Replacement of Loops at the Entrance of the Active Pocket of Streptococcus thermophilus 4,6-α-Glucanotransferase Changes Its Catalytic Activity and Product Specificity.

To explore the roles of loops around active pocket in the reuteran type 4,6-α-glucanotransferase (StGtfB) from S. thermophilus, they were individually or simultaneously replaced with those of an isomalto/maltopolysaccharides type 4,6-α-glucanotransferase from L. reuteri. StGtfB with the replaced loops A1, A2 (A1A2) and A1, A2, B (A1A2B), respectively, showed 1.41- and 0.83-fold activities of StGtfB. Two mutants reduced crystallinity and increased starch disorder at 2, 4, and 8 U/g more than StGtfB and increased DP ≤ 5 short branches of starch by 38.01% at 2 U/g, much more than StGtfB by 4.24%. A1A2B modified starches had the lowest retrogradation over 14 days. A1A2 modified starches had the highest percentage of slowly digestible fractions, ranging from 40.32% to 43.34%. StGtfB and its mutants bind substrates by hydrogen bonding and van der Waals forces at their nonidentical amino acid residues, suggesting that loop replacement leads to a different conformation and changes activity and product structure.

RuPHOX-Ru Catalyzed Asymmetric Cascade Hydrogenation of 3-Substituted Chromones for the Synthesis of Corresponding Chiral Chromanols​.

An efficient RuPHOX-Ru catalyzed asymmetric cascade hydrogenation of 3-substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3-substituted chromanols in high yields with excellent enantio- and diastereoselectivities (up to 99% yield, >99% ee and >20:1 dr). Control reactions and deuterium labelling experiments revealed that a dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation. The resulting products allow for several transformations and it was shown that the protocol provides a practical and alternative strategy for the synthesis of chiral 3-substituted chromanols and their derivatives.

The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Due to its uncertain pathogenesis, there is currently no treatment available for AD. Increasing evidences have linked cellular senescence to AD, although the mechanism triggering cellular senescence in AD requires further exploration. To investigate the involvement of cellular senescence in AD, we explored the effects of cadmium chloride (CdCl2) exposure, one of the potential environmental risk factors for AD, on neuron senescence in vivo and in vitro. ß-amyloid (Aß) and tubulin-associated protein (tau) pathologies were found to be enhanced by CdCl2 exposure in the in vitro models, while p53/p21/Rb cascade-related neuronal senescence pathways were activated. Conversely, the use of melatonin, a cellular senescence inhibitor, or a cadmium ion chelator suppressed CdCl2-induced neuron senescence, along with the Aß and tau pathologies. Mechanistically, CdCl2 exposure activated the suppressor enhancer Lin-12/Notch 1-like (SEL1L)/HMG-CoA reductase degradation 1 (HRD1)-regulated endoplasmic reticulum-associated degradation (ERAD), which enhanced the ubiquitin degradation of sigma-1 receptor (SigmaR1) by specifically recognizing its K142 site, resulting in the activation of the p53/p21/Rb pathway via the induction of Ca2+ dyshomeostasis and mitochondrial dysfunction. In the in vivo models, the administration of the SigmaR1 agonist ANAVEX2-73 rescues neurobehavioral inhibition and alleviates cellular senescence and AD-like pathology in the brain tissue of CdCl2-exposed mice. Consequently, the present study revealed a novel senescence-associated regulatory route for the SEL1L/HRD1/SigmaR1 axis that affects the pathological progression of CdCl2 exposure-associated AD. CdCl2 exposure activated SEL1L/HRD1-mediated ERAD and promoted the ubiquitinated degradation of SigmaR1, activating p53/p21/Rb pathway-regulated neuronal senescence. The results of the present study suggest that SigmaR1 may function as a neuroprotective biomarker of neuronal senescence, and pharmacological activation of SigmaR1 could be a promising intervention strategy for AD therapy.

Changes in Life's Essential 8 and risk of cardiovascular disease in Chinese people.

BACKGROUND: The American Heart Association recently released an updated algorithm for evaluating cardiovascular health-Life's Essential 8 (LE8). However, the associations between changes in LE8 score over time and risk of cardiovascular disease (CVD) remain unclear. METHODS: We investigated associations between 6-year changes (2006-12) in LE8 score and risk of subsequent CVD events (2012-20) among 53 363 Chinese men and women from the Kailuan Study, who were free from CVD in 2012. The LE8 score was calculated based on eight components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 4281 incident CVD cases during a median of 7.7 years of follow-up. Compared with participants whose LE8 scores remained stable in a 6-year period, those with the large increases of LE8 score over the 6-year period had a lower risk of CVD, heart disease and stroke in the subsequent 8 years [HRs and 95% CIs: 0.67 (0.64, 0.70) for CVD, 0.65 (0.61, 0.69) for heart disease, 0.71 (0.67, 0.76) for stroke, all Ptrend < 0.001]. Conversely, those with the large decreases of LE8 score had 47%, 51% and 41% higher risk for CVD, heart disease and stroke, respectively. These associations were consistent across the subgroups stratified by risk factors. CONCLUSIONS: Improving LE8 score in a short- and moderate-term was associated with a lower CVD risk, whereas decreased LE8 score over time was associated with a higher risk.

m6A regulates heterochromatin in mammalian embryonic stem cells.

As the most well-studied modification in mRNA, m6A has been shown to regulate multiple biological processes, including RNA degradation, processing, and translation. Recent studies showed that m6A modification is enriched in chromatin-associated RNAs and nascent RNAs, suggesting m6A might play regulatory roles in chromatin contexts. Indeed, in the past several years, a number of studies have clarified how m6A and its modulators regulate different types of chromatin states. Specifically, in the past 2-3 years, several studies discovered the roles of m6A and/or its modulators in regulating constitutive and facultative heterochromatin, shedding interesting lights on RNA-dependent heterochromatin formation in mammalian cells. This review will summarize and discuss the mechanisms underlying m6A's regulation in different types of heterochromatin, with a specific emphasis on the regulation in mammalian embryonic stem cells, which exhibit distinct features of multiple heterochromatin marks.

Distinct uric acid trajectories are associated with incident cardiac conduction block.

BACKGROUND: The association of longitudinal uric acid (UA) changes with cardiac conduction block risk is unclear. We aimed to identify the trajectories of UA and explore its association with cardiac conduction block. METHODS: A total of 67,095 participants with a mean age of 53.12 years were included from the Kailuan cohort in Tangshan, China, who were free of cardiac conduction block and with repeated measurements of UA from 2006 to 2012. UA trajectories during 2006 to 2012 were identified by group-based trajectory modeling. Cox proportional hazard regression models were used to assess the association of UA trajectories with cardiac conduction block. RESULTS: We categorized three observed discrete trajectories of UA during 2006-2012 period: low-stable, moderate-stable, and high-stable. Over a median follow-up of 6.19 years, we identified 1405 (2.09%) incident cardiac conduction block. Compared to those in the low-stable trajectory, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) of cardiac conduction block in the moderate-stable and high-stable trajectory were 1.30 (1.16-1.47) and 1.86 (1.56-2.22), and HRs of atrioventricular block were 1.39 (1.12-1.72) and 2.90 (2.19-3.83), and HRs of bundle branch blocks were 1.27 (1.10-1.47) and 1.43 (1.13-1.79). Notably, although the average UA level in the moderate-stable UA trajectory group is within the normal range, the risk of cardiac conduction block has increased. CONCLUSIONS: The moderate-stable and high-stable trajectories are associated with increased risk for new-onset cardiac conduction block. Monitoring UA trajectories may assist in identifying subpopulations at higher risk for cardiac conduction block.

Multiple isotopes decipher the nitrogen cycle in the cascade reservoirs and downstream in the middle and lower Yellow River: Insight for reservoir drainage period.

Intensive anthropogenic activities, such as excessive nitrogen input and dam construction, have altered the nitrogen cycle in the global river system. However, the focus on the source, transformation and fate of nitrogen in the Yellow River is still scarce. In this study, the multiple isotopes (δ15N-NO3-, δ18O-NO3-, δ15N-NH4+ and δ15N-PN) were deciphered to explore the nitrogen cycling processes and the driving factors in the thermally stratified cascade reservoirs (Sanmenxia Reservoir: SMXR and Xiaolangdi Reservoir: XLDR) and Lower Yellow River (LYR) during the drainage period of the XLDR. In the SMXR, algal bloom triggered the assimilation process in the upper layer before the SMX Dam, followed by remineralization and subsequent nitrification processes in the lower water layers. The nitrification reaction in the XLDR progressively increased along both longitudinal and vertical directions to the lower layer of the XLD Dam, which was linked to the variation in the water residence time of riverine, transition and lentic zones. The robust nitrification rates in the lower layer of the lentic zone coincided with the substantial depletion of nitrate isotopic composition and enrichment of both δ15N-PN and δ15N-NH4+, indicating the longer water residence time not only promoted the growth of the nitrifying population but also facilitated the remineralization to enhance NH4+ availability. In the LYR, the slight nitrate assimilation, as indicated by nitrate isotopic composition and fractionation models, was the predominant nitrogen transformation process. The Bayesian isotope mixing model results showed that manure and sewage was the dominant nitrate source (50 %) in the middle and lower Yellow River. Notably, the in-reservoir nitrification was a significant nitrate source (27 %) in the XLDR and LYR. Our study deepens the understanding of anthropogenic activities impacting the nitrogen cycle in the river-reservoir system, providing valuable insight into water quality management and nitrogen cycle mechanisms in the Yellow River.

Effect of 10-year cumulative blood pressure exposure on atherosclerotic cardiovascular disease of different age groups: kailuan cohort study.

Background: The level at which cumulative blood pressure (BP) can increase the risk of ASCVD in different age groups remains unclear. This study aimed to investigate the association of 10-year cumulative BP levels with the long-term risk of ASCVD of different age groups. Methods: Cumulative BP exposure was assessed using the time-weighted average (TWA) BP divided into four BP groups. The participants were also divided into four groups according to their baseline age (<50, 50-59, 60-69, or ≥70 years). The association between TWA BP and the risk of ASCVD was assessed by age group using multivariate Cox models. The China-PAR prediction model was used to assess the ability of TWA BP to predict ASCVD. Results: In the group aged <50 years, the hazard ratios and 95% confidence intervals for the risk of ASCVD were 2.66 (1.04-6.80), 3.38 (1.54-7.43), and 3.13 (1.36-7.24) for the elevated BP, stage 1 hypertension, and stage 2 hypertension groups, respectively, when compared with the normal BP group. There was a significant difference in the risk of ASCVD between the age groups, with participants aged <50 years having the highest risk, followed by those aged 50-59, 60-69, and ≥70 years. Conclusions: The risk of ASCVD with high cumulative BP exposure was age-dependent, with a gradual decrease in risk with increasing age.

Association of air pollution and risk of chronic kidney disease: A systematic review and meta-analysis.

Although epidemiological studies have evaluated the association between ambient air pollution and chronic kidney disease (CKD), the results remain mixed. To clarify the nature of the association, we conducted a comprehensive systematic review and meta-analysis to assess the global relationship between air pollution and CKD. The Web of Science, PubMed, Embase and Cochrane Library databases systematically were searched for studies published up to July 2023 and included 32 studies that met specific criteria. The random effects model was used to derive overall risk estimates for each pollutant. The meta-analysis estimated odds ratio (ORs) of risk for CKD were 1.42 (95% confidence interval [CI]: 1.31-1.54) for each 10 µg/m3 increase in PM2.5 ; 1.20 (95% CI: 1.14-1.26) for each 10 µg/m3 increase in PM10 ; 1.07 (95% CI: 1.05-1.09) for each 10 µg/m3 increase in NO2 ; 1.03 (95% CI: 1.02-1.03) for each 10 µg/m3 increase in NOX ; 1.07 (95% CI: 1.01-1.12) for each 1 ppb increase in SO2 ; 1.03 (95% CI: 1.00-1.05) for each 0.1 ppm increase in CO. Subgroup analysis showed that this effect varied by gender ratio, age, study design, exposure assessment method, and income level. Furthermore, PM2.5 , PM10 , and NO2 had negative effects on CKD even within the World Health Organization-recommended acceptable concentrations. Our results further confirmed the adverse effect of air pollution on the risk of CKD. These findings can contribute to enhance the awareness of the importance of reducing air pollution among public health officials and policymakers.

Evolution of dissolved organic nitrogen chemistry during transportation to the marginal sea: Insights from nitrogen isotope and molecular composition analyses.

Estuaries are hotspots where terrestrially originated dissolved organic matter (DOM) is modified in molecular composition before entering marine environments. However, very few research has considered nitrogen (N) modifications of DOM molecules in estuaries, limiting our understanding of dissolved organic nitrogen (DON) cycling and the associated carbon cycling in estuaries. This study integrated optical, stable isotopes (δ15N and δ13C) and molecular composition (FT-ICR MS) to characterize the transformation of DOM in the Yangtze River Estuary. Both concentration of dissolved organic carbon (DOC) and DON decreased with increasing salinity, while their δ13C and δ15N increased with the increasing salinity. A significant positive correlation was found between δ15N and δ13C during the transportation of DOM to marginal seas, indicating that the behavior of both DOC and DON are primarily controlled by the mixing of freshwater and the seawater in the YRE. During the mixing process, the DON addition was observed using the conservative mixing curves. In the view of molecular composition, DOM molecules became more aromatic as the number of N atoms increased. Spearman correlations reveal that DOM molecules with fewer N atoms exhibited a higher enrichment in protein-like components, while those with more N atoms were more enriched in humic-like components. In addition, the δ15N and δ13C tended to increase as the N content of DOM decreased. Therefore, DON molecules with fewer N atoms were likely to be transformed into those with more N atoms based on the isotopic fractionation theory. This study establishes a linkage between the molecular composition and the δ15N of DOM, and discovers the N transformation pattern within DOM molecules during the transportation to marginal seas.

Arterial stiffness and risk of new-onset fragility fracture in Chinese men and women: The Kailuan cohort study.

BACKGROUND: Previous studies have shown an association between increased arterial stiffness and reduced bone mineral density. However, the relationship between arterial stiffness and fragility fracture remains unclear. In this study, we explored the impact of arterial stiffness on the risk of new-onset fragility fracture. METHODS: The study included 53,107 participants in the Kailuan Study in whom brachial-ankle pulse wave velocity (baPWV) measurements were obtained between 2010 and 2021. All participants were free of fragility fractures at baseline. A Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for incident fragility fracture on the baseline baPWV groups: <1400 cm/s (reference), 1400 ≤ baPWV < 1800 cm/s, and ≥1800 cm/s. RESULTS: In total, 327 incident fragility fractures were recorded during an average follow-up of 4.99 ± 3.02 years. After adjustment for potential confounders, the HR for the risk of new-onset fragility fracture was 1.66 (95 % CI 1.14-2.42) for the arterial stiffness group in comparison with the normal baPWV group. The risk of fragility fracture was higher in men (HR 1.64, 95 % CI 1.05-2.57). There was a linear association between higher baPWV and fragility fracture. CONCLUSIONS: Arterial stiffness as measured by baPWV was associated with the risk of fragility fracture.

A signal R3-type, CAPRICE-like MYB transcription factor from Dendrobium nobile controls trichome and root-hair development in Arabidopsis.

The CAPRICE-like MYB transcription factors with R3 MYB motif play a central role in regulating trichome and root-hair development in plants. We identified the homologous gene of ENHANCER OF TRY AND CPC (ETC) in Arabidopsis from Dendrobium nobile Lindl with full cDNA sequence and genomic sequence (CAPRICE-LIKE MYB, DnCPL and DngCPL) respectively. Phylogenic analyses revealed a close relationship of CAPRICE-like MYB TFs between D. nobile and A. thaliana. Promoter analysis indicated that DnCPL is specifically expressed in trichome basal cells of leaf epidermis and root hairs. Overexpression of DnCPL results in the suppression of trichome formation and overproduction of root hairs. In transgenic plants overexpressing DnCPL and DngCPL, trichome formation was inhibited, moreover, no trichomes were observed in tissues of aerial parts, and root-hair differentiation was significantly enhanced by strongly repressing endogenous genes of AtCPC, AtTCL1, and AtTCL2 expression, thereby enhancing AtTRY expression. The DnCPL RNAi plants formed fewer lateral roots with a corresponding change in AtCPC, AtTCL1 and AtTCL2 expression. These results suggest that Dendrobium and Arabidopsis partially use similar transcription factors for epidermal cell differentiation and the CPC-like R3 MYB, DnCPL, may be a key common regulator of plant trichome and root-hair development. The results also provided genes and means of regulation to improve the survival ratio of artificially cultivated Dendrobium with more lateral roots.

Comparative genomics predict specific genes in potential mucorales identification.

Mucoralean fungi could cause mucormycosis in humans, particularly in immunodeficient individuals and those with diabetes mellitus or trauma. With plenty of species and genera, their molecular identification and pathogenicity have a large deviation. Reported cases of mucormycosis showed frequent occurrence in Rhizopus species, Mucor species, and Lichtheimia species. We analyzed the whole genome sequences of 25 species of the top 10 Mucorales genera, along with another 22 important pathogenic non-Mucorales species, to dig the target genes for monitoring Mucorales species and identify potential genomic imprints of virulence in them. Mucorales-specific genes have been found in various orthogroups extracted by Python script, while genus-specific genes were annotated covering cellular structure, biochemistry metabolism, molecular processing, and signal transduction. Proteins related to the virulence of Mucorales species varied with distinct significance in copy numbers, in which Orthofinder was conducted. Based on our fresh retrospective analysis of mucormycosis, a comparative genomic analysis of pathogenic Mucorales was conducted in more frequent pathogens. Specific orthologs between Mucorales and non-Mucoralean pathogenic fungi were discussed in detail. Referring to the previously reported virulence proteins, we included more frequent pathogenic Mucorales and compared them in Mucorales species and non-Mucorales species. Besides, more samples are needed to further verify the potential target genes.

Bridge connection between depression and anxiety symptoms and lifestyles in Chinese residents from a network perspective.

Background: Lifestyle habits are vital components of the culture of mental health treatment settings. We examined the bridge connection between depressive and anxiety symptoms and lifestyles from a network perspective using a population-based study. Methods: Face-to-face interviews were conducted with a provincially representative sample of 13,768 inhabitants from the Guangdong Sleep and Psychosomatic Health Survey based on standardized evaluation techniques. We identified the central symptoms by expected influence. The interconnection between depression and anxiety symptoms, as well as the bridge connectivity linking depression-anxiety symptoms and lifestyle factors, were assessed using the bridge centrality index. Network stability and sensibility analyses were performed using a case-dropping bootstrap procedure. Results: The core symptom that exhibited the highest expected influence was fatigue or little energy, followed by uncontrollable worry, trouble relaxing, and sad mood in the depression-anxiety symptoms network, while guilt was the most interconnected symptom and had the highest bridge strength. Surrounding nodes of each node explained an average variance of 57.63%. Additionally, suicidal thoughts were recognized as collective bridging symptoms connecting lifestyle variables in the network integrating depression-anxiety symptoms with lifestyle factors. Current tobacco and alcohol consumption were positively associated with suicidal thoughts and irritability. Habitual diet rhythm and physical exercise frequency were linked to suicidal thoughts, guilt, and poor appetite or overeating. Suicidal thoughts, irritability, and guilt indicated the greatest connectivity with lifestyle factors. All networks had high stability and accuracy. Conclusion: These highlighted core and bridge symptoms could serve as latent targets for the prevention and intervention of comorbid depression and anxiety. It might be crucial for clinical practitioners to design effective and targeted treatment and prevention strategies aiming at specific lifestyles and behaviors.

Depression, anxiety and insomnia in Chinese older adults and their family caregivers during the COVID-19 pandemic: an actor-partner interdependence model approach.

Aims: This study aimed to explore the dyadic effects of depression and anxiety on insomnia symptoms in Chinese older adults and their caregivers living in a community setting. Methods: Data were collected from 1,507 pairs of older adults and their caregivers who were in the Guangdong Mental Health Survey in China. The 9-item Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder module 7 (GAD-7), and Insomnia Severity Index (ISI) were used to measure depression, anxiety, and insomnia symptoms. Actor-Partner Interdependence Models (APIM) were used to determine whether anxiety or depression symptoms predicted individual or dyadic insomnia. Results: Older adults' and caregivers' depression and anxiety had significant positive correlations with their own and their caregivers' insomnia symptoms (all P < 0.001). Actor effects were found between depression and insomnia symptoms in both older adults and caregivers (B = 0.695, P < 0.001; B = 0.547, P < 0.001, respectively), with one significant partner effects (B = 0.080, P = 0.007). Actor effects were also found between anxiety and insomnia symptoms in both older adults and caregivers (B = 0.825, P < 0.001; B = 0.751, P < 0.001, respectively), with one significant partner effects (B = 0.097, P = 0.004). However, the caregivers' depression and anxiety were not associated with older adults' insomnia symptoms in the APIM analyses. Conclusions: Older adults and their caregivers had an interrelationship between psychological distress and insomnia. Consequently, healthcare providers might consider involving dyads when designing programs to reduce insomnia and improve psychological distress for family caregivers.

The impact of fasting plasma glucose variability on osteoporotic fractures.

Purpose: To investigate the impact of FPG variability on osteoporotic fractures in the entire community population. Methods: All participants were from the Kailuan Study. Participants completed three consecutive surveys from 2006-2007, 2008-2009, and 2010-2011. We excluded individuals with an osteoporotic fracture in or prior to the index year and those without complete FPG records at the first 3 examinations. All participants were followed from the date of the 3rd examination to the first occurrence of an endpoint event or December 31, 2021. According to the SD of FPG levels, the included subjects were divided into three groups. A Cox proportional hazards model was performed to further analyze the effect of different FPG-SD groups on the risk of osteoporotic fractures. Results: Ultimately, the study population included 57295 participants. During a median follow-up time of 11.00 years, we documented 772 new osteoporotic fracture cases. When evaluating the FPG-SD level as a categorical variable, the HRs for osteoporotic fractures were 1.07 (95% CI: 0.89-1.29) for T2 and 1.32 (95% CI: 1.10-1.60) for T3 when compared with T1. We found that increased FPG variability was associated with a greater risk of osteoporotic fractures in people with diabetes than in those without diabetes (47% vs. 32%). Conclusion: Increased FPG variability was an independent predictor of incident osteoporotic fracture, especially in individuals older than 50 years old, nonobese individuals, diabetes patients, and individuals with positive FPG-SD variability.

3,5,6-Trichloro-2-pyridinol confirms ototoxicity in mouse cochlear organotypic cultures and induces cytotoxicity in HEI-OC1 cells.

The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 µM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.

METTL14 regulates chromatin bivalent domains in mouse embryonic stem cells.

METTL14 (methyltransferase-like 14) is an RNA-binding protein that partners with METTL3 to mediate N6-methyladenosine (m6A) methylation. Recent studies identified a function for METTL3 in heterochromatin in mouse embryonic stem cells (mESCs), but the molecular function of METTL14 on chromatin in mESCs remains unclear. Here, we show that METTL14 specifically binds and regulates bivalent domains, which are marked by trimethylation of histone H3 lysine 27 (H3K27me3) and lysine 4 (H3K4me3). Knockout of Mettl14 results in decreased H3K27me3 but increased H3K4me3 levels, leading to increased transcription. We find that bivalent domain regulation by METTL14 is independent of METTL3 or m6A modification. METTL14 enhances H3K27me3 and reduces H3K4me3 by interacting with and probably recruiting the H3K27 methyltransferase polycomb repressive complex 2 (PRC2) and H3K4 demethylase KDM5B to chromatin. Our findings identify an METTL3-independent role of METTL14 in maintaining the integrity of bivalent domains in mESCs, thus indicating a mechanism of bivalent domain regulation in mammals.

Association of the time course of Chinese visceral adiposity index accumulation with cardiovascular events in patients with hypertension.

BACKGROUND: The Chinese visceral adiposity index (CVAI), a simple surrogate measure of visceral fat, is significantly associated with cardiovascular disease (CVD) risk in the general population. This study aimed to evaluate the association of cumulative CVAI (cumCVAI) exposure and its accumulation time course with CVD risk among patients with hypertension. METHODS: This prospective study involved 15,350 patients with hypertension from the Kailuan Study who were evaluated at least three times in the observation period of 2006 to 2014 (2006-2007, 2010-2011, and 2014-2015) and who were free of myocardial infarction and stroke before 2014. The cumCVAI was calculated as the weighted sum of the mean CVAI for each time interval (value × time). The time course of CVAI accumulation was categorized by splitting the overall accumulation into early (cumCVAI06 - 10) and late (cumCVAI10 - 14) accumulation, or the slope of CVAI versus time from 2006 to 2014 into positive and negative. RESULTS: During the 6.59-year follow-up period, 1,184 new-onset CVD events were recorded. After adjusting for confounding variables, the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD were 1.35 (1.13-1.61) in the highest quartile of cumCVAI, 1.35 (1.14-1.61) in the highest quartile of the time-weighted average CVAI, 1.26 (1.12-1.43) in those with a cumulative burden > 0, and 1.43 (1.14-1.78) for the group with a 10-year exposure duration. When considering the time course of CVAI accumulation, the HR (95% CI) for CVD was 1.33 (1.11-1.59) for early cumCVAI. When considering the combined effect of cumCVAI accumulation and its time course, the HR (95% CI) for CVD was 1.22 (1.03-1.46) for cumCVAI ≥ median with a positive slope. CONCLUSIONS: In this study, incident CVD risk depended on both long-term high cumCVAI exposure and the duration of high CVAI exposure among patients with hypertension. Early CVAI accumulation resulted in a greater risk increase than later CVAI accumulation, emphasizing the importance of optimal CVAI control in early life.