. When results suggested mediation, we evaluated methylation as mediator. Increased PM2.5 concentration was positively associated with all 4 inflammation proteins and negatively associated with DNA methylation at regulatory loci for tumor necrosis factor alpha (TNF-α) and soluble intercellular adhesion molecule-1. A 10-μg/m3 increase in average PM2.5 during the 24 hours preceding blood draw corresponded to a 4.4% increase in TNF-α and a statistically significant decrease in methylation at one of the two studied candidate CpG loci for TNF-α. Epigenetics may play an important role in mediating effects of PM2.5 on inflammatory pathways.

There is increasing interest in quasi-experimental research to evaluate whether actions taken to improve air quality will benefit public health. We conducted a quasi-experimental study to evaluate inflammatory response to changes in air quality during the 2014 Nanjing Youth Olympics in China. We repeatedly measured 8 biomarkers of systemic inflammation in 31 healthy adults and obtained hourly air pollutant concentrations from a nearby fixed-site monitoring station. We used linear mixed-effect models to examine the associations between air quality changes and blood biomarkers. Air pollutant concentrations decreased apparently during the Youth Olympics. Concomitantly, we observed significant decreases in levels of soluble cluster of differentiation 40 (CD40) ligand and interleukin 1β (geometric means ratios were 0.45 and 0.24, respectively) from the pre-Olympic period to the intra-Olympic period. Afterwards, levels of C-reactive protein and vascular cell adhesion molecule 1 increased significantly (geometric means ratios were 2.22 and 1.29, respectively) in the post-Olympic period. Fine particulate matter and ozone were significantly associated with soluble CD40 ligand, P-selectin, interleukin 1β, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Other pollutants showed positive but nonsignificant associations. Our study indicated that reduced air pollution, especially fine particulate matter and ozone, during the 2014 Nanjing Youth Olympics was associated with alleviated systemic inflammation in healthy adults.

Besides expanding the spectrum of KCNQ1 mutations causing Jervell and Lange-Nielsen Syndrome (JLNS), the results showed diversity of its phenotypes, and emphasized the importance of molecular genetic analysis in confirming clinical diagnosis and making diagnosis possible before the emergency symptoms for deaf individuals.This study aimed to investigate four patients from three Chinese families with congenital hearing loss clinically and genetically.Genetic analysis of previously reported deafness genes based on massively parallel sequencing was conducted in more than five thousand Chinese hearing loss patients. Detailed clinical features of the patients with compound heterozygous or homozygous mutations of KCNQ1 gene were collected and analyzed.Compound mutations of KCNQ1 were found to be the genetic etiology of four patients from three families. Among the six KCNQ1 mutations, c.546C A was identified as a novel mutation, c.965C T had been reported in JLNS, while c.683 + 5G A, c.1484_1485delCT, c.905C T and c.1831G A were previously reported in LQT1. In addition to congenital profound hearing loss in all subjects, two sibling subjects showed typical JLNS cardiac phenotype of prolonged QTc and recurrent syncopal episodes. One subject presented not only JLNS, but also iron-deficiency anemia and epilepsy. The other subject did not present any cardiac phenotype.

Objectives To analyze complications associated with minimally invasive cochlear implantation by comparing data from different centers, to discuss major reasons for complications, and to refine implantation techniques to decrease them. Patients Patients who underwent cochlear implantation at our center by the same surgeon (the corresponding author of this article) from March 2006 to March 2015 were enrolled. Intervention First, a retrospective analysis of the complications associated with minimally invasive cochlear implantation at our center was performed. Second, published reports from other centers that describe complications were reviewed. Differences between complications in our cohort and other studies were evaluated. Main outcome measure Strategies for reducing complications were assessed and modifications in surgical protocol proposed accordingly. Results In total, 1,014 patients underwent 1,065 cochlear implantations. There were 28 complications (7 major, 21 minor) and only 2 reimplantations for the entire cohort, with no case of severe infection, flap necrosis, or device extrusion. The major complications were electrode misplacement, magnet displacement, implant failure secondary to trauma, and temporary cerebrospinal fluid leakage. The rates of major complications in our cohort were very low (0.6%) compared with those in the literature. Conclusion Preoperative surgical planning based on individual patient anatomy and employment of soft surgical techniques can minimize surgical complications.

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the CpG sequence in the Abat promoter, which subsequently increases expression of Abat. Increased Abat expression in chondrocytes leads to enhanced mitochondrial respiration and elevated expression of catabolic genes. Overexpression of Abat in murine knee joints via lentiviral injection results in accelerated cartilage degradation following surgical induction of OA. In contrast, lentiviral-based knockdown of Abat attenuates the expression of IL-1β-induced catabolic genes in primary murine articular chondrocytes in vitro and also protects against murine articular cartilage degradation in vivo. Strikingly, treatment with the FDA-approved small-molecule Abat inhibitor, vigabatrin, significantly prevents the development of injury-induced OA in mice. In summary, these studies establish Abat as an important new target for therapies to prevent OA.

Current studies indicate that long-term exposure to ambient fine particulate matter (PM(2.5)) is related with global mortality, yet no studies have explored relationships of PM(2.5) and its species with DNAm PhenoAge acceleration (DNAmPhenoAccel), a new epigenetic biomarker of phenotypic age. We identified which PM(2.5) species had association with DNAmPhenoAccel in a one-year exposure window in a longitudinal cohort. We collected whole blood samples from 683 elderly men in the Normative Aging Study between 1999 and 2013 (n = 1,254 visits). DNAm PhenoAge was calculated using 513 CpGs retrieved from the Illumina Infinium HumanMethylation450 BeadChip. Daily concentrations of PM(2.5) species were measured at a fixed air-quality monitoring site and one-year moving averages were computed. Linear mixed-effect (LME) regression and Bayesian kernel machine (BKM) regression were used to estimate the associations. The covariates included chronological age, body mass index (BMI), cigarette pack years, smoking status, estimated cell types, batch effects etc. Benjamini-Hochberg false discovery rate at a 5% false positive threshold was used to adjust for multiple comparison. During the study period, the mean DNAm PhenoAge and chronological age in our subjects were 68 and 73 years old, respectively. Using LME model, only lead and calcium were significantly associated with DNAmPhenoAccel. For example, an interquartile range (IQR, 0.0011 μg/m(3)) increase in lead was associated with a 1.29-year [95% confidence interval (CI): 0.47, 2.11] increase in DNAmPhenoAccel. Using BKM model, we selected PM(2.5), lead, and silicon to be predictors for DNAmPhenoAccel. A subsequent LME model showed that only lead had significant effect on DNAmPhenoAccel: 1.45-year (95% CI: 0.46, 2.46) increase in DNAmPhenoAccel following an IQR increase in one-year lead. This is the first study that investigates long-term effects of PM(2.5) components on DNAmPhenoAccel. The results demonstrate that lead and calcium contained in PM(2.5) was robustly associated with DNAmPhenoAccel.

As a kind of information deception, price deception is adopted by some online sellers as an approach to mislead the consumers into buying their products. However, when consumers have sufficient knowledge about the price information, the effect of price deception on their purchase decision making remains elusive. Therefore, behavioural and event-related potentials measures were combined to investigate this issue. Behaviourally, a higher purchase rate and reduced reaction time were observed in the truthful condition relative to the deceptive condition, suggesting that the truthful condition was more favourable to the participants. At the neural level, the truthful condition triggered an attenuated N2 and an increased LPP compared with the deceptive condition, indicating less cognitive and decisional conflict and more positive evaluation of the truthful condition. Taken together, these results revealed the negative impact of price deception on purchase decision making and its potential neural substrates.

Elderly individuals who are never smokers but have the same height and chronological age can have substantial differences in lung function. The underlying biological mechanisms are unclear. To evaluate the associations of different biomarkers of aging (BoA) and lung function, we performed a repeated-measures analysis in the Normative Aging Study using linear mixed-effect models. We generated GrimAgeAccel, PhenoAgeAccel, extrinsic and intrinsic epigenetic age acceleration using a publically available online calculator. We calculated Zhang's DNAmRiskScore based on 10 CpGs. We measured telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) using quantitative real-time polymerase chain reaction. A pulmonary function test was performed measuring forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC), FEV1, and maximum mid-expiratory flow (MMEF). Epigenetic-based BoA were associated with lower lung function. For example, a one-year increase in GrimAgeAccel was associated with a 13.64 mL [95% confidence interval (CI), 5.11 to 22.16] decline in FEV1; a 0.2 increase in Zhang's DNAmRiskScore was associated with a 0.009 L/s (0.005 to 0.013) reduction in MMEF. No association was found between TL/mtDNA-CN and lung function. Overall, this paper shows that epigenetics might be a potential mechanism underlying pulmonary dysfunction in the elderly.

Background Genetic variants in TMPRSS3 have been causally linked to autosomal recessive nonsyndromic hearing loss (HL) at the DFNB8 and DFNB10 loci. These variants include both single nucleotide and copy number variations (CNVs). In this study, we aim to identify the genetic cause in three Chinese subjects with prelingual profound sensorineural HL. Methods We applied targeted genomic enrichment and massively parallel sequencing to screen 110 genes associated with nonsyndromic HL in the three affected subjects. CNVplex® analysis and polymerase chain reaction (PCR) were performed for CNV detection. Results We identified biallelic variations in TMPRSS3 including a novel complex genomic rearrangement and a novel missense mutation, c.551T>C. We have mapped the breakpoints of the genomic rearrangement and showed that it consisted of two deletions and an inversion encompassing exon 3 to exon 9 of TMPRSS3. Conclusion Our study expanded the mutational spectrum of TMPRSS3 to include complex genomic rearrangements. It showcased the importance of an integrative approach to investigate CNVs and their contribution to HL.

Background Ambient fine particulate matter (PM2.5) air pollution has been associated with increased airway inflammation, but the roles of various PM2.5 constituents remain to be determined. Objectives To investigate the acute effects of PM2.5 constituents on fractional exhaled nitric oxide (FeNO), a well-established biomarker of respiratory inflammation. Methods A longitudinal panel study was performed among 32 healthy young adults in Shanghai, China from January 12th to February 6th, 2015. FeNO was repeatedly measured, 6–8 times per subject. Real-time mass concentration of ambient PM2.5 and chemical constituents were obtained from a nearby monitoring station. Linear mixed-effect models were applied to evaluate the association between FeNO and PM2.5 constituents, with the adjustment of age, gender, body mass index, temperature, relative humidity and day of week. The robustness of constituents’ effects was also evaluated. Results A total of 234 effective measurements of FeNO were obtained with a geometric mean of 13.1 ppb. The PM2.5-FeNO associations were strongest at lags of 0–6 h and diminished at lags longer than 12 h. An interquartile range increase in PM2.5 constituents (NH4+, NO3−, K+, SO42− and elemental carbon) at lags of 0–6 h were significantly associated with increments in FeNO by 12.3%, 11.3%, 11.1%, 9.6% and 10.7%, respectively. After controlling for PM2.5 total mass and the colinearity, only elemental carbon remained significant. Conclusion Several chemical constituents of PM2.5 may impact FeNO following acute exposure. Elemental carbon in particular may be the primary component responsible for increased airway inflammation.

Background: The underlying intermediate mechanisms about the association between fine particulate matter (PM2.5) air pollution and blood pressure (BP) were unclear. Few epidemiological studies have explored the potential mediation effects of angiotensin-converting enzyme (ACE) and its DNA methylation. Methods: We designed a longitudinal panel study with 4 follow-ups among 36 healthy college students in Shanghai, China from December 17, 2014 to July 11, 2015. We measured personal real-time exposure to PM2.5, serum ACE level, and blood methylation of ACE gene and the repetitive elements. We applied linear mixed-effects models to examine the effects of PM2.5 on ACE protein, DNA methylation and BP markers. Furthermore, we conducted mediation analyses to evaluate the potential pathways. Results: An interquartile range increase (26.78 μg/m3) in 24-h average exposure to PM2.5 was significantly associated with 1.12 decreases in ACE average methylation (%5mC), 13.27% increase in ACE protein, and increments of 1.13 mmHg in systolic BP, 0.66 mmHg in diastolic BP and 0.82 mmHg in mean arterial pressure. ACE hypomethylation mediated 11.78% (P = 0.03) of the elevated ACE protein by PM2.5. Increased ACE protein accounted for 3.90 ~ 13.44% (P = 0.35 ~ 0.68) of the elevated BP by PM2.5. Repetitive-element methylation was also decreased but did not significantly mediate the association between PM2.5 and BP. Conclusions: This investigation provided strong evidence that short-term exposure to PM2.5 was significantly associated with BP, ACE protein and ACE methylation. Our findings highlighted a possible involvement of ACE and ACE methylation in the effects of PM2.5 on elevating BP. Keywords: Fine particulate matter, Blood pressure, Angiotensin-converting enzyme, DNA methylation, Panel study

Background: Practical approaches to protect individuals from ambient particulate matter (PM) are urgently needed in developing countries. Evidence on the health benefits of wearing particulate-filtering respirators is limited. Objectives: We evaluated the short-term cardiovascular health effects of wearing respirators in China. Methods: A randomized crossover trial was performed in 24 healthy young adults in Shanghai, China in 2014. The subjects were randomized into two groups and wore particulate-filtering respirators for 48 hr alternating with a 3-week washout interval. Heart rate variability (HRV) and ambulatory blood pressure (BP) were continuously monitored during the 2nd 24 hr in each intervention. Circulating biomarkers were measured at the end of each intervention. Linear mixed-effect models were applied to evaluate the effects of wearing respirators on health outcomes. Results: During the intervention periods, the mean daily average concentration of PM with an aerodynamic diameter < 2.5 μm (PM2.5) was 74.2 μg/m3. Compared with the absence of respirators, wearing respirators was associated with a decrease of 2.7 mmHg [95% confidence interval (CI): 0.1, 5.2 mmHg] in systolic BP and increases of HRV parameters, including 12.5% (95% CI: 3.8%, 21.2%) in high frequency (HF) power, 10.9% (95% CI: 1.8%, 20.0%) in the root mean square of the successive differences, and 22.1% (95% CI: 3.6%, 40.7%) in the percentage of normal RR intervals with duration > 50 msec different from the previous normal RR interval (pNN50). The presence of respirators was also associated with a decrease of 7.8% (95% CI: 3.5%, 12.1%) in the ratio of low frequency (LF)/HF power. Conclusions: Short-term wearing of particulate-filtering respirators may produce cardiovascular benefits by improving autonomic nervous function and reducing BP. Citation: Shi J, Lin Z, Chen R, Wang C, Yang C, Cai J, Lin J, Xu X, Ross JA, Zhao Z, Kan H. 2017. Cardiovascular benefits of wearing particulate-filtering respirators: a randomized crossover trial. Environ Health Perspect 125:175–180; http://dx.doi.org/10.1289/EHP73

Clinical studies show that dysfunction of the dopamine (DA) system could differently modulate N2 and P3 components in a Go/Nogo task, a classical inhibition task. However, results of previous clinical studies cannot be arbitrarily generalized to healthy adults. Thus, the present exploratory study aimed to investigate whether there are significant and variable relationships between individual differences of the DA system in normal healthy persons and N2- and P3-related sub-processes of inhibition in a Go/Nogo task. DA function was measured by spontaneous eye blink rate (EBR), which is an effective clinical and non-invasive measure and strongly related to the activity of the central dopaminergic system. A total of 28 young adults participated in this experiment. Results showed that Nogo-N2 and Nogo-P3 of all participants were larger than Go-N2 and Go-P3, while Nogo-N2 and Nogo-P3 were significantly related with Nogo-accuracy. Moreover, it was shown that higher EBRs were significantly correlated with larger and more negative N2 amplitudes under Go- and Nogo-conditions; however, there were no significant correlations between participants’ EBRs and N2 latencies, and between EBRs and average amplitudes of P3 under the two conditions. Based on these results, we concluded that the central DA system was associated with the N2-related conflict monitoring rather than P3-related sub-process of inhibition.

Background Globally, toxic metal exposures are a well-recognized risk factor for many adverse health outcomes. DNA methylation-based measures of biological aging are predictive of disease, but have poorly understood relationships with metal exposures. Objective We performed a pilot study examining the relationships of 24-h urine metal concentrations with three novel DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. Methods We utilized a previously established urine panel of five common metals [arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg)] found in a subset of the elderly US Veterans Affairs Normative Aging Study cohort (N = 48). The measures of DNA methylation-based biological age were calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. Bayesian Kernel Machine Regression (BKMR) was used to determine metals most important to the aging outcomes and the relationship of the cumulative metal mixture with the outcomes. Individual relationships of important metals with the biological aging outcomes were modeled using fully-adjusted linear models controlling for chronological age, renal function, and lifestyle/environmental factors. Results Mn was selected as important to PhenoAge. A 1 ng/mL increase in urine Mn was associated with a 9.93-year increase in PhenoAge (95%CI: 1.24, 18.61, p = 0.03). The cumulative urine metal mixture was associated with increases in PhenoAge. Compared to a model where each metal in the mixture is set to its 50th percentile value, every one-unit increase of the cumulative mixture with each metal at its 70th percentile was associated with a 2.53-year increase in PhenoAge (95%CI: 0.10, 4.96, P Conclusion Our results add novel evidence that metals detected in urine are associated with increases in biological aging and suggest that these DNA methylation-based measures may be useful for identifying individuals at-risk for diseases related to toxic metal exposures. Further research is necessary to confirm these findings more broadly.

Objective To investigate the role of glycogen metabolism in regulating rheumatoid fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and its underlying mechanism. Methods FLSs were separated from synovial tissues (STs) obtained from rheumatoid arthritis (RA) patients. Glycogen content was determined by periodic acid Schiff staining. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression of cytokines and matrix metalloproteinases (MMPs) was evaluated by quantitative real-time PCR. FLS proliferation was detected by EdU incorporation. Migration and invasion were measured by Boyden chamber assay. Results Glycogen levels and glycogen synthase 1 (GYS1) expression were significantly increased in the ST and FLSs of RA patients. TNF-α or hypoxia induced GYS1 expression and glycogen synthesis in RA FLSs. GYS1 knockdown by shRNA decreased the expression of IL-1β, IL-6, CCL-2, MMP-1, and MMP-9 and proliferation and migration by increasing AMP-activated protein kinase (AMPK) activity in RA FLS. AMPK inhibitor or knockdown AMPK could reverse the inhibitory effect of GYS1 knockdown on the inflammatory response in RA FLSs; however, an AMPK agonist blocked RA FLS activity. We further determined that hypoxia-inducible factor-1α mediates TNF-α- or hypoxia-induced GYS1 expression and glycogen levels. Local joint depletion of GYS1 or intraperitoneal administration with an AMPK agonist ameliorated the severity of arthritis in rats with collagen-induced arthritis. Conclusion Our data demonstrate that GYS1-mediated glycogen accumulation contributes to FLS-mediated synovial inflammation in RA by blocking AMPK activation. In our knowledge, this is a first study linking glycogen metabolism to chronic inflammation. Inhibition of GYS1 might be a novel therapeutic strategy for chronic inflammatory arthritis, including RA.

Background: MicroRNAs (miRNAs) are a key factor in epigenetic regulation of gene expression, but miRNA responses to fine particulate matter (PM2.5) air pollution and their potential contribution to cardiovascular effects of PM2.5 are unknown. Objective: We explored the potential influence of PM2.5 on the expression of selected cytokines relevant to systemic inflammation, coagulation, and vasoconstriction, and on miRNAs that may regulate their expression. Methods: We designed a double-blind, randomized crossover study in which true and sham air purifiers were used to expose 55 healthy young adult students in Shanghai, China, to reduced or ambient levels of indoor PM2.5 during two-week periods, and we measured the expression (mRNA and protein) of 10 serum cytokines, and miRNAs that target them, after each intervention period. We used linear mixed-effect models to estimate associations of the intervention, and time-weighted personal PM2.5 exposures, with the cytokines, mRNA, and miRNAs; we also explored potential mediation by miRNAs. Results: The findings were generally consistent for associations with the intervention and for associations with an interquartile range increase in time-weighted PM2.5. Specifically, higher PM2.5 exposure was positively associated with the expression (mRNA, protein, or both) of interleukin-1 (encoded by IL1), IL6, tumor necrosis factor (encoded by TNF), toll-like receptor 2 (encoded by TLR2), coagulation factor 3 (encoded by F3), and endothelin 1 (encoded by EDN1), and was negatively associated with miRNAs (miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and miR-199a-5p) predicted to target mRNAs of IL1, TNF, TLR2, and EDN1. Conclusions: Our findings require confirmation but suggest that effects of PM2.5 on cardiovascular diseases may be related to acute effects on cytokine expression, which may be partly mediated through effects of PM2.5 on miRNAs that regulate cytokine expression. https://doi.org/10.1289/EHP1447

It remains unknown how fine particulate matter (PM2.5) constituents affect differently the fractional concentration of exhaled nitric oxide (FeNO, a biomarker of airway inflammation) and the DNA methylation of its encoding gene (NOS2A). We aimed to investigate the short-term effects of PM2.5 constituents on NOS2A methylation and FeNO. We designed a longitudinal study among chronic obstructive pulmonary disease (COPD) patients with six repeated health measurements in Shanghai, China. We applied linear mixed-effect models to evaluate the associations. We observed that the inverse association between PM2.5 and methylation at position 1 was limited within 24 h, and the positive association between PM2.5 and FeNO was the strongest at lag 1 day. Organic carbon, element carbon, NO3(-) and NH4(+) were robustly and significantly associated with decreased methylation and elevated FeNO. An interquartile range increase in total PM2.5 and the four constituents was associated with decreases of 1.19, 1.63, 1.62, 1.17, and 1.14 in percent methylation of NOS2A, respectively, and increases of 13.30%,16.93%, 8.97%, 18.26%, and 11.42% in FeNO, respectively. Our results indicated that organic carbon, element carbon, NO3(-) and NH4(+) might be mainly responsible for the effects of PM2.5 on the decreased NOS2A DNA methylation and elevated FeNO in COPD patients.

Several previous studies proposed a link between particulate matter (PM) pollution and mitochondrial DNA copy number (MtDNAcn) and telomere length (TL). However, this evidence is quite limited and inconsistent, especially on how the particle size affects the associations and on whether there exists such an association with gaseous pollutants.We aimed to investigate the short-term associations of size-fractionated PM and gaseous pollutants with blood MtDNAcn and TL.We conducted a longitudinal panel study involving 6 repeated measurements among 35 Type 2 diabetes patients in Shanghai, China from April to June 2013. We measured the real-time concentrations of size-fractionated PM (0.25-10 μm) and criteria gaseous pollutants. Blood MtDNAcn and TL were tested by a quantitative real-time PCR-based assay. Linear mixed-effect models were used to explore their short-term associations using multiple lag periods, after controlling for individual characteristics, time trends and weather conditions.In general, there were inverse but statistically non-significant associations between all pollutants and MtDNAcn. Coarse PM appeared to be more closely linked with MtDNAcn than smaller PM. The associations between various air pollutants and TL were generally positive but very weak. There were no clear lag patterns for these associations. The associations between air pollutants and MtDNAcn and TL were strengthened but still not significant among those who did not take statins regularly.This study did not support short-term associations of PM or gaseous pollutants with blood MtDNAcn and TL in type 2 diabetes patients.

Little is known regarding how the size distribution of particulate matter (PM) air pollution influences its effect on blood pressure (BP), especially among patients with diabetes. The objective of this study was to explore the short-term associations between size-fractionated PM and BP among diabetes patients. We scheduled 6 repeated BP examinations every 2 weeks from 13 April 2013 to 30 June 2013 in a panel of 35 type 2 diabetes mellitus patients recruited from an urban community in Shanghai, China. We measured real-time PM concentrations in the size range of 0.25 to 10 μm. We used linear mixed-effect models to examine the short-term association of size-fractionated PM and BP after controlling for individual characteristics, mean temperature, relative humidity, day of the week, years with diabetes and use of antihypertensive medication. The association with systolic BP and pulse pressure strengthened with decreasing diameter. The size fractions with the strongest associations were 0.25 to 0.40 μm for number concentrations and ≤2.5 μm for mass concentrations. Furthermore, these effects occurred immediately even after 0–2 h and lasted for up to 48 h following exposure. An interquartile range increase in 24-h average number concentrations of PM0.25–0.40 was associated with increases of 3.61 mm Hg in systolic BP and 2.96 mm Hg in pulse pressure. Females, patients younger than 65 years of age and patients without antihypertensive treatment were more susceptible to these effects. Our results revealed important size and temporal patterns of PM in elevating BP among diabetes patients in China. Keywords: Air pollution, Particulate matter, Diameter, Blood pressure, Diabetes, Panel study

The central dopamine system (DA) has a significant role in the executive function (EF). The spontaneous eye blink rate (EBR) is an effective clinical and non-invasive measure, which is strongly related to the activity of the central dopaminergic system. Previous studies show significant relationships between the two main dimensions of EF (i.e., shifting and inhibition) and the central DA system as measured by EBR. However, most of these studies involve only one EF task for shifting or inhibition; whether or not these relationships are replicated by other EF tasks remains unclear. Besides, the relationship between EBR and another important EF dimension-updating-also remains unknown. The present study examined the correlation between EBR and several EF tasks that captured all the three EF dimensions: shifting, inhibition, and updating. A total of 61 healthy participants were subjected to EBR testing and EF tasks. Results showed that EBR had a different relationship with each of the three tested EF dimensions. An increase in EBR levels was related to an increase in accuracy in shifting and inhibition tasks, a decrease in shifting and inhibition cost, and a decrease in accuracy in updating tasks. These results imply that the role of the central DA system in shifting and inhibition differs from its role in updating.

BACKGROUND Short-term associations between size-fractionated particulate air pollution and circulating biomarkers are not well established, especially in developing countries with high levels of particulate matter (PM). METHODS We designed a panel study involving 34 healthy young adults to evaluate acute effects of size-fractionated PM on 13 circulating biomarkers of inflammation, coagulation, and vasoconstriction. We measured real-time, size-fractionated number concentrations of PM (aerodynamic diameters from 0.25 to 10 μm, mass concentrations of PM < 10 μm) over four follow-up measurements. The short-term associations between size-fractionated PM and biomarkers were assessed using linear mixed effect models. RESULTS We found positive associations between short-term exposure to PM and 10 biomarkers. PM with smaller size had stronger associations. The size fractions with the strongest associations were 0.25-0.40 μm for number concentrations and

Osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs) is regulated by various factors, including bone morphogenetic proteins (BMPs), Notch, growth hormones and mitogen-activated protein kinases (MAPKs). Tribbles homolog 3 (TRIB3), a pseudokinase, plays an important role in cancer cells and adipocytes. However, TRIB3 function in osteogenic differentiation is unknown, although it is involved in regulating signaling pathways associated with osteogenic differentiation. Here, we found that TRIB3 was highly expressed during osteogenic differentiation in hBMSCs. Inhibition of focal adhesion kinase (FAK) or phosphatidylinositol 3-kinase (PI3K) resulted in a significant decrease in TRIB3 expression, and expression of TRIB3 was restored by increasing insulin-like growth factor-1 (IGF-1) via activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling. TRIB3 knock-down enhanced proliferation and decreased osteogenic differentiation at the middle stage of differentiation, and these effects were reversed by inhibiting the activation of extracellular signal-regulated kinase (ERK)-1/2. In conclusion, TRIB3 plays an important role in proliferation and osteogenic differentiation by regulating ERK1/2 activity at the middle stage of differentiation, and expression of TRIB3 is regulated by FAK in a PI3K/AKT-dependent manner.

Synovial sarcoma (SS) is a highly aggressive malignant soft tissue sarcoma with typical characteristics of both epithelial and mesenchymal differentiation. Matrix metalloproteinase-14 (MMP-14) is reported to play an important role in some of these tumors. It induces epithelial-to-mesenchymal transition (EMT) in some carcinomas, such as breast and prostate cancers. However, the role of MMP-14 in the pathogenesis of SS remains unclear. Therefore, we investigated the role of MMP-14 and EMT/mesenchymal-to-epithelial transition in SS. The expression of MMP-14 and EMT-related proteins was determined in 37 SS cases and transfected cells by immunohistochemistry staining and Western blotting. The invasion ability of transfected cells was determined by transwell invasion assay. The expression rates of MMP-14, E-cadherin, N-cadherin, and vimentin were 75.7%, 54.1%, 75.7%, and 100%, respectively, in the cases of SS. The expression of MMP-14 correlated negatively with E-cadherin and positively with N-cadherin in monophasic fibrous SS. The MMP-14 protein expression was higher in stage III/IV than in stage I/II. After MMP-14 was transfected into SW982 cells, MMP-14, N-cadherin, and vimentin expression was up-regulated, and E-cadherin expression was down-regulated. High expression of MMP-14 enhanced the invasive ability of SW982 cells. Our findings suggest that MMP-14 enhances the invasive ability of SW982 cells by inducing EMT. By this action, it may play an important role in the occurrence and development of SS.

Despite advanced understanding of signaling mediated by local and systemic factors, the role of epigenetic factors in the regulation of bone regeneration remains vague. The DNA methyltransferases (Dnmts) Dnmt3a and Dnmt3b have tissue specific expression patterns and create unique methylation signatures to regulate gene expression. Using a stabilized murine tibia fracture model we find that Dnmt3b is induced early in fracture healing, peaks at 10 days post fracture (dpf), and declines to nearly undetectable levels by 28 dpf. Dnmt3b expression was cell-specific and stage-specific. High levels were observed in chondrogenic lineage cells within the fracture callus. To determine the role of Dnmt3b in fracture healing, Agc1CreERT2;Dnmt3bf/f (Dnmt3bAgc1ER) mice were generated to delete Dnmt3b in chondrogenic cells. Dnmt3bAgc1ER fracture displayed chondrogenesis and chondrocyte maturation defect, and a delay in the later events of angiogenesis, ossification, and bone remodeling. Biomechanical studies demonstrated markedly reduced strength in Dnmt3bAgc1ER fractures and confirmed the delay in repair. The angiogenic response was reduced in both vessel number and volume at 10 and 14 dpf in Dnmt3bAgc1ER mice. Immunohistochemistry showed decreased CD31 expression, consistent with the reduced angiogenesis. Finally, in vitro angiogenesis assays with human umbilical vein endothelial cells (HUVECs) revealed that loss of Dnmt3b in chondrocytes significantly reduced tube formation and endothelial migration. To identify specific angiogenic factors involved in the decreased callus vascularization, a protein array was performed using conditioned media isolated from control and Dnmt3b loss-of-function chondrocytes. Several angiogenic factors, including CXCL12 and osteopontin (OPN) were reduced in chondrocytes following loss of Dnmt3b. DNA methylation analysis further identified hypomethylation in Cxcl12 promoter region. Importantly, the defects in tube formation and cell migration could be rescued by administration of CXCL12 and/or OPN. Altogether, our findings establish that Dnmt3b positively regulates chondrocyte maturation process, and its genetic ablation leads to delayed angiogenesis and fracture repair.

Using event-related potentials, this study investigated how financial herding or antiherding affected the valuation of subsequent outcomes. For each trial, subjects decided whether to buy the stock according to its net money flow information which could be used to reflect the strength of buying power or selling power of the stock. The return on investment (ROI) as feedback included the increase or decrease percentage after subjects’ responses. Results showed that, compared with herding, antiherding induced larger discrepancies of FRN and P300 amplitude between positive ROI and negative ROI, indicating that individuals under antiherding condition had stronger motivation and paid more attention in the evaluation process of ROI. Moreover, only for positive ROI, the amplitudes of FRN and P300 were modulated by two kinds of behaviors. We suggested that individuals making antiherd decisions were more confident with their own ability and choices, which reduced the positive outcome prediction error and gave more mental resources to evaluate positive outcome. However, negative outcomes evoked no different motivational meaning and negative emotion for individuals between herding and antiherding. The study may provide new insights into neurocognitive processes of herding and antiherding in financial market.

iASPP is a member of the apoptosis-stimulating proteins of p53 (ASPP) family and negatively regulates the apoptotic function of p53. In a hematopoietic system, overexpression of iASPP results in blockage of apoptosis, which may play a role in regulating hematopoietic stem cell (HSC) numbers. To address this, we first analyzed the expression of iASPP in patients with acute leukemia (AL) and found it was highly expressed in patients with AL. We further established a transgenic mouse model in which human iASPP was specifically expressed in hematopoietic cells. Overexpression of iASPP led to an increase in the proportion of long-term HSCs, short-term HSCs, multipotent progenitors, and common myeloid progenitor. HSCs from iASPP transgenic mice had an advantage in long-term reconstitution potential. In addition, the hematopoietic cells from iASPP transgenic mice exhibited a significantly lower level of p53 dependent apoptosis. After irradiation damage, hematopoietic cells of iASPP transgenic mice had a higher level of γ-H2AX expression, which lasted for a longer time. These results provide the first evidence that the iASPP can increase HSC populations and reconstitution capacity. Interestingly, in response to cell damage stimuli, hematopoietic cells can be protected against apoptosis by iASPP; meanwhile these apoptosis-resistant cells would have more mutation accumulation, which might be the potential risk for malignant transformation.-Jia, Y., Peng, L., Rao, Q., Xing, H., Huai, L., Yu, P., Chen, Y., Wang, C., Wang, M., Mi, Y., Wang, J. Oncogene iASPP enhances self-renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation.

Deoxyschizandrin is an active lignin ingredient originating from Schisandra chinensis (Turcz.) Baill or Schisandrae Sphenantherae Fructus. In the present study, a novel and efficient strategy was developed for the in vivo screening and identification of deoxyschizandrin metabolites using ultra high performance liquid chromatography combined with triple TOF mass spectrometry (UPLC-TOF/MS/MS). This strategy was characterized by the following: a novel and unique multiple mass defect filter (MMDF) combined with an on-line data acquisition method that is dependent on dynamic background subtraction (DBS) was developed to trace all of the probable metabolites of deoxyschizandrin. The MMDF and DBS methods could trigger an IDA scan for the low-level metabolites that are masked by background noise and endogenous components. A combination of data processing methods including extracted ion chromatography (XIC), mass defect filtering (MDF), product ion filtering (PIF) and neutral loss filtering (NLF) were employed to identify the metabolites of deoxyschizandrin. Next, the structures of the metabolites were elucidated based on an accurate mass measurement, the fragmentation patterns of the parent drug and relevant drug bio-transformation knowledge. Finally, an important parameter ClogP was used to estimate the retention time of isomers. Based on the proposed strategy, 51 metabolites (including 49 phase I and 2 phase II metabolites) were identified in rats after the oral administration of deoxyschizandrin. Among these metabolites, 41 metabolites were characterized in the rat urine, and 28 metabolites were identified in the rat bile. The results indicated that oxidization was the main metabolic pathway and that the methoxy group and the biphenyl cyclooctene were the metabolic sites. Conjugation with sulfate and cysteine groups produced two phase-II metabolites. This study firstly reported the description of deoxyschizandrin metabolism in vivo. This study provided a practical strategy for rapidly screening and identifying metabolites, and this methodology can be widely applied for the structural characterization of the metabolites of other compounds.

The evidence concerning the association between ambient temperature and mortality is limited in developing countries, especially in China. We assessed the effects of temperature on daily mortality between 2005 and 2008 in Suzhou, China. A Poisson regression model combined with a distributed-lag nonlinear model was used to examine the association between temperature and daily mortality. We investigated effect modification by individual characteristics, including gender, age and educational attainment. We found significant non-linear effects of temperature on total and cardiovascular mortality. Heat effects were immediate and lasted for 1-2 days, whereas cold effects persisted for 10 days. The relative risk of total morality associated with extreme cold temperature (1st percentile of temperature, -0.3 °C) over lags 0-14 days was 1.75 [95% confidence interval (CI): 1.43, 2.14)], compared with the minimum mortality temperature (26 °C). The relative risk associated with extremely hot temperature (99th percentile of temperature, 32.6 °C) over lags 0-3 days was 1.43 (95% CI: 1.31, 1.56). We did not observe significant modifying effect by gender, age or educational level. This study showed that exposure to both hot and cold temperatures was associated with increased mortality in Suzhou. Our findings may have implications for developing intervention strategies for extreme cold and hot temperatures.

Background The underlying mechanisms about the association between ambient fine particulate matter (PM 2.5 ) and lung function were unclear. Few epidemiological studies have evaluated the potential mediating effects of serum club cell secretory protein (Clara) (CC16), a biomarker of pulmonary epithelium integrity. Objectives To evaluate the short-term effect of personal PM 2.5 exposure on lung function and to explore the potential mediating role of CC16 in this effect. Methods We enrolled 36 healthy, nonsmoking college students for a panel study in Shanghai, China from December 17, 2014 to July 11, 2015. We measured personal and real-time exposure to PM 2.5 for 72 h preceding each of four rounds of health examinations, including lung function test and serum CC16 measurement. We used linear mixed-effect models to examine the effects of PM 2.5 on lung function and CC16 over various lag times. Furthermore, we analyzed the mediating effect of CC16 in the association between PM 2.5 and lung function. Results Average PM 2.5 exposure ranged from 36 to 52 μg/m3 across different lag periods. PM 2.5 exposure was negatively associated with lung function and positively associated with serum CC16 concentration. The effect of PM 2.5 on CC16 occurred earlier than that on lung function. For instance, an interquartile range (IQR) increase in 0–2 h average exposure to PM 2.5 was significantly associated with a 4.84% increase in serum CC16; and an IQR increase in 3–6 h average exposure to PM 2.5 was significantly associated with a 1.08% decrease in 1-sec forced expiratory volume. These effects lasted up to 24 h after exposure. Increased serum CC16 contributed 3.9%–36.3% of the association between PM 2.5 and impaired lung function. Conclusions Acute exposure to PM 2.5 might induce an immediate decrease in lung function by virtue of the loss of pulmonary epithelium integrity.

The accumulation of cytosolic dsDNA plays important roles in the regulation of cellular processes. However, whether cytosolic dsDNA is involved in the pathogenesis of rheumatoid arthritis (RA) is not clear. Therefore, the present study investigated the roles of cytosolic dsDNA in the modulation of inflammatory responses of fibroblast-like synoviocytes (FLS) in patients with RA. FLS were obtained from active RA patients. dsDNA accumulation in the cytosol was detected by immunofluorescence staining and the Qubit® dsDNA HS Assay. Immunohistochemistry was employed to detect the dsDNA and cGMP-AMP synthase (cGAS) expression in the synovium. Short hairpin RNA (shRNA) was used to knockdown the expression of cGAS and stimulator of interferon genes (STING). Protein expression was detected by Western blotting and immunofluorescence staining. We observed increased cytosolic dsDNA and cGAS expression in FLS and synovium from RA patients. dsDNA and cGAS expression correlated with the severity of rheumatoid synovitis. Transfection of dsDNA into the cytosol of RA FLS promoted pro-inflammatory cytokines production. DNaseII overexpression downregulated cytosolic dsDNA expression and inhibited dsDNA-induced cytokines secretion. We also found that dsDNA and TNF-α enhanced cGAS and STING expression, and dsDNA-induced cytokine secretion was reduced by cGAS or STING knockdown. Furthermore, we determined that the dsDNA-induced phosphorylation of IRF3 and NF-κBp65 was decreased by DNaseII overexpression or cGAS/STING knockdown. Overall, our findings show that increased cytosolic dsDNA level promoted inflammatory responses via the cGAS/STING pathway in RA FLS, which suggests that cytosolic dsDNA accumulation is an important contributor to FLS-mediated rheumatoid synovial inflammation.