Boronic Acid-Decorated Carbon Dot-Based Semiselective Multichannel Sensor Array for Cytokine Discrimination and Oral Cancer Diagnosis.

Cytokines are essential components of the immune system and are recognized as significant biomarkers. However, detection of a single cytokine is not precise and reliable enough to satisfy the requirements for diagnosis. Herein, we developed a pattern recognition-based method for the multiplexed sensing of cytokines, which involves three-color-emitting boronic acid-decorated carbon dots (BCDs) and arginine-modified titanium carbide (Ti3C2 MXenes) as the sensor array. Initially, the fluorescence signals of the three BCDs were quenched by Ti3C2 MXenes. In the presence of cytokines, the fluorescence intensity of the BCDs was restored or further quenched by different cytokines. The fluorescence response occurs in two steps: first, boronic acid interacts with cis-diol functional groups of cytokines, and second, arginine headgroup selectively interacts with glycans. By exploiting the different competing binding of the BCDs and the cytokines toward Ti3C2 MXenes, seven cytokines and their mixtures can be effectively discriminated at a concentration of 20 ng mL-1. Furthermore, our sensor array demonstrated an excellent performance in classifying human oral cancer saliva samples from healthy individuals with clinically relevant specificity. The noninvasive method offers a rapid approach to cytokine analysis, benefiting early and timely clinical diagnosis and treatment.

A new chromosome-scale genome of wild Brassica oleracea provides insights into the domestication of Brassica crops.

The cultivated diploid Brassica oleracea is an important vegetable crop, but the genetic basis of its domestication remains largely unclear in the absence of high-quality reference genomes of wild B. oleracea. Here, we report the first chromosome-level assembly of the wild Brassica oleracea L. W03 genome (total genome size, 630.7 Mb; scaffold N50, 64.6 Mb). Using the newly assembled W03 genome, we constructed a gene-based B. oleracea pangenome and identified 29 744 core genes, 23 306 dispensable genes, and 1896 private genes. We re-sequenced 53 accessions, representing six potential wild B. oleracea progenitor species. The results of the population genomic analysis showed that the wild B. oleracea populations had the highest level of diversity and represents the most closely related population to modern-day horticultural B. oleracea. In addition, the WUSCHEL gene was found to play a decisive role in domestication and to be involved in cauliflower and broccoli curd formation. We also illustrate the loss of disease-resistance genes during selection for domestication. Our results provide new insights into the domestication of B. oleracea and will facilitate the future genetic improvement of Brassica crops.

Design, synthesis and biological evaluation of aloperine derivatives as potential anticancer agents.

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 µM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.

Targeted Protein Degradation Mediated by Genetically Engineered Lysosome-Targeting Exosomes.

Protein-degrading chimeras are superior drug modalities compared to traditional protein inhibitors because of their effective therapeutic performance. So far, various targeted protein degradation strategies, including proteolysis-targeting chimeras and lysosome-targeting chimeras, have emerged as essential technologies for tackling diseases caused by abnormal protein expression. Here, we report the development and application of lysosome-targeting exosomes (LYTEXs) for the selective degradation of membrane protein targets. LYTEXs are genetically engineered exosomes expressing multivalent single-chain fragment variables, simultaneously recognizing cell-surface lysosome-targeting and to-be-degraded protein. We show that by targeting the lysosome-directing asialoglycoprotein receptor, bispecific LYTEXs can induce lysosomal degradation of membrane-associated therapeutic targets. This strategy provides a generalizable, easy-to-prepare platform for modulating surface protein expression, with the advantage of therapeutic delivery.

Proteomics analysis of enzyme systems and pathway changes during the moromi fermentation of soy sauce mash.

BACKGROUND: During the brewing of soy sauce, the conversion of multiple substances is driven by various microorganisms and their secreted enzyme systems. Soy sauce mash is an important source of enzyme systems during moromi fermentation, but the changes of enzyme systems in soy sauce mash during moromi fermentation are poorly understood. In order to explore the predominant enzyme systems existing during moromi fermentation and to explain the characteristics of the enzyme system changes, an enzymatic activities assay and 4D-label-free proteomics analysis were conducted on soy sauce mash at different stages of fermentation. RESULTS: The activities of hydrolytic enzymes in soy sauce mash decreased continuously throughout the fermentation process, while most of the characteristic physicochemical substances in soy sauce mash supernatant had already accumulated at the early stage of fermentation. Four hydrolytic enzymes were found to be positively correlated with important physicochemical indexes by principal component analysis and Pearson correlation analysis. The proteomics analysis revealed three highly upregulated enzymes and two enzymes that were present in important metabolic pathways throughout the fermentation process. Furthermore, it was found that Aspergillus oryzae was able to accumulate various nutrients in the soy sauce mash by downregulating most of its metabolic pathways. CONCLUSION: Enzymes present with excellent properties during the moromi fermentation period could be obtained from these results. Meanwhile, the characterization of the metabolic pathways of microorganisms during the moromi fermentation period was revealed. The results provide a basis for more scientific and purposeful improvement of moromi fermentation in the future. © 2024 Society of Chemical Industry.

Comparative analysis of microbial composition and functional characteristics in dental plaque and saliva of oral cancer patients.

BACKGROUND: The oral cavity is home to various ecological niches, each with its own unique microbial composition. Understanding the microbial communities and gene composition in different ecological niches within the oral cavity of oral cancer (OC) patients is crucial for determining how these microbial populations contribute to disease progression. METHODS: In this study, saliva and dental plaque samples were collected from patients with OC. Metagenomic sequencing was employed to analyze the microbial community classification and functional composition of the different sample groups. RESULTS: The results of the study revealed significant differences in both the function and classification of microbial communities between saliva and dental plaque samples. The diversity of microbial species in saliva was found to be higher compared to  that in plaque samples. Notably, Actinobacteria were enriched in the dental plaque of OC patients. Furthermore, the study identified several inter-group differential marker species, including Prevotella intermedia, Haemophilus parahaemolyticus, Actinomyces radius, Corynebacterium matruchitii, and Veillonella atypica. Additionally, 1,353 differential genes were annotated into 23 functional pathways. Interestingly, a significant correlation was observed between differentially labeled species and Herpes simplex virus 1 (HSV-1) infection, which may be related to the occurrence and development of cancer. CONCLUSIONS: Significant differences in the microbial and genetic composition of saliva and dental plaque samples were observed in OC patients. Furthermore, pathogenic bacteria associated with oral diseases were predominantly enriched in saliva. The identification of inter-group differential biomarkers and pathways provide insights into the relationship between oral microbiota and the occurrence and development of OC.

In Situ Chiral Template Approach to Synthesize Homochiral Lead Iodides for Second-Harmonic Generation.

Homochiral halide perovskites have gained increasing attention because of their fascinating optoelectronic properties and prospective applications in laser technologies. However, the limited choice of chiral organic templates severely restricts their structural diversity and second-harmonic generation (SHG) effects. Here, we present an in situ chiral template approach for the synthesis of one-dimensional (1D) homochiral lead iodides. A chiral imine (L-ipp) template was generated in situ by reacting L-proline (L-pro) and acetone under ambient conditions. Notably, L-ipp can cooperate with L-pro to direct the formation of a homochiral lead iodide with dual chiral templates, which is unprecedented in crystalline metal halides. The homochiral lead iodide containing both L-ipp and L-pro shows a strong SHG response of 8.0 times that of KH2 PO4 (8.0×KDP). The SHG efficiency is one of the largest values reported to date for any homochiral lead halides under 1064 nm laser irradiation. A comparative study shows that homochiral 1D lead iodides containing either L-ipp or L-pro exhibit relatively weak SHG responses (≤1.0×KDP). This work demonstrates the advantage of using two different chiral templates over a single chiral template in enhancing the SHG responses of halide materials.

Bioinformatic and functional analysis of OsDHN2 under cadmium stress.

As a toxic heavy metal, cadmium (Cd) is one of the principal pollutants influencing rice productivity and food security. Despite several studies, the underlying mechanism of Cd response in plants remains largely unclear. Dehydrins are part of the late embryogenesis abundant (LEA) family which protect plants against abiotic stresses. In this study, a Cd-responsive LEA gene, OsDHN2, was functionally characterized. The chromosome localization results indicated that OsDHN2 was located on chromosome 2 of rice. Meanwhile, cis-acting elements, such as MBS (MYB binding site involved in drought-inducibility), ARE (anaerobic induction), and ABRE (abscisic acid), were present in the OsDHN2 promoter region. Expression pattern analysis also showed that OsDHN2 expression was induced in both roots and shoots under Cd stress. Overexpression of OsDHN2 improved Cd tolerance and reduced Cd concentration in yeast. Moreover, increased expression levels of SOD1, CTA1, GSH1, or CTT1 were found in transgenic yeast under Cd stress, suggesting the increased antioxidant enzymatic activities. These results suggested that OsDHN2 is a Cd-responsive gene that has the potential to improve resistance to Cd in rice.

RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling.

Astrocytes contribute to chronic neuroinflammation in a variety of neurodegenerative diseases, including Parkinson's disease (PD), the most common movement disorder. However, the precise role of astrocytes in neuroinflammation remains incompletely understood. Herein, we show that regulator of G-protein signaling 5 (RGS5) promotes neurodegenerative process through augmenting astrocytic tumor necrosis factor receptor (TNFR) signaling. We found that selective ablation of Rgs5 in astrocytes caused an inhibition in the production of cytokines resulting in mitigated neuroinflammatory response and neuronal survival in animal models of PD, whereas overexpression of Rgs5 had the opposite effects. Mechanistically, RGS5 switched astrocytes from neuroprotective to pro-inflammatory property via binding to the receptor TNFR2. RGS5 also augmented TNFR signaling-mediated pro-inflammatory response by interacting with the receptor TNFR1. Moreover, interrupting RGS5/TNFR interaction by either RGS5 aa 1-108 or small molecular compounds feshurin and butein, suppressed astrocytic cytokine production. We showed that the transcription of astrocytic RGS5 was controlled by transcription factor early B cell factor 1 whose expression was reciprocally influenced by RGS5-modulated TNF signaling. Thus, our study indicates that beyond its traditional role in G-protein coupled receptor signaling, astrocytic RGS5 is a key modulator of TNF signaling circuit with resultant activation of astrocytes thereby contributing to chronic neuroinflammation. Blockade of the astrocytic RGS5/TNFR interaction is a potential therapeutic strategy for neuroinflammation-associated neurodegenerative diseases.

The increase of Nrf2 m6A modification induced by FTO downregulation promotes hippocampal neuron injury and aggravates the progression of epilepsy in a rat model.

Epilepsy is a common chronic neurological disorder characterized by widespread neuronal death. The purpose of this study was to investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) m6A methylation in epilepsy. To create epileptic models, the rats were given Lithium chloride and pilocarpine, and isolated primary rat hippocampal neurons were cultured in an Mg2+ -free medium. The frequency of seizures was recorded in the epilepsy group of rats. The functional tests included TUNEL, MTT, and flow cytometry. Mechanistically, RNA degradation assay, RNA immunoprecipitation, and methylated RNA immunoprecipitation were performed. In epileptic models, Nrf2 and fat mass and obesity-associated (FTO) levels were downregulated, whereas YT521-B homology (YTH) domain family protein 2 (YTHDF2) was upregulated. Additionally, in epileptic models, there was a rise in the m6A methylation level of Nrf2 mRNA. Overexpressing FTO increased cell viability and reduced apoptosis, but Nrf2 interference reversed these effects. Meanwhile, FTO overexpression decreased the m6A methylation of Nrf2 mRNA. Moreover, YTHDF2 bound to Nrf2 mRNA and decreased its stability. Furthermore, FTO overexpression reduced seizure frequency in rats and inhibited hippocampal neuron apoptosis via lowering the m6A methylation level of Nrf2 mRNA. Overexpressing FTO reduced m6A methylation of Nrf2 mRNA, increased cell viability, suppressed apoptosis, and slowed the progression of epileptic diseases, which is linked to YTHDF2 binding to m6A-modified Nrf2 and promoting its degradation, as well as downregulating Nrf2 expression in hippocampal neurons.

VLPs containing stalk domain and ectodomain of matrix protein 2 of influenza induce protection in mice.

BACKGROUND: As a result of antigenic drift, current influenza vaccines provide limited protection against circulating influenza viruses, and vaccines with broad cross protection are urgently needed. Hemagglutinin stalk domain and ectodomain of matrix protein 2 are highly conserved among influenza viruses and have great potential for use as a universal vaccine. METHODS: In this study, we co-expressed the stalk domain and M2e on the surface of cell membranes and generated chimeric and standard virus-like particles of influenza to improve antigen immunogenicity. We subsequently immunized BALB/c mice through intranasal and intramuscular routes. RESULTS: Data obtained demonstrated that vaccination with VLPs elicited high levels of serum-specific IgG (approximately 30-fold higher than that obtained with soluble protein), induced increased ADCC activity to the influenza virus, and enhanced T cell as well as mucosal immune responses. Furthermore, mice immunized by VLP had elevated level of mucosal HA and 4M2e specific IgA titers and cytokine production as compared to mice immunized with soluble protein. Additionally, the VLP-immunized group exhibited long-lasting humoral antibody responses and effectively reduced lung viral titers after the challenge. Compared to the 4M2e-VLP and mHA-VLP groups, the chimeric VLP group experienced cross-protection against the lethal challenge with homologous and heterologous viruses. The stalk domain specific antibody conferred better protection than the 4M2e specific antibody. CONCLUSION: Our findings demonstrated that the chimeric VLPs anchored with the stalk domain and M2e showed efficacy in reducing viral loads after the influenza virus challenge in the mice model. This antibody can be used in humans to broadly protect against a variety of influenza virus subtypes. The chimeric VLPs represent a novel approach to increase antigen immunogenicity and are promising candidates for a universal influenza vaccine.

Simvastatin induces pyroptosis via ROS/caspase-1/GSDMD pathway in colon cancer.

BACKGROUND: The outcome of patients with colon cancer is still unsatisfied nowadays. Simvastatin is a type of statins with anti-cancer activity, but its effect on colon cancer cells remains unclear. The present study is intended to determine the underlying mechanism of simvastatin in treatment of colon cancer. METHODS: The viability and pyroptosis rate of cells treated and untreated with simvastatin were analysed by CCK-8 and flow cytometry assays, respectively. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production. Levels of pyroptosis markers were detected by western blotting analysis or immunofluorescence staining. Besides, the anticancer properties of simvastatin on colon cancer were further demonstrated using a cell line based xenograft tumor model. RESULTS: Simvastatin treatment in HCT116 and SW620 induced pyroptosis and suppressed cell proliferation, with changes in the expression level of NLPR3, ASC, cleaved-caspase-1, mature IL-1ß, IL-18 and GSDMD-N. Moreover, inhibition of caspase-1 and ROS attenuated the effects of simvastatin on cancer cell viability. In addition, it was identified that simvastatin has an anti-tumor effect by down-regulating ROS production and inducing downstream caspase-1 dependent pyroptosis in the subcutaneous transplantation tumors of HCT116 cells in BALB/c nude mice. CONCLUSIONS: Our in vitro and in vivo results indicated that simvastatin induced pyroptosis through ROS/caspase-1/GSDMD pathway, thereby serving as a potential agent for colon cancer treatment. Video Abstract.

Glycemic Variability and the Risk of Diabetic Peripheral Neuropathy: A Meta-Analysis.

Glycemic variability (GV) has been related to complications in patients with diabetes. The aim of the systematic review and meta-analysis was to investigate whether GV is also associated with the incidence of diabetic peripheral neuropathy (DPN). A systematic search of Medline, Web of Science, Embase, and Cochrane Library database was conducted to identify relevant observational studies with longitudinal follow-up. The Newcastle-Ottawa Scale was used for study quality evaluation. A random-effects model was utilized to pool the results, accounting for heterogeneity. Ten observational studies including 72 565 patients with diabetes were included. The quality score was 8-9, indicating generally good quality of the included studies. With a mean follow-up duration of 7.1 years, 11 532 patients (15.9%) were diagnosed as DPN. Compared to patients with low GV, patients with high GV were associated with an increased risk incidence of DPN (risk ratio: 1.51, 95% confidence interval: 1.23 to 1.85, p<0.001; I2=78%). In addition, subgroup analysis showed consistent results in patients with type 1 and type 2 diabetes, and in studies evaluating the short-term and long-term GV (p for subgroup difference=0.82 and 0.53). Finally, results of subgroup analysis also suggested that the association between GV and risk of DPN were not significantly affected by study design, follow-up durations, diagnostic methods for DPN, adjustment of mean glycated hemoglobin A1c, or study quality scores (p for subgroup difference all>0.05). A high GV may be associated with an increased incidence of DPN.

Host-Guest Symmetry and Charge Matching in Glycine-Templated Metal Sulfate-Oxalates Obtained by a Solvent-Free Method.

Two metal sulfate-oxalates, (Hgly)2·Zn(SO4)(C2O4) (1) and Hgly·In(SO4)(C2O4)(gly) (2), were prepared under solvent-free conditions, where gly = glycine. They have similar layered structures despite the fact that aliovalent metal ions are used as structural nodes. Notably, glycine molecules play dual roles as a protonated cation and a zwitterionic ligand in compound 2. The two compounds display moderate second-harmonic-generation (SHG) responses, confirming their noncentrosymmetric structures. Theoretical calculations were performed to reveal the origin of their SHG responses.

Host-Guest Symmetry Matching in Two Crystalline Magnesium Sulfate Oxalates Obtained Via a Solvent-Free Route.

The combination of π-conjugated oxalate anion with sulfate group has been explored in the solvent-free synthesis of two new magnesium sulfate oxalates. One of them has a layered structure crystallized in the noncentrosymmetric space group Ia, while the other has a chainlike structure crystallized in the centrosymmetric space group P21/c. The noncentrosymmetric solid has a wide optical bandgap and exhibits a moderate second-harmonic-generation response. Density functional theory calculations were carried out to disclose the origin of its second-order nonlinear-optical response.

Two van der Waals Layered Antimony(III) Phosphites as UV Optical Materials.

Herein, two new Sb3+-based phosphites, Sb2O2(HPO3) (I) and Sb2O(HPO3)2 (II), were successfully obtained by ingeniously combining Sb3+-based polyhedra containing stereochemically active lone pair (SCALP) and HPO3 polar groups. Both reported compounds exhibit unique 2D van der Waals layered structures, [Sb4O4(HPO3)2]∞ and [Sb2O(HPO3)2]∞, respectively, which favors compounds with large optical anisotropy. Interestingly, the different curvatures of the two layers resulted in the two title compounds showing significantly different birefringences (0.079@546 and 0.046@546 nm, respectively). Both compounds endow wide optical band gaps (4.32 and 4.54 eV, respectively), which indicates their potential as promising ultraviolet (UV) birefringent crystals. The synthesis of the two title compounds enriched Sb3+-based phosphites in the UV region and provided guidance for the subsequent synthesis of superior optical materials.

Predicting highly dynamic traffic noise using rotating mobile monitoring and machine learning method.

Traffic noise, characterized by its highly fluctuating nature, is the second biggest environmental problem in the world. Highly dynamic noise maps are indispensable for managing traffic noise pollution, but two key difficulties exist in generating these maps: the lack of large amounts of fine-scale noise monitoring data and the ability to predict noise levels in the absence of noise monitoring data. This study proposed a new noise monitoring method, the Rotating Mobile Monitoring method, that combines the advantages of stationary and mobile monitoring methods and expands the spatial extent and temporal resolution of noise data. A monitoring campaign was conducted in the Haidian District of Beijing, covering 54.79 km of roads and a total area of 22.15 km2, and gathered 18,213 A-weighted equivalent noise (LAeq) measurements at 1-s intervals from 152 stationary sampling sites. Additionally, street view images, meteorological data and built environment data were collected from all roads and stationary sites. Using computer vision and GIS analysis tools, 49 predictor variables were measured in four categories, including microscopic traffic composition, street form, land use and meteorology. Six machine learning models and linear regression models were trained to predict LAeq, with random forest performing the best (R2 = 0.72, RMSE = 3.28 dB), followed by K-nearest neighbors regression (R2 = 0.66, RMSE = 3.43 dB). The optimal random forest model identified distance to the major road, tree view index, and the maximum field of view index of cars in the last 3 s as the top three contributors. Finally, the model was applied to generate a 9-day traffic noise map of the study area at both the point and street levels. The study is easily replicable and can be extended to a larger spatial scale to obtain highly dynamic noise maps.

Associations between urban exposome and recurrence risk among survivors of acute myocardial infarction in Beijing, China.

Few previous studies have investigated the impacts of coexposure to multiple urban environmental factors on the prognosis of acute myocardial infarction (AMI) events. This study aimed to evaluate the associations between the urban exposome and AMI recurrence. We used data from 88,509 AMI patients from a large cohort obtained from the Beijing Cardiovascular Disease Surveillance System between 2013 and 2019. Twenty-six types of urban exposures were assessed within 300-m, 500-m, and 1000-m buffers of patients' home addresses in the baseline and cumulative average levels. We used the Cox proportional hazard model along with the Elastic Net (ENET) algorithm to estimate the hazard ratios (HRs) of recurrent AMI per interquartile range increase in each selected urban exposure. The increased risk of AMI recurrence was significantly associated with lower urban function diversity in the 500-m buffer, longer distance to subway stations and higher PM2.5 for both baseline and cumulative average exposure. The cumulative averages of two urban factors, including the distance to parks, and the density of fruit and vegetable shops in the 1000-m buffer, were also identified as significant factors affecting the risk of AMI recurrence. These findings can help improve the urban design for promoting human cardiovascular health.

Neighborhood infrastructure-related risk factors and non-communicable diseases: a systematic meta-review.

BACKGROUND: With rapid urbanization, the urban environment, especially the neighborhood environment, has received increasing global attention. However, a comprehensive overview of the association between neighborhood risk factors and human health remains unclear due to the large number of neighborhood risk factor-human health outcome pairs. METHOD: On the basis of a whole year of panel discussions, we first obtained a list of 5 neighborhood domains, containing 33 uniformly defined neighborhood risk factors. We only focused on neighborhood infrastructure-related risk factors with the potential for spatial interventions through urban design tools. Subsequently, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic meta-review of 17 infrastructure-related risk factors of the 33 neighborhood risk factors (e.g., green and blue spaces, proximity to major roads, and proximity to landfills) was conducted using four databases, Web of Science, PubMed, OVID, and Cochrane Library, from January 2000 to May 2021, and corresponding evidence for non-communicable diseases (NCDs) was synthesized. The review quality was assessed according to the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) standard. RESULTS: Thirty-three moderate-and high-quality reviews were included in the analysis. Thirteen major NCD outcomes were found to be associated with neighborhood infrastructure-related risk factors. Green and blue spaces or walkability had protective effects on human health. In contrast, proximity to major roads, industry, and landfills posed serious threats to human health. Inconsistent results were obtained for four neighborhood risk factors: facilities for physical and leisure activities, accessibility to infrastructure providing unhealthy food, proximity to industry, and proximity to major roads. CONCLUSIONS: This meta-review presents a comprehensive overview of the effects of neighborhood infrastructure-related risk factors on NCDs. Findings on the risk factors with strong evidence can help improve healthy city guidelines and promote urban sustainability. In addition, the unknown or uncertain association between many neighborhood risk factors and certain types of NCDs requires further research.

Association of neighborhood physical activity facilities with incident cardiovascular disease.

BACKGROUND: The availability of physical activity (PA) facilities in neighborhoods is hypothesized to influence cardiovascular disease (CVD), but evidence from individual-level long-term cohort studies is limited. We aimed to assess the association between neighborhood exposure to PA facilities and CVD incidence. METHODS: A total of 4658 participants from the Chinese Multi-provincial Cohort Study without CVD at baseline (2007-2008) were followed for the incidence of CVD, coronary heart disease (CHD), and stroke. Availability of PA facilities was defined as both the presence and the density of PA facilities within a 500-m buffer zone around the participants' residential addresses. Time-dependent Cox regression models were performed to estimate the associations between the availability of PA facilities and risks of incident CVD, CHD, and stroke. RESULTS: During a median follow-up of 12.1 years, there were 518 CVD events, 188 CHD events, and 355 stroke events. Analyses with the presence indicator revealed significantly lower risks of CVD (hazard ratio [HR] 0.80, 95% confidence interval ([CI] 0.65-0.99) and stroke (HR 0.76, 95% CI 0.60-0.97) in participants with PA facilities in the 500-m buffer zone compared with participants with no nearby facilities in fully adjusted models. In analyses with the density indicator, exposure to 2 and ≥ 3 PA facilities was associated with 35% (HR 0.65, 95% CI 0.47-0.91) and 28% (HR 0.72, 95% CI 0.56-0.92) lower risks of CVD and 40% (HR 0.60, 95% CI 0.40-0.90) and 38% (HR 0.62, 95% CI 0.46-0.84) lower risks of stroke compared with those without any PA facilities in 500-m buffer, respectively. Effect modifications between presence of PA facilities and a history of hypertension for incident stroke (P = 0.049), and a history of diabetes for incident CVD (P = 0.013) and stroke (P = 0.009) were noted. CONCLUSIONS: Residing in neighborhoods with better availability of PA facilities was associated with a lower risk of incident CVD. Urban planning intervention policies that increase the availability of PA facilities could contribute to CVD prevention.