Changes in Sleep Patterns, Genetic Susceptibility, and Incident Cardiovascular Disease in China.

Importance: The associations of changes in sleep patterns with incident cardiovascular disease (CVD) are not fully elucidated, and whether these associations are modified by genetic susceptibility remains unknown. Objectives: To investigate the associations of 5-year changes in sleep patterns with incident CVD and whether genetic susceptibility modifies these associations. Design, Setting, and Participants: This prospective cohort study of the Dongfeng-Tongji cohort was conducted from 2008 to 2018 in China. Eligible participants included those with complete sleep information at baseline survey (2008-2010) and the first follow-up survey (2013); participants who had no CVD or cancer in 2013 were prospectively assessed until 2018. Statistical analysis was performed in November 2023. Exposures: Five-year changes in sleep patterns (determined by bedtime, sleep duration, sleep quality, and midday napping) between 2008 and 2013, and polygenic risk scores (PRS) for coronary heart disease (CHD) and stroke. Main Outcomes and Measures: Incident CVD, CHD, and stroke were identified from 2013 to 2018. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% CIs. Results: Among 15 306 individuals (mean [SD] age, 65.8 [7.4] years; 8858 [57.9%] female and 6448 male [42.1%]), 5474 (35.78%) had persistent unfavorable sleep patterns and 3946 (25.8%) had persistent favorable sleep patterns. A total of 3669 incident CVD cases were documented, including 2986 CHD cases and 683 stroke cases, over a mean (SD) follow-up of 4.9 (1.5) years. Compared with those with persistent unfavorable sleep patterns, individuals with persistent favorable sleep patterns over 5 years had lower risks of incident CVD (HR, 0.80; 95% CI, 0.73-0.87), CHD (HR, 0.84; 95% CI, 0.76-0.92), and stroke (HR, 0.66; 95% CI, 0.54-0.82) in the subsequent 5-year period. No significant effect modification by PRS was observed for sleep pattern change and CHD or stroke risk. However, sleep pattern changes and PRS were jointly associated with the CHD and stroke risk in a dose-dependent manner, with the lowest risk being among those with persistent favorable sleep patterns combined with low PRS (HR for CHD, 0.65; 95% CI, 0.52-0.82 and HR for stroke, 0.48; 95% CI, 0.29-0.79). Conclusions and Relevance: In this cohort study of middle-aged and older Chinese adults, individuals with persistent favorable sleep patterns had a lower CVD risk, even among those with higher genetic risk. These findings highlight the importance of maintaining favorable sleep patterns for CVD prevention.

Prospective findings from the Dongfeng-Tongji cohort: Exposure to various metals, the expression of microRNA-4286, and the incidence of acute coronary syndrome.

Mounting evidence suggests that metal/metalloid exposure is related to the adverse health effects. Our prior investigation revealed a positive relation between the plasma level of microRNA-4286 (miR-4286) and an increased risk of developing acute coronary syndrome (ACS). However, it is a lack of studies evaluating the connection between metal/metalloid exposure and miRNA expression on ACS. In the prospective Dongfeng-Tongji cohort, we performed a nested case-control study. A total of 480 ACS and 480 controls were carefully selected based on similar age, sex, and blood collection time. Using inductively coupled plasma mass spectrometry, we assessed the plasma concentrations of 24 different metals. Quantitative real-time polymerase chain reaction was used to analyze the plasma miR-4286. We examined the relations of plasma metals with miR-4286 levels, the incidence of ACS, and the potential interactions. Using the multivariate conditional logistic regression models, we observed that the adjusted odds ratios (95% confidence intervals [CI]) for incident ACS were 1.79 (1.03, 3.12; P-trend = 0.03), 0.60 (0.41, 0.87; P-trend = 0.008), and 0.66 (0.46, 0.93; P-trend = 0.02), when comparing the extreme tertiles of aluminum, rubidium, and selenium, respectively. There was a relation between the concentration of rubidium in plasma and a decrease in the level of plasma miR-4286 (percent difference [95% CI]: -13.36% [-22.74%, -2.83%]; P-trend = 0.01). Both multiplicative (P interaction = 0.009) and additive interactions (relative excess risk due to interaction [95% CI]: 0.82 [0.59, 1.06]) were noted in our observation regarding the relationship between plasma aluminum and miR-4286 in incident ACS. The findings indicated that plasma aluminum was positively while plasma rubidium and selenium were negatively linked to an increased risk of developing ACS. Plasma aluminum exposure and plasma miR-4286 expression might synergistically affect the incident ACS risk. Controlling aluminum exposure was important for ACS prevention, especially for individuals with high expression of plasma miR-4286.

Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway.

Background: Effector T cell activation, migration, and proinflammatory cytokine production are crucial steps in autoimmune disorders such as multiple sclerosis (MS). While several therapeutic approaches targeting T cell activation and proinflammatory cytokines have been developed for the treatment of autoimmune diseases, there are no therapeutic agents targeting the migration of effector T cells, largely due to our limited understanding of regulatory mechanisms of T cell migration in autoimmune disease. Here we reported that midline-1 (Mid1) is a key regulator of effector T cell migration in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. Methods: Mid1-/- mice were generated by Crispr-Cas9 technology. T cell-specific Mid1 knockout chimeric mice were generated by adoptive transfer of Mid1-/- T cells into lymphocyte deficient Rag2-/- mice. Mice were either immunized with MOG35-55 (active EAE) or received adoptive transfer of pathogenic T cells (passive EAE) to induce EAE. In vitro Transwell® assay or in vivo footpad injection were used to assess the migration of T cells. Results: Mid1 was significantly increased in the spinal cord of wild-type (Wt) EAE mice and disruption of Mid1 in T cells markedly suppressed the development of both active and passive EAE. Transcriptomic and flow cytometric analyses revealed a marked reduction in effector T cell number in the central nervous system of Mid1-/- mice after EAE induction. Conversely, an increase in the number of T cells was observed in the draining lymph nodes of Mid1-/- mice. Mice that were adoptively transferred with pathogenic Mid1-/- T cells also exhibited milder symptoms of EAE, along with a lower T cell count in the spinal cord. Additionally, disruption of Mid1 significantly inhibited T-cell migration both in vivo and in vitro. RNA sequencing suggests a suppression in multiple inflammatory pathways in Mid1-/- mice, including mTOR signaling that plays a critical role in cell migration. Subsequent experiments confirmed the interaction between Mid1 and mTOR. Suppression of mTOR with rapamycin or microtubule spindle formation with colcemid blunted the regulatory effect of Mid1 on T cell migration. In addition, mTOR agonists MHY1485 and 3BDO restored the migratory deficit caused by Mid1 depletion. Conclusion: Our data suggests that Mid1 regulates effector T cell migration to the central nervous system via mTOR/microtubule pathway in EAE, and thus may serve as a potential therapeutic target for the treatment of MS.

Patterns of sleep quality and its influence factors: A latent class model among students of medical university in Hubei Province, China.

BACKGROUND: Sleep problem among undergraduate students has become one of the most pressing public health problems. This study aimed to explore the latent class of sleep patterns and the factors affecting sleep in Chinese students of medical university. METHODS: 3423 students participated in the cross-sectional study. The survey consisted of the reduced Morningness-Evening Questionnaire, the Pittsburgh Sleep Quality Index, and Health-Promoting Lifestyle Profile-II. Latent profile analysis and multinominal logistic regression analysis were performed. RESULTS: Three potential sleep categories were identified: "sleep disorder group" (1.87 %), "daytime dysfunction group" (24.42 %), and "good sleep group" (73.71 %). Compared with the "good sleep group," the "sleep disorder group" showed monthly living expenses (RMB) ≥ 3000 yuan (OR) = 13.04), interpersonal relationships as poor (OR = 3.71), health status as poor (OR = 45.09), circadian rhythm as eveningness (OR = 6.17), and poor health-promoting lifestyles (OR = 2.090) as its risk factors (all p < 0.05). Meanwhile, sophomore (OR = 1.75), junior (OR = 1.52), interpersonal relationships as poor (OR = 1.88), health status as poor (OR = 4.62), intermediate-chronotype (OR = 2.19), eveningness chronotype (OR = 5.66), and health-promoting lifestyles as poor (OR = 1.55) were identified as risk factors for the "daytime dysfunction group" (all p < 0.05). LIMITATIONS: Causal conclusions can not be drawn and recall bias in data collection. CONCLUSIONS: Significant population heterogeneity was found in the sleep quality. Implementing targeted interventions focusing on circadian rhythm and lifestyle is crucial to improve the sleep quality of students with different conditions.

Associations between plasma metal/metalloid mixtures and the risk of central obesity: A prospective cohort study of Chinese adults.

Central obesity has increased rapidly over the past decade and posed a substantial disease burden worldwide. Exposure to metals/metalloids has been acknowledged to be involved in the development of central obesity through regulation of cortisol, insulin resistance, and glucocorticoid receptor reduction. Despite the importance, it is lack of prospective study which comprehensively evaluate the relations between multiple metals exposure and central obesity. We explored the prospective associations of plasma metal concentrations with central obesity in a prospective study of the Dongfeng-Tongji cohort. The present study included 2127 participants with a 6.87-year mean follow-up duration. We measured 23 plasma metal/metalloid concentrations at baseline. The associations between metals and incident central obesity were examined utilizing the Cox proportional hazard regression in single and multiple metals models. Additionally, we applied elastic net (ENET), Bayesian kernel machine regression (BKMR), plasma metal score (PMS), and quantile-based g-computation (Qgcomp) models to explore the joint associations of metal mixtures with central obesity. After adjusting potential confounders, we found significant associations of plasma manganese (Mn) and thallium (Tl) concentrations with a higher risk of central obesity, whereas plasma rubidium (Rb) concentration was associated with a lower risk of central obesity both in single and multiple metals models (all FDR <0.05). The ENET and Qqcomp models verified similar metals (Mn, Rb, and Tl) as important predictors for central obesity. The results of both BKMR model and PMS suggested cumulative exposure to metal mixtures was associated with a higher risk of central obesity. Our findings suggested that co-exposure to metals was associated with a higher risk of central obesity. This study expands our knowledge that the management of metals/metalloids exposure may be beneficial for the prevention of new-onset central obesity, which may subsequently alleviate the disease burden of late-life health outcomes.

Lipidomics identified novel cholesterol-independent predictors for risk of incident coronary heart disease: Mediation of risk from diabetes and aggravation of risk by ambient air pollution.

INTRODUCTION: Previous lipidomics studies have identified various lipid predictors for cardiovascular risk, however, with limited predictive increment, sometimes using too many predictor variables at the expense of practical efficiency. OBJECTIVES: To search for lipid predictors of future coronary heart disease (CHD) with stronger predictive power and efficiency to guide primary intervention. METHODS: We conducted a prospective nested case-control study involving 1,621 incident CHD cases and 1:1 matched controls. Lipid profiling of 161 lipid species for baseline fasting plasma was performed by liquid chromatography-mass spectrometry. RESULTS: In search of CHD predictors, seven lipids were selected by elastic-net regression during over 90% of 1000 cross-validation repetitions, and the derived composite lipid score showed an adjusted odds ratio of 3.75 (95% confidence interval: 3.15, 4.46) per standard deviation increase. Addition of the lipid score into traditional risk model increased c-statistic to 0.736 by an increment of 0.077 (0.063, 0.092). From the seven lipids, we found mediation of CHD risk from baseline diabetes through sphingomyelin (SM) 41:1b with a considerable mediation proportion of 36.97% (P < 0.05). We further found that the positive associations of phosphatidylcholine (PC) 36:0a, SM 41:1b, lysophosphatidylcholine (LPC) 18:0 and LPC 20:3 were more pronounced among participants with higher exposure to fine particulate matter or its certain components, also to ozone for LPC 18:0 and LPC 20:3, while the negative association of cholesteryl ester (CE) 18:2 was attenuated with higher black carbon exposure (P < 0.05). CONCLUSION: We identified seven lipid species with greatest predictive increment so-far achieved for incident CHD, and also found novel biomarkers for CHD risk stratification among individuals with diabetes or heavy air pollution exposure.

Associations of multiple plasma metals with osteoporosis: findings from the Dongfeng-Tongji cohort.

With the aging population, osteoporosis has become a more prevalent public health issue. Existing researches have indicated significant relations of single metal exposure with osteoporosis (e.g., lead, copper, and zinc), whereas the evidence regarding the joint association of metal mixtures with osteoporosis remain limited and inconclusive. A total of 4924 participants from the Dongfeng-Tongji cohort were included in the present study. Plasma levels of 23 metals were determined by inductively coupled plasma mass spectrometry, and the presence of osteoporosis was defined as a bone mineral density T-score ≤ - 2.5. We applied stepwise regression, plasma metal score, and quantile g-computation model to evaluate the association between plasma metal mixtures and osteoporosis risk. Of the 4924 participants, the prevalence of osteoporosis was 10.9% (N = 265) in males and 27.5% (N = 684) in females. In the multiple-metals model, arsenic was positively associated with osteoporosis in males, while zinc was positively associated with osteoporosis in females. Comparing extreme quartiles, the multivariate-adjusted ORs of osteoporosis were 2.20 (95% CI, 1.29, 3.79; P-trend = 0.006) for arsenic in males and 2.16 (95% CI, 1.44, 3.23; P-trend < 0.001) for zinc in females. The plasma metal score was significantly and positively associated with a higher risk of osteoporosis, with ORs (95% CI) comparing extreme quartiles were 5.00 (95% CI, 3.36, 7.65; P-trend < 0.001) in males and 1.76 (95% CI, 1.35, 2.29; P-trend < 0.001) in females. Furthermore, the results of quantile g-computation revealed a consistent positive trend of metal mixtures with risk of osteoporosis and suggested the dominant role of arsenic in males and zinc in females, respectively. Our findings highlighted the importance of controlling metal mixtures exposure for the prevention of osteoporosis in the middle-aged and elder population. Further prospective studies in larger populations are warranted to confirm our findings.

Circulating organochlorine pesticide levels, genetic predisposition and the risk of incident type 2 diabetes.

Persistent organochlorine pesticide (OCP) has been associated with type 2 diabetes (T2D), and genetic polymorphism might modify such an association. However, prospective evidence remains scarce. We conducted a nested case-control study comprising 1006 incident diabetic cases and 1006 matched non-diabetic controls [sex and age (±5 years)] from 2008 to 2013 (mean follow-up period: ∼4.6 years) based on the Dongfeng-Tongji cohort in Shiyan City of China, determined baseline levels of nineteen OCPs, and examined the associations of circulating OCPs, both individually and collectively, with incident T2D risk. We also constructed overall genetic risk score (GRS) based on 161 T2D-associated variants and five pathway-specific cluster GRSs based on established variants derived from the Asian population. Compared with the first quartile of serum ß-BHC levels, the multivariable-adjusted ORs (95% CIs) of incident T2D risk in the second, third, and fourth quartiles were 0.98 (0.70-1.39), 1.43 (0.99-2.07), and 1.75 (1.14-2.68), respectively (FDR-adjusted Ptrend = 0.03). A positive association was observed between serum OCP mixture and incident T2D risk and can be largely attributed to ß-BHC. Furthermore, serum ß-BHC and p,p'-DDE showed significant interactions with the GRS for lipodystrophy, a T2D-related pathway representing fat redistribution to viscera, on T2D risk (Pinteraction < 0.05). In conclusion, higher circulating OCP levels were independently associated with an increased risk of T2D, with ß-BHC possibly being the major contributor. Genetic predisposition to T2D-related morbidity, such as visceral adiposity, should be considered when assessing the risk of T2D conferred by OCPs.

Linggui Zhugan decoction delays ventricular remodeling in rats with chronic heart failure after myocardial infarction through the Wnt/ß-catenin signaling pathway.

CONTEXT: Traditional Chinese medicine plays an important role in the prevention and treatment of heart failure (HF). Linggui Zhugan decoction has been approved for clinical treatment of chronic HF. However, the mechanism is still unclear. OBJECTIVE: The effect of Linggui Zhugan decoction on the Wnt/ß-catenin signaling pathway in rat myocardium was studied to investigate the mechanism by Linggui Zhugan decoction effects ventricular remodeling in rats with heart failure after myocardial infarction. METHOD: A rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery. After 6 weeks of intervention with Linggui Zhugan decoction, the effect of Linggui Zhugan decoction on the cardiac function of chronic HF model rats was observed. Myocardial infarct size was measured by triphenyl tetrazolium chloride (TTC) staining. Enzyme linked immunosorbent assays (ELISAs) were used to measure NT-proBNP and sST-2 concentrations in rat serum. Hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were used to observe the morphology of myocardial tissue; immunohistochemistry was used to detect the protein expression of type I collagen and type III collagen in myocardial tissue; and mRNA expression levels of Wnt3a, GSK-3ß, ß-catenin, and c-Myc in the infarct marginal zone were detected using PCR. Protein expression of Wnt3a, p-GSK-3ß, GSK-3ß, and ß-catenin in the infarct marginal zone was detected using western blot. RESULTS: Compared with the control, Linggui Zhugan decoction reduced the levels of serum ST-2 and NT-proBNP, improved cardiac function, and reduced the deposition of collagen fiber. In addition, Linggui Zhugan decoction inhibited the expression of Wnt3a, p-GSK-3ß, and ß-catenin in cardiomyocytes. CONCLUSION: Linggui Zhugan decoction inhibits the expression of several key proteins in the Wnt/ß-catenin signaling pathway, delays cardiomyocyte hypertrophy and fibrosis, and improves cardiac function.

Bedtime, sleep pattern, and incident cardiovascular disease in middle-aged and older Chinese adults: The dongfeng-tongji cohort study.

OBJECTIVES: To investigate the associations of bedtime and a low-risk sleep pattern with incident cardiovascular disease (CVD). METHODS: A total of 31,500 retirees were included from the Dongfeng-Tongji cohort in 2008-2010 and 2013. Sleep information was collected by questionnaires. CVD events were identified through the health care system until December 31, 2018. Cox proportional hazards regression models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average follow-up of 7.2 years, 8324 cases of incident CVD, including 6557 coronary heart disease (CHD) and 1767 stroke, were documented. U-shaped associations of bedtime with the risks of incident CVD and stroke were observed. Compared with bedtime between 10:01 p.m.-11:00 p.m., the HR (95% CI) for CVD was 1.10 (1.01-1.20) for ≤9:00 p.m., 1.07 (1.01-1.13) for 9:01 p.m.-10:00 p.m., and 1.32 (1.11-1.58) for >12:00 a.m., respectively, mainly driven by stroke risk (22%, 14%, and 70% higher for ≤9:00 p.m., 9:01 p.m.-10:00 p.m., and >12:00 a.m., respectively). The number of low-risk sleep factors, namely bedtime between 10:01 p.m.-12:00 a.m., sleep duration of 7-< 8 h/night, good/fair sleep quality, and midday napping ≤60 min, exhibited dose-dependent relationships with CVD, CHD, and stroke risks. Participants with 4 low-risk sleep factors had a respective 24%, 21%, and 30% lower risk of CVD, CHD, and stroke than those with 0-1 low-risk sleep factor. CONCLUSIONS: Individuals with early or late bedtimes had a higher CVD risk, especially stroke. Having low-risk sleep habits is associated with lower CVD risks.

Bedtime, sleep duration, and sleep quality and all-cause mortality in middle-aged and older Chinese adults: The Dongfeng-Tongji cohort study.

OBJECTIVE: This study aims to investigate the associations of bedtime and its combination with sleep duration and sleep quality with all-cause mortality. METHODS: We conducted a prospective cohort study using data collected from 2008 to 2018 in the Dongfeng-Tongji cohort. Among 40,097 participants aged 62.1 on average at baseline, we applied Cox regression models to assess hazard ratios and 95% confidence intervals for mortality risk. RESULTS: During a mean follow-up of 8.2years, 4345 deaths were documented. U-shaped associations of bedtime and sleep duration with all-cause mortality were observed. Compared with bedtime between 10:01 PM and 11:00 PM, the hazard ratio (95% confidence interval) for all-cause mortality was 1.34 (1.20-1.49) for ≤9:00 PM, 1.18 (1.09-1.27) for 9:01-10:00 PM, and 1.50 (1.13-2.00) for >12:00 AM, respectively. Participants with sleep duration of <6, 6-<7, 8-<9, and ≥9 h/night had a respective 39%, 21%, 11%, and 25% higher all-cause mortality risk than those sleeping 7-<8 h/night. Additionally, participants with a healthy sleep score of 3, characterized as proper bedtime (10:01 PM-12:00 AM), moderate sleep duration (7-<8h/night), and good/fair sleep quality, had a significantly 36% (hazard ratio, 0.64; 95% confidence interval, 0.56-0.74) lower all-cause mortality risk than those with a score of 0. CONCLUSIONS: Individuals with early or late bedtimes and short or long sleep duration were at higher all-cause mortality risks. Having healthy sleep habits may significantly reduce death risk.

Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design.

Emerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization.

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

Nontargeted Metabolomics Revealed Novel Association Between Serum Metabolites and Incident Acute Coronary Syndrome: A Mendelian Randomization Study.

Background This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.

Two-century sediment records of atmospheric mercury variations in North China and their relations with regional and global emissions.

Sedimentary mercury (Hg) records from remote areas are significant for revealing historical variations of regional Hg and understanding the influence of regional and global Hg emissions. In this study, sediment cores were retrieved from two subalpine lakes in Shanxi Province in North China and employed to reconstruct atmospheric Hg variations over the last two centuries. The two records show similar anthropogenic Hg fluxes and evolution trends, corresponding with that they were affected mainly by regional atmospheric Hg deposition. Before ~1950, the records show negligible Hg pollution signals. Atmospheric Hg in the region had increased rapidly since the 1950s, lagged more than a half-century compared to the global Hg. This indicates that they were seldom affected by Hg emissions dominated by Europe and North America after the industrial revolution. The Hg increases since the 1950s in the two records corresponded well with rapid industrial developments in and around Shanxi Province after the founding of the China, implying the dominant contribution of domestic Hg emissions. By comparing other Hg records, we find that widespread increases in atmospheric Hg in China likely occurred post ~1950. This study rouses to re-examine historical variations in atmospheric Hg at various settings, which is significant to understanding global Hg cycling in the industrial era.

The Searsville Lake Site (California, USA) as a candidate Global boundary Stratotype Section and Point for the Anthropocene series.

Cores from Searsville Lake within Stanford University's Jasper Ridge Biological Preserve, California, USA, are examined to identify a potential GSSP for the Anthropocene: core JRBP2018-VC01B (944.5 cm-long) and tightly correlated JRBP2018-VC01A (852.5 cm-long). Spanning from 1900 CE ± 3 years to 2018 CE, a secure chronology resolved to the sub-annual level allows detailed exploration of the Holocene-Anthropocene transition. We identify the primary GSSP marker as first appearance of 239,240Pu (372-374 cm) in JRBP2018-VC01B and designate the GSSP depth as the distinct boundary between wet and dry season at 366 cm (6 cm above the first sample containing 239,240Pu) and corresponding to October-December 1948 CE. This is consistent with a lag of 1-2 years between ejection of 239,240Pu into the atmosphere and deposition. Auxiliary markers include: first appearance of 137Cs in 1958; late 20th-century decreases in δ15N; late 20th-century elevation in SCPs, Hg, Pb, and other heavy metals; and changes in abundance and presence of ostracod, algae, rotifer and protozoan microfossils. Fossil pollen document anthropogenic landscape changes related to logging and agriculture. As part of a major university, the Searsville site has long been used for research and education, serves users locally to internationally, and is protected yet accessible for future studies and communication about the Anthropocene. Plain Word Summary: The Global boundary Stratotype Section and Point (GSSP) for the proposed Anthropocene Series/Epoch is suggested to lie in sediments accumulated over the last ~120 years in Searsville Lake, Woodside, California, USA. The site fulfills all of the ideal criteria for defining and placing a GSSP. In addition, the Searsville site is particularly appropriate to mark the onset of the Anthropocene, because it was anthropogenic activities-the damming of a watershed-that created a geologic record that now preserves the very signals that can be used to recognize the Anthropocene worldwide.

Linggui Zhugan Decoction activates the SIRT1-AMPK-PGC1α signaling pathway to improve mitochondrial and oxidative damage in rats with chronic heart failure caused by myocardial infarction.

Objective: To investigate the effects of Linggui Zhugan Decoction on mitochondrial and oxidative damage in rats with chronic heart failure after myocardial infarction and the related mechanisms. Methods: Chronic heart failure after myocardial infarction was established by coronary artery ligation. Heart failure rats were randomly divided into three groups: Model group (n = 11), Linggui Zhugan Decoction group (n = 12), and captopril group (n = 11). Rats whose coronary arteries were only threaded and not ligated were sham group (n = 11). Cardiac function, superoxide dismutase (SOD), malondialdehyde (MDA) contents, soluble growth-stimulating expression factor (ST2), and N-terminal B-type brain natriuretic peptide precursor (NTproBNP) levels were analyzed after treatment. Moreover, the level of mitochondrial membrane potential was detected by JC-1 staining, the ultrastructural of myocardial mitochondria were observed by transmission electron microscopy. The related signal pathway of silent information regulator factor 2-related enzyme 1 (SIRT1), adenylate activated protein kinase (AMPK), phosphorylated adenylate activated protein kinase (p-AMPK), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is an important pathway to regulate mitochondrial energy metabolism, and to initiate mitochondrial biogenesis. The expression level was detected by Western blot and reverse transcription to explore the mechanism of the decoction. Results: Compared with the model rats, Linggui Zhugan Decoction significantly improved cardiac function (p < 0.05), reduced MDA production (p < 0.01), increased SOD activity (p < 0.05), reduced ST-2(p < 0.01), and NT-proBNP(p < 0.05) levels, increased mitochondrial membrane potential, and improved mitochondria function. In addition, Linggui Zhugan Decoction upregulated the expression of SIRT1, p-AMPK, PGC-1α protein, and mRNA in cardiac myocytes. Conclusion: Linggui Zhugan Decoction can improve the cardiac function of heart failure rats by enhancing myocardial antioxidant capacity and protecting the mitochondrial function, the mechanism is related to activating SIRT1/AMPK/PGC-1α signaling pathway.

The role of myeloid-derived immunosuppressive cells in cardiovascular disease.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population found in the bone marrow, peripheral blood, and tumor tissue. Their role is mainly to inhibit the monitoring function of innate and adaptive immune cells, which leads to the escape of tumor cells and promotes tumor development and metastasis. Moreover, recent studies have found that MDSCs are therapeutic in several autoimmune disorders due to their strong immunosuppressive ability. Additionally, studies have found that MDSCs have an important role in the formation and progression of other cardiovascular diseases, such as atherosclerosis, acute coronary syndrome, and hypertension. In this review, we will discuss the role of MDSCs in the pathogenesis and treatment of cardiovascular disease.

Ideal cardiovascular health and mortality: pooled results of three prospective cohorts in Chinese adults.

BACKGROUND: Evidence on the relations of the American Heart Association's ideal cardiovascular health (ICH) with mortality in Asians is sparse, and the interaction between behavioral and medical metrics remained unclear. We aimed to fill the gaps. METHODS: A total of 198,164 participants without cancer and cardiovascular disease (CVD) were included from the China Kadoorie Biobank study (2004-2018), Dongfeng-Tongji cohort (2008-2018), and Kailuan study (2006-2019). Four behaviors (i.e., smoking, physical activity, diet, body mass index) and three medical factors (i.e., blood pressure, blood glucose, and blood lipid) were classified into poor, intermediate, and ideal levels (0, 1, and 2 points), which constituted 8-point behavioral, 6-point medical, and 14-point ICH scores. Results of Cox regression from three cohorts were pooled using random-effects models of meta-analysis. RESULTS: During about 2 million person-years, 20,176 deaths were recorded. After controlling for demographic characteristics and alcohol drinking, hazard ratios (95% confidence intervals) comparing ICH scores of 10-14 vs. 0-6 were 0.52 (0.41-0.67), 0.44 (0.37-0.53), 0.54 (0.45-0.66), and 0.86 (0.64-1.14) for all-cause, CVD, respiratory, and cancer mortality. A higher behavioral or medical score was independently associated with lower all-cause and CVD mortality among the total population and populations with different levels of behavioral or medical health equally, and no interaction was observed. CONCLUSIONS: ICH was associated with lower all-cause, CVD, and respiratory mortality among Chinese adults. Both behavioral and medical health should be improved to prevent premature deaths.

Mercury Pollution History in Tropical and Subtropical American Lakes: Multiple Impacts and the Possible Relationship with Climate Change.

Sediment cores obtained from 11 tropical and subtropical American lakes revealed that local human activities significantly increased mercury (Hg) inputs and pollution levels. Remote lakes also have been contaminated by anthropogenic Hg through atmospheric depositions. Long-term sediment-core profiles revealed an approximately 3-fold increase in Hg fluxes to sediments from c. 1850 to 2000. Generalized additive models indicate that c. 3-fold increases in Hg fluxes also occurred since 2000 in the remote sites, while Hg emissions from anthropogenic sources have remained relatively stable. The tropical and subtropical Americas are vulnerable to extreme weather events. Air temperatures in this region have shown a marked increase since the 1990s, and extreme weather events arising from climate change have increased. When comparing Hg fluxes to recent (1950-2016) climatic changes, results show marked increases in Hg fluxes to sediments during dry periods. The Standardized Precipitation-Evapotranspiration Index (SPEI) time series indicate a tendency toward more extreme drier conditions across the study region since the mid-1990s, suggesting that instabilities in catchment surfaces caused by climate change are responsible for the elevated Hg flux rates. Drier conditions since c. 2000 appear to be promoting Hg fluxes from catchments to lakes, a process that will likely be exacerbated under future climate-change scenarios.