Proanthocyanidins Ameliorate LPS-Inhibited Osteogenesis of PDLSCs by Restoring Lysine Lactylation.

Periodontitis is a bacteria-induced inflammatory disease characterized by the progressive destruction of periodontal supporting tissues. Periodontal ligament stem cells (PDLSCs) are capable of differentiating into osteoblasts, which is an important stem cell source for endogenous periodontal tissue regeneration. Lysine lactylation (Kla) is a novel post-translational modification of proteins that is recently thought to be associated with osteogenic differentiation. Here, we found that lactylation levels are reduced both in the periodontal tissue of rats with periodontitis and lipopolysaccharide (LPS)-stimulated human PDLSCs. Proanthocyanidins were able to promote the osteogenesis of inflamed PDLSCs by restoring lactylation levels. Mechanistically, proanthocyanidins increased lactate production and restored the lactylation levels of PDLSCs, which recovered osteogenesis of inflamed PDLSCs via the Wnt/ß-catenin pathway. These results provide evidence on how epigenetic regulation by pharmacological agents influence the osteogenic phenotype of stem cells and the process of periodontal tissue repair. Our current study highlights the valuable potential of natural product proanthocyanidins in the regenerative engineering of periodontal tissues.

Nanocarrier Design for Dual-Targeted Therapy of In-Stent Restenosis.

The injury-triggered reocclusion (restenosis) of arteries treated with angioplasty to relieve atherosclerotic obstruction remains a challenge due to limitations of existing therapies. A combination of magnetic guidance and affinity-mediated arterial binding can pave the way to a new approach for treating restenosis by enabling efficient site-specific localization of therapeutic agents formulated in magnetizable nanoparticles (MNPs) and by maintaining their presence at the site of arterial injury throughout the vulnerability period of the disease. In these studies, we investigated a dual-targeted antirestenotic strategy using drug-loaded biodegradable MNPs, surface-modified with a fibrin-avid peptide to provide affinity for the injured arterial wall. The MNPs were characterized with regard to their magnetic properties, efficiency of surface functionalization, disassembly kinetics, and interaction with fibrin-coated substrates. The antiproliferative effects of MNPs formulated with paclitaxel were studied in vitro using a fetal cell line (A10) exhibiting the defining characteristics of neointimal smooth muscle cells. Animal studies examined the efficiency of combined (physical/affinity) MNP targeting to stented arteries in Sprague Dawley rats using fluorimetric analysis and fluorescent in vivo imaging. The antirestenotic effect of the dual-targeted therapy was determined in a rat model of in-stent restenosis 28 days post-treatment. The results showed that MNPs can be efficiently functionalized to exhibit a strong binding affinity using a simple two-step chemical process, without adversely affecting their size distribution, magnetic properties, or antiproliferative potency. Dual-targeted delivery strongly enhanced the localization and retention of MNPs in stented carotid arteries up to 7 days post-treatment, while minimizing redistribution of the carrier particles to peripheral tissues. Of the two targeting elements, the effect of magnetic guidance was shown to dominate arterial localization (p = 0.004 vs. 0.084 for magnetic targeting and peptide modification, respectively), consistent with the magnetically driven MNP accumulation step defining the extent of the ultimate affinity-mediated arterial binding and subsequent retention of the carrier particles. The enhanced arterial uptake and sustained presence of paclitaxel-loaded MNPs at the site of stent deployment were associated with a strong inhibition of restenosis in the rat carotid stenting model, with both the neointima-to-media ratio (N/M) and % stenosis markedly reduced in the dual-targeted treatment group (1.62 ± 0.2 and 21 ± 3 vs. 2.17 ± 0.40 and 29 ± 6 in the control animals; p < 0.05). We conclude that the dual-targeted delivery of antirestenotic agents formulated in fibrin-avid MNPs can provide a new platform for the safe and effective treatment of in-stent restenosis.

Website Investigation of Pet Weight Management-Related Information and Services Offered by Ontario Veterinary Practices.

Pet owners rely on information and advice from their veterinary practice to effectively manage their pet's weight. This study investigated weight management information and services displayed on practice websites in Ontario, Canada. Information collected from the websites of 50 randomly selected small and mixed-animal practices included practice and staff demographics and the type of weight management services, products, and information advertised or displayed. The most frequently advertised weight management service and product were nutritional counselling (34%) and therapeutic diets (25%), respectively. Current bodyweight measurement was advertised on just over half of the websites (54%), while physical therapy counselling was the least-advertised service (16%). Further statistical analyses were performed in an exploratory fashion to determine areas for future research. Binary logistic regression analyses were used to investigate the association between practice demographics and the type of weight management information advertised online. A maximum of two predictor variables were included in each regression model. Exploratory analyses indicated that when controlling for the number of veterinarians in each practice, having a higher number of veterinary technicians was associated with increased odds of a practice website advertising current bodyweight measurement by 80.1% (odds ratio (OR) = 1.80, p = 0.05). Additionally, when controlling the number of veterinary technicians, having a higher number of veterinarians was associated with increased odds of a practice website advertising sales of therapeutic diets by 119.0% (OR = 2.19, p = 0.04). When using corporate practices as reference, independently owned practices had decreased odds of advertising sales of treats and weight management accessories on their practice websites by 78.7% (OR = 0.21, p = 0.03). These preliminary results suggest that advertising weight management information is not prioritized on veterinary practice websites in Ontario, especially those with lower staff numbers. The findings of this study raise awareness on the current state of weight management promotion for pets on veterinary practice websites and highlight ways to improve upon a practice's online presence.

Supramolecularly Engineered Conjugate of Bacteria and Cell Membrane-Coated Magnetic Nanoparticles for Enhanced Ferroptosis and Immunotherapy of Tumors.

Although various ferroptosis inducers including magnetic nanoparticles (Fe3 O4 ) and iron-organic frameworks have been applied in cancer treatment, the mild immunogenicity, low targeting efficiency to the tumor, and poor tissue penetration have limited the therapeutic efficacy. Herein, a supramolecularly engineered conjugate between living bacteria (facultative anaerobic Salmonella typhimurium VNP20009, VNP) and cancer cell membranes-coated Fe3 O4 nanoparticles is developed for improving targeted delivery of Fe3 O4 nanoparticles into the tumor tissue and for synergistic ferroptosis and immunotherapy of tumor. The enhanced ferroptosis induced by both Fe3 O4 nanoparticles and the loaded ferroptosis inducing agent (sulfasalazine (SAS)) effectively inhibits tumor growth and generates immune response via immunogenic cell death (ICD). The colonization of VNP in tumors also induces adaptive immune responses and further promotes ferroptosis. Fundamentally, the supramolecular conjugate of VNP and cell membranes-coated Fe3 O4 can potentiate the therapeutic capability of each other through mutually magnifying the ferroptosis and immunotherapy, resulting in significantly enhanced antitumor effects.

Prediction models of all-cause mortality among older adults in nursing home setting: A systematic review and meta-analysis.

Background and Aims: Few studies have meta-analyzed different prognostic models developed for older adults, especially nursing home residents. We aimed to systematically review and meta-analyze the performance of all published models that predicted all-cause mortality among older nursing home residents. Methods: We systematically searched PubMed and EMBASE from the databases' inception to January 1, 2020 to capture studies developing and/or validating a prognostic/prediction model for all-cause mortality among nursing home residents. We then carried out both qualitative and quantitative analyses evaluating these models' risks of bias and applicability. Results: The systematic search yielded 23,975 articles. We identified 28 indices that predicted the risk of all-cause mortality from 14 days to 39 months among older adults in nursing homes. The most used predictors were age, sex, body weight, swallowing problem, congestive heart failure, shortness of breath, body mass index, and activities of daily living. Of the 28 indices, 8 (29%) and 3 (11%) were internally and externally validated, respectively. None of the indices was validated in more than one cohort. Of the 28 indices, 22 (79%) reported the C-statistic, while only 6 (6%) reported the 95% confidence interval for the C statistic in the development cohorts. In the validation cohorts, 11 (39%) reported the C-statistic and 8 (29%) reported the 95% confidence interval. The meta-analyzed C statistic for all indices is 0.733 (95% prediction interval: 0.669-0.797). All studies/indices had high risks of bias and high concern for applicability according to PROBAST. Conclusion: We identified 28 indices for predicting all-cause mortality among older nursing home residents. The overall quality of evidence was low due to a high degree of bias and poor reporting of model performance statistics. Before any prediction model could be recommended in routine care, future research is needed to rigorously validate existing prediction models and evaluate their applicability and develop new prediction models.

Autocatalytic base editing for RNA-responsive translational control.

Genetic circuits that control transgene expression in response to pre-defined transcriptional cues would enable the development of smart therapeutics. To this end, here we engineer programmable single-transcript RNA sensors in which adenosine deaminases acting on RNA (ADARs) autocatalytically convert target hybridization into a translational output. Dubbed DART VADAR (Detection and Amplification of RNA Triggers via ADAR), our system amplifies the signal from editing by endogenous ADAR through a positive feedback loop. Amplification is mediated by the expression of a hyperactive, minimal ADAR variant and its recruitment to the edit site via an orthogonal RNA targeting mechanism. This topology confers high dynamic range, low background, minimal off-target effects, and a small genetic footprint. We leverage DART VADAR to detect single nucleotide polymorphisms and modulate translation in response to endogenous transcript levels in mammalian cells.

ADAR1p110 promotes Enterovirus D68 replication through its deaminase domain and inhibition of PKR pathway.

BACKGROUND: Severe respiratory and neurological diseases caused by human enterovirus D68 (EV-D68) pose a serious threat to public health, and there are currently no effective drugs and vaccines. Adenosine deaminase acting on RNA1 (ADAR1) has diverse biological functions in various viral infections, but its role in EV-D68 infections remains undetermined. METHODS: Rhabdomyosarcoma (RD) and human embryonic kidney 293 T (293 T) cells, and HeLa cells were used to evaluate the expression level of ADAR1 upon EV-D68 (Fermon strain) and human parainfluenza virus type 3 (HPIV3; NIH47885) infection, respectively. Knockdown through silencing RNA (siRNA) and overexpression of either ADAR1p110 or ADAR1p150 in cells were used to determine the function of the two proteins after viral infection. ADAR1p110 double-stranded RNA binding domains (dsRBDs) deletion mutation was generated using a seamless clone kit. The expression of ADAR1, EV-D68 VP1, and HPIV3 hemagglutinin-neuraminidase (HN) proteins was identified using western blotting. The median tissue culture infectious dose (TCID50) was applied to detect viral titers. The transcription level of EV-D68 mRNA was analyzed using reverse transcription-quantitative PCR (RT-qPCR) and the viral 5'-untranslated region (5'-UTR)-mediated translation was analyzed using a dual luciferase reporter system. CONCLUSION: We found that the transcription and expression of ADAR1 was inhibited upon EV-D68 infection. RNA interference of endogenous ADAR1 decreased VP1 protein expression and viral titers, while overexpression of ADAR1p110, but not ADAR1p150, facilitated viral replication. Immunofluorescence assays showed that ADAR1p110 migrated from the nucleus to the cytoplasm after EV-D68 infection. Further, ADAR1p110 lost its pro-viral ability after mutations of the active sites in the deaminase domain, and 5'-UTR sequencing of the viral genome revealed that ADAR1p110 likely plays a role in EV-D68 RNA editing. In addition, after ADAR1 knockdown, the levels of both phosphorylated double-stranded RNA dependent protein kinase (p-PKR) and phosphorylated eukaryotic initiation factor 2α (p-eIF2α) increased. Attenuated translation activity of the viral genome 5'-UTR was also observed in the dual-luciferase reporter assay. Lastly, the deletion of ADAR1p110 dsRBDs increased the level of p-PKR, which correlated with a decreased VP1 expression, indicating that the promotion of EV-D68 replication by ADAR1p110 is also related to the inhibition of PKR activation by its dsRBDs. Our study illustrates that ADAR1p110 is a novel pro-viral factor of EV-D68 replication and provides a theoretical basis for EV-D68 antiviral research.

Triterpenoids from the fruits of Melia azedarach L. and their cytotoxic activities.

Eleven undescribed tetracyclic triterpenoids, meliazedarachins A-K, along with twenty-six known compounds were isolated from the fruits of Melia azedarach L.. Their structures were determined by HRESIMS, UV, IR, NMR, X-ray diffraction, electronic circular dichroism (ECD) spectra, and the modified Mosher's method. The cytotoxic activities of all the isolates were measured. Meliazedarachin K and mesendanin N showed cytotoxicity against five human cancer cell lines with IC50 values ranging from 9.02 to 31.31 µM. Meliazedarachin K showed significant cytotoxicity against HCT116 cell line with IC50 value of 9.02 ± 0.84 µM. 21α-methylmelianodiol showed significant cytotoxicity against HCT116 and RKO cell lines with IC50 values of 10.16 ± 1.22 and 8.57 ± 0.80 µM, respectively.

Trends in Diet Quality Among Older US Adults From 2001 to 2018.

Importance: Poor diet is a major risk factor for chronic diseases, disability, and death in the US. As older adults comprise the fastest-growing population segment in the US, it is crucial to describe dietary trends among older adults to identify opportunities and challenges for improving health in old age. Objective: To characterize trends in overall dietary quality and key food components and nutrients among older US adults by age, sex, race and ethnicity, marital status, educational level, and income. Design, Setting, and Participants: This serial cross-sectional study used 24-hour dietary recall data from 10 837 adults aged 65 years or older in 9 National Health and Nutrition Examination Survey cycles (2001-2002 to 2017-2018). Statistical analysis was conducted from June 1 to October 1, 2021. Exposures: Calendar year and sociodemographic subgroups. Main Outcomes and Measures: Survey-weighted, energy-adjusted mean diet scores and proportions of older US adults with poor, intermediate, or ideal diet scores based on the American Heart Association (AHA) 2020 Strategic Impact Goals for diet. Additional outcomes included the AHA secondary score and the Healthy Eating Index (HEI)-2015 score. Results: A total of 10 837 individuals (5423 women [50.0%]; 6339 White participants [58.5%]; mean [SD] age, 73.9 [0.1] years) were analyzed. Overall dietary quality deteriorated from 2001 to 2018 among older adults. The mean primary AHA score (total = 50 points) decreased from 19.84 (95% CI, 19.40-20.29) to 18.28 (95% CI, 17.84-18.73; a decrease of 7.9%; P < .001 for trend). The mean secondary AHA score (total = 80 points) decreased from 34.75 (95% CI, 34.11-35.39) to 31.83 (95% CI, 31.17-32.48; a decrease of 8.4%; P < .001 for trend). The mean HEI-2015 score (total = 100 points) decreased from 47.82 (95% CI, 47.11-48.52) to 45.25 (95% CI, 44.53-45.98; a decrease of 5.4%; P < .001 for trend). Based on the primary AHA score, the proportion of US older adults with a poor diet quality significantly increased from 50.9% to 60.9%, the proportion with an intermediate diet quality significantly decreased from 48.6% to 38.7%, and the proportion with ideal diet quality remained consistently low (0.4% in both 2001-2002 and 2017-2018). Dietary variations were identified by sociodemographic subgroups. We found a significant decreasing trend in diet scores among both sexes and all age groups except for those aged 75 to 79 years. Conclusions and Relevance: The findings of this cross-sectional study suggest that dietary quality worsened for most dietary components among older US adults between 2001 and 2018. Despite improvement in some dietary components, more than half of older US adults still have poor dietary quality.

RNA-responsive elements for eukaryotic translational control.

The ability to control translation of endogenous or exogenous RNAs in eukaryotic cells would facilitate a variety of biotechnological applications. Current strategies are limited by low fold changes in transgene output and the size of trigger RNAs (trRNAs). Here we introduce eukaryotic toehold switches (eToeholds) as modular riboregulators. eToeholds contain internal ribosome entry site sequences and form inhibitory loops in the absence of a specific trRNA. When the trRNA is present, eToeholds anneal to it, disrupting the inhibitory loops and allowing translation. Through optimization of RNA annealing, we achieved up to 16-fold induction of transgene expression in mammalian cells. We demonstrate that eToeholds can discriminate among viral infection status, presence or absence of gene expression and cell types based on the presence of exogenous or endogenous RNA transcripts.

Association of Retail Environment and Neighborhood Socioeconomic Status With Mortality Among Community-Dwelling Older Adults in the United States: Cardiovascular Health Study.

BACKGROUND: Few studies have examined the association of neighborhood environment and mortality among community-dwelling older populations. Geographic Information Systems-based measures of neighborhood physical environment may provide new insights on the health effects of the social and built environment. METHOD: We studied 4 379 community-dwelling older adults in the United States aged 65 years and older from the Cardiovascular Health Study. Principal component analysis was used to identify neighborhood components from 48 variables assessing facilities and establishments, demographic composition, socioeconomic status, and economic prosperity. We used a Cox model to evaluate the association of neighborhood components with 5-year mortality. Age, sex, race, education, income, marital status, body mass index, smoking status, disability, coronary heart disease, and diabetes were included as covariates. We also examined the interactions between neighborhood components and sex and race (Black vs White or other). RESULTS: We identified 5 neighborhood components, representing facilities and resources, immigrant communities, community-level economic deprivation, resident-level socioeconomic status, and residents' age. Communities' economic deprivation and residents' socioeconomic status were significantly associated with 5-year mortality. We did not find interactions between sex or race and any of the 5 neighborhood components. The results were similar in a sensitivity analysis where we used 10-year mortality as the outcome. CONCLUSIONS: We found that communities' economic status but not facilities in communities was associated with mortality among older adults. These findings revealed the importance and benefits living in a socioeconomically advantaged neighborhood could have on health among older residents with different demographic backgrounds.

Sarc-Graph: Automated segmentation, tracking, and analysis of sarcomeres in hiPSC-derived cardiomyocytes.

A better fundamental understanding of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has the potential to advance applications ranging from drug discovery to cardiac repair. Automated quantitative analysis of beating hiPSC-CMs is an important and fast developing component of the hiPSC-CM research pipeline. Here we introduce "Sarc-Graph," a computational framework to segment, track, and analyze sarcomeres in fluorescently tagged hiPSC-CMs. Our framework includes functions to segment z-discs and sarcomeres, track z-discs and sarcomeres in beating cells, and perform automated spatiotemporal analysis and data visualization. In addition to reporting good performance for sarcomere segmentation and tracking with little to no parameter tuning and a short runtime, we introduce two novel analysis approaches. First, we construct spatial graphs where z-discs correspond to nodes and sarcomeres correspond to edges. This makes measuring the network distance between each sarcomere (i.e., the number of connecting sarcomeres separating each sarcomere pair) straightforward. Second, we treat tracked and segmented components as fiducial markers and use them to compute the approximate deformation gradient of the entire tracked population. This represents a new quantitative descriptor of hiPSC-CM function. We showcase and validate our approach with both synthetic and experimental movies of beating hiPSC-CMs. By publishing Sarc-Graph, we aim to make automated quantitative analysis of hiPSC-CM behavior more accessible to the broader research community.

Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization.

Progressive loss of cardiac systolic function in arrhythmogenic cardiomyopathy (ACM) has recently gained attention as an important clinical consideration in managing the disease. However, the mechanisms leading to reduction in cardiac contractility are poorly defined. Here, we use CRISPR gene editing to generate human induced pluripotent stem cells (iPSCs) that harbor plakophilin-2 truncating variants (PKP2tv), the most prevalent ACM-linked mutations. The PKP2tv iPSC­derived cardiomyocytes are shown to have aberrant action potentials and reduced systolic function in cardiac microtissues, recapitulating both the electrical and mechanical pathologies reported in ACM. By combining cell micropatterning with traction force microscopy and live imaging, we found that PKP2tvs impair cardiac tissue contractility by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. These findings highlight the interplay between cell-cell adhesions and sarcomeres required for stabilizing cardiomyocyte structure and function and suggest fundamental pathogenic mechanisms that may be shared among different types of cardiomyopathies.

Curcumin Inhibits Replication of Human Parainfluenza Virus Type 3 by Affecting Viral Inclusion Body Formation.

Human Parainfluenza Virus Type 3 (HPIV3) is one of the main pathogens that cause acute lower respiratory tract infections in infants and young children. However, there are currently no effective antiviral drugs and vaccines. Herein, we found that a natural compound, curcumin, inhibits HPIV3 infection and has antiviral effects on entry and replication of the virus life cycle. Immunofluorescence and western blotting experiments revealed that curcumin disrupts F-actin and inhibits viral inclusion body (IB) formation, thus inhibiting virus replication. Curcumin can also downregulate cellular PI4KB and interrupt its colocalization in viral IBs. This study verified the antiviral ability of curcumin on HPIV3 infection and preliminarily elucidated its influence on viral replication, providing a theoretical basis for antiviral drug development of HPIV3 and other parainfluenza viruses.

Oxypeucedanin is a Mechanism-based Inactivator of CYP2B6 and CYP2D6.

BACKGROUND: Herbal medicine Angelica dahurica is widely employed for the treatment of rheumatism and pain relief in China. Oxypeucedanin is a major component in the herb. OBJECTIVES: The objectives of this study are aimed at the investigation of mechanism-based inactivation of CYP2B6 and CYP2D6 by oxypeucedanin, characterization of the reactive metabolites associated with the enzyme inactivation, and identification of the P450s participating in the bioactivation of oxypeucedanin. METHODS: Oxypeucedanin was incubated with liver microsomes or recombinant CYPs2B6 and 2D6 under designed conditions, and the enzyme activities were measured by monitoring the generation of the corresponding products. The resulting reactive intermediates were trapped with GSH and analyzed by LC-MS/MS. RESULTS: Microsomal incubation with oxypeucedanin induced a time-, concentration-, and NADPH-dependent inhibition of CYPs2B6 and 2D6 with kinetic values of KI/kinact 1.82 µM/0.07 min-1 (CYP2B6) and 8.47 µM/0.044 min-1 (CYP2D6), respectively. Ticlopidine and quinidine attenuated the observed time-dependent enzyme inhibitions. An epoxide and/or γ-ketoenal intermediate(s) derived from oxypeucedanin was/were trapped in microsomal incubations. CYP3A4 was the primary enzyme involved in the bioactivation of oxypeucedanin. CONCLUSION: Oxypeucedanin was a mechanism-based inactivator of CYP2B6 and CYP2D6. An epoxide and/or γ- ketoenal intermediate(s) may be responsible for the inactivation of the two enzymes.

Direct laser writing for cardiac tissue engineering: a microfluidic heart on a chip with integrated transducers.

We have developed a microfluidic platform for engineering cardiac microtissues in highly-controlled microenvironments. The platform is fabricated using direct laser writing (DLW) lithography and soft lithography, and contains four separate devices. Each individual device houses a cardiac microtissue and is equipped with an integrated strain actuator and a force sensor. Application of external pressure waves to the platform results in controllable time-dependent forces on the microtissues. Conversely, oscillatory forces generated by the microtissues are transduced into measurable electrical outputs. We demonstrate the capabilities of this platform by studying the response of cardiac microtissues derived from human induced pluripotent stem cells (hiPSC) under prescribed mechanical loading and pacing. This platform will be used for fundamental studies and drug screening on cardiac microtissues.

Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency.

[Figure: see text].

Subclinical Vascular Disease Burden and Premature Mortality Among Middle-aged Adults: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Whether high burden of subclinical vascular disease (SVD) is associated with increased premature mortality among middle-aged adults is not adequately understood. The association of midlife SVD burden with premature mortality among middle-aged adults free of clinical cardiovascular disease (CVD) could provide further insights into stratifying premature death beyond clinical CVD. OBJECTIVE: To determine whether high burden of subclinical vascular disease is associated with increased premature mortality among middle-aged adults. DESIGN: We leveraged data from the Atherosclerosis Risk in Communities Study. PARTICIPANTS: Thirteen thousand eight hundred seventy-six community-dwelling blacks and whites aged 45-64 years from the Atherosclerosis Risk in Communities Study. MAIN MEASURES: Each SVD measure-ankle-brachial index, carotid intima-media thickness, and electrocardiogram-was scored 0 (no abnormalities), 1 (minor abnormalities), or 2 (major abnormalities). An index was constructed as the sum of three measures, ranging from 0 (lowest burden) to 6 (highest burden). We used the Cox proportional-hazards model to determine the association of SVD burden with premature mortality (death before age 70) among persons free of clinical CVD. We then tested the difference in point estimates between SVD and clinical CVD. KEY RESULTS: Among persons without CVD, the premature death was 1.7, 2.1, 2.5, and 3.8 per 1000 person-years among those with an SVD score of 0 (lowest burden), 1, 2, and 3-6 (highest burden), respectively. After multivariable-adjustment, highest SVD burden (score = 3-6; HR = 1.47) was significantly associated with premature death among persons initially without CVD. In the model where persons with and without CVD were included, high SVD burden (score: 3-6 vs. 0) and CVD did not have hugely different association with premature death (HR = 1.49 vs. 1.68; P = 0.32 for comparison). CONCLUSIONS: Midlife SVD burden was associated with premature mortality and it could stratify premature death beyond clinical CVD. It is important to take SVD into account when designing interventions for reducing premature mortality.

Residential Proximity to Major Roadways and Prevalent Hypertension Among Older Women and Men: Results From the Chinese Longitudinal Healthy Longevity Survey.

Background and Objectives: Prior studies suggested that residential proximity to major roadways was associated with increased risks of cardiovascular diseases in developed countries, for which one explanation is that road proximity could heighten the risks of hypertension. However, the association of residential distance to major roadways with hypertension is still unclear in low- and middle-income countries (LMICs) with levels of air pollution and socioeconomic development distinctively different from developed countries. Methods: We derived data from the eighth wave of the Chinese Longitudinal Healthy Longevity Survey, a nationwide prospective cohort. The present study included 12,881 individuals older than 65 years (mean age, 85.2 ± 11.7 years) with 55.8% of them being female. We ascertained the residential proximity to major roadways based on self-reports and hypertension was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. We then used logistic regression to examine the association between residential distance to major roadways and hypertension. Results: The odds ratios (ORs) of hypertension for participants living 50 to 100, 101 to 200, and ≥200 meters from major roads were 1.17 [95% confidence interval (95% CI) = 1.02-1.33], 1.21 (95% CI = 1.05-1.41), and 1.22 (95% CI = 1.10-1.34), respectively, compared to those living within 50 m (P for trend < 0.001). Significant effects of modifications from socioeconomic status and accessibility to health care resources were observed (Ps for interaction < 0.05). Compared to living within 50 m from a major roadway, the ORs of hypertension for living ≥50 m were higher in manual/agricultural workers, low-education groups, participants without household ventilation, and participants lacking in health education and health care resources. We observed considerable variations across geographic regions with the association in question attenuating in Eastern China but remaining significant in other regions. Conclusion: Residential proximity to major roadways was associated with lower odds of hypertension among older adults in China. The utility of residential proximity to major roadways as a marker of increased risks of hypertension and cardiovascular diseases may need to be revisited in LMICs.

Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization.

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets.