Plasma lipidomic profile of depressive symptoms: a longitudinal study in a large sample of community-dwelling American Indians in the strong heart study.

Dyslipidemia has been associated with depression, but individual lipid species associated with depression remain largely unknown. The temporal relationship between lipid metabolism and the development of depression also remains to be determined. We studied 3721 fasting plasma samples from 1978 American Indians attending two exams (2001-2003, 2006-2009, mean ~5.5 years apart) in the Strong Heart Family Study. Plasma lipids were repeatedly measured by untargeted liquid chromatography-mass spectrometry (LC-MS). Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies for Depression (CES-D). Participants at risk for depression were defined as total CES-D score ≥16. Generalized estimating equation (GEE) was used to examine the associations of lipid species with incident or prevalent depression, adjusting for covariates. The associations between changes in lipids and changes in depressive symptoms were additionally adjusted for baseline lipids. We found that lower levels of sphingomyelins and glycerophospholipids and higher level of lysophospholipids were significantly associated with incident and/or prevalent depression. Changes in sphingomyelins, glycerophospholipids, acylcarnitines, fatty acids and triacylglycerols were associated with changes in depressive symptoms and other psychosomatic traits. We also identified differential lipid networks associated with risk of depression. The observed alterations in lipid metabolism may affect depression through increasing the activities of acid sphingomyelinase and phospholipase A2, disturbing neurotransmitters and membrane signaling, enhancing inflammation, oxidative stress, and lipid peroxidation, and/or affecting energy storage in lipid droplets or membrane formation. These findings illuminate the mechanisms through which dyslipidemia may contribute to depression and provide initial evidence for targeting lipid metabolism in developing preventive and therapeutic interventions for depression.

AdipoRon Ameliorates Synaptic Dysfunction and Inhibits tau Hyperphosphorylation through the AdipoR/AMPK/mTOR Pathway in T2DM Mice.

There is growing evidence showing that adiponectin (APN) can improve Alzheimer's disease(AD)-like pathological changes by improving insulin resistance. However, the role of AdipoRon (an Adiponectin receptor agonist) on synaptic plasticity and cognitive dysfunction in the early stages of type 2 diabetes mellitus(T2DM) remains unknown. In this study, we investigated the neuroprotective effect and the molecular mechanism underlying the effect of AdipoRon in T2DM mice. We found that AdipoRon significantly restored the cognitive deficits in T2DM mice, including shorter escape latency, more crossing times, increased distances, and percentage of time in the target quadrant. In addition, AdipoRon treatment up-regulated synaptic proteins (PSD95, SYN, GAP43, and SYP), increased the number of hippocampal synapses and attenuated synaptic damage, including the length, the number and the density of dendritic spines in CA1 and DG regions. Furthermore, AdipoRon attenuated Tau phosphorylation at multiple AD-related sites (p-tau 205, p-tau 396, p-tau 404) by promoting AdipoR expression and activating the AMPK/mTOR pathway. Our data suggests that AdipoRon exerts neuroprotective effects on the T2DM mice, which may be mediated by the activation of the AdipoR/AMPK/mTOR signaling pathway.

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease.

BACKGROUND: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. RESULTS: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

O-B(F)←N Functionalized Copolymers with Delayed Fluorescence and P-Type Semiconducting Characteristics.

Conjugated polymers with integrating properties of delayed fluorescence and photovoltaic responses simultaneously are scarcely reported due to the generally contradictory requirements for molecular structures to achieve the two properties. Herein, an O-B(F)←N functionalized fused unit (M) with multiple resonance features, small energy gap between lowest singlet excited state (S1) and triplet excited state (T1) (ΔEST = 0.23 eV), and delayed fluorescence (τD = 0.75 µs), is designed. Selecting three benzodithiophene (BDT) derivatives as co-units to copolymerize with M, leading to a series of O-B(F)←N embedded polymers also maintaining delayed fluorescence (τD = 0.4-0.5 µs). Moreover, p-type semiconductor characteristics are tested for these polymers with hole mobilities in the range of 10-6-10-5 cm2/Vs. Devices with obviously photovoltaic responses are prepared using these polymers as donors and Y6 as the acceptor, affording a preliminary efficiency of 5.05%. This work successfully demonstrates an effective strategy to design conjugated polymers with integrating properties of delayed fluorescence and photovoltaic performance simultaneously by introducing O-B(F)←N functional groups to polymer backbones.

Learning from vertically distributed data across multiple sites: An efficient privacy-preserving algorithm for Cox proportional hazards model with variable selection.

OBJECTIVE: To develop a lossless distributed algorithm for regularized Cox proportional hazards model with variable selection to support federated learning for vertically distributed data. METHODS: We propose a novel distributed algorithm for fitting regularized Cox proportional hazards model when data sharing among different data providers is restricted. Based on cyclical coordinate descent, the proposed algorithm computes intermediary statistics by each site and then exchanges them to update the model parameters in other sites without accessing individual patient-level data. We evaluate the performance of the proposed algorithm with (1) a simulation study and (2) a real-world data analysis predicting the risk of Alzheimer's dementia from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Moreover, we compared the performance of our method with existing privacy-preserving models. RESULTS: Our algorithm achieves privacy-preserving variable selection for time-to-event data in the vertically distributed setting, without degradation of accuracy compared with a centralized approach. Simulation demonstrates that our algorithm is highly efficient in analyzing high-dimensional datasets. Real-world data analysis reveals that our distributed Cox model yields higher accuracy in predicting the risk of Alzheimer's dementia than the conventional Cox model built by each data provider without data sharing. Moreover, our algorithm is computationally more efficient compared with existing privacy-preserving Cox models with or without regularization term. CONCLUSION: The proposed algorithm is lossless, privacy-preserving and highly efficient to fit regularized Cox model for vertically distributed data. It provides a suitable and convenient approach for modeling time-to-event data in a distributed manner.

mTOR pathway candidate genes and physical activity interaction on breast cancer risk in black women from the women's circle of health study.

BACKGROUND: Physical activity has been shown to affect the mammalian target of rapamycin (mTOR) signaling pathway and consequently breast carcinogenesis. Given that Black women in the USA are less physically active, it is not well understood whether there are gene-environment interactions between mTOR pathway genes and physical activity in relation to breast cancer risk in Black women. METHODS: The study included 1398 Black women (567 incident breast cancer cases and 831 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with levels of vigorous physical activity in relation to breast cancer risk overall and by ER-defined subtypes using Wald test with 2-way interaction term and multivariable logistic regression. RESULTS: AKT1 rs10138227 (C > T) and AKT1 rs1130214 (C > A) were only associated with a decreased risk of ER + breast cancer among women with vigorous physical activity (odds ratio [OR] = 0.15, 95% confidence interval (CI) 0.04, 0.56, for each copy of the T allele, p-interaction = 0.007 and OR = 0.51, 95% CI 0.27, 0.96, for each copy of the A allele, p-interaction = 0.045, respectively). MTOR rs2295080 (G > T) was only associated with an increased risk of ER + breast cancer among women with vigorous physical activity (OR = 2.24, 95% CI 1.16, 4.34, for each copy of the G allele; p-interaction = 0.043). EIF4E rs141689493 (G > A) was only associated with an increased risk of ER- breast cancer among women with vigorous physical activity (OR = 20.54, 95% CI 2.29, 184.17, for each copy of the A allele; p-interaction = 0.003). These interactions became non-significant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: Our findings suggest that mTOR genetic variants may interact with physical activity in relation to breast cancer risk in Black women. Future studies should confirm these findings.

mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study.

BACKGROUND: Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. METHODS: The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. RESULTS: The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.

Improving Photovoltaic Performance of All-Polymer Solar Cells by Adding an Amorphous B←N Embedded Polymer as the Third Component.

Currently, most of the disclosed ternary strategies to improve photovoltaic performance of all-polymer solar cells (all-PSCs) commonly focus on the guest polymers having similar structures with the host polymer donors or acceptors. Herein, this work develops a distinctive ternary method that adding an amorphous B←N embedded polymer named BN-Cl-2fT to a crystallized host polymer blend of PM6 (a commercialized polymer donor) and PY-TT (a copolymer of Y6 and thieno[3,2-b]thiophene). Although the structures between BN-Cl-2fT and PM6 and PY-TT are completely different, excellent miscibility is found between BN-Cl-2fT and both of the host PM6 and PY-TT, which can be interpreted by the crowded phenyl groups anchoring along the backbone of BN-Cl-2fT, leading to weak self-aggregation. Glazing incidence wide-angle X-ray diffraction (GIWAXS) measurements explicitly confirm the crystallization of PM6 and PY-TT and amorphous feature of BN-Cl-2fT. Furthermore, adding 10 wt% BN-Cl-2fT to PM6:PY-TT can significantly enhance the crystallization of the host polymers. Thus the ternary devices based on PM6:PY-TT:BN-Cl-2fT afford promote short-circuit current density (JSC , 23.29 vs. 21.80 mA cm-2 ), fill factor (FF, 62.4% vs. 60.0%), and power conversion efficiency (PCE, 13.70% vs. 12.23%) in contrast to these parameters of binary devices based on PM6:PY-TT. This work provides a unique and enlightening avenue to design high performance all-PSCs by adding amorphous B←N embedded polymers as guest component to enhance host-crystallization.

mTOR pathway candidate genes and energy intake interaction on breast cancer risk in Black women from the Women's Circle of Health Study.

BACKGROUND: Excessive energy intake has been shown to affect the mammalian target of the rapamycin (mTOR) signaling pathway and breast cancer risk. It is not well understood whether there are gene-environment interactions between mTOR pathway genes and energy intake in relation to breast cancer risk. METHODS: The study included 1642 Black women (809 incident breast cancer cases and 833 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes and quartiles of energy intake in relation to breast cancer risk overall and by ER- defined subtypes using Wald test with a 2-way interaction term. RESULTS: AKT1 rs10138227 (C > T) was only associated with a decreased overall breast cancer risk among women in quartile (Q)2 of energy intake, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.40, 0.91 (p-interaction = 0.042). Similar results were found in ER- tumors. AKT rs1130214 (C > A) was associated with decreased overall breast cancer risk in Q2 (OR = 0.63, 95% CI 0.44, 0.91) and Q3 (OR = 0.65, 95% CI 0.48, 0.89) (p-interaction = 0.026). HIF-1α C1772T rs11549465 (C > T) was associated with decreased overall breast cancer risk in Q4 (OR = 0.29, 95% CI 0.14, 0.59, p-interaction = 0.007); the results were similar in ER+ tumors. These interactions became non-significant after correction for multiple comparisons. CONCLUSION: Our findings suggest that mTOR genetic variants may interact with energy intake in relation to breast cancer risk, including the ER- subtype, in Black women. Future studies should confirm these findings.

Shape recovery from fusion of polarization binocular vision and shading.

The shape from polarization can recover the fine texture of the target surface. However, the gradient field for shape recovery by polarization is ambiguous, which is caused by the multi-value of the azimuth angle. In response to the problem, a method of correcting the ambiguity by the fusion of polarization binocular vision and shading information is proposed in this paper. An iterative optimization algorithm is designed to estimate the direction of the light source, which provides the basis for the shading method to calculate the depth map. Additionally. the low-frequency depth map generated by binocular matching is used to correct the polarization gradient field. The polarization gradient field of the holes and small zenith angle regions in the binocular are corrected by the improved shading method. In the experiment, four different material target objects were used for shape recovery and compared with other methods. The results of the fusion method proposed are better in terms of fine texture. At the camera working distance of  700 mm, the resolving power performs well and demonstrates that changes in the depth of at least 0.1 mm can be distinguished from that recovery result.

Chitosan Microspheres Loaded with Curcumin and Gallic Acid: Modified Synthesis, Sustainable Slow Release, and Enhanced Biological Property.

Improving the utilization rate of loaded-drugs is of huge importance for generating chitosan-based (CS) micro-carriers. This study aims to fabricate a novel CS microspheres co-delivered curcumin (Cur) and gallic acid (Ga) to assess drug loading and release kinetics, the blood compatibility and anti-osteosarcoma properties. The present study observes the interaction between CS and Cur/Ga molecules and estimates the change in crystallinity and loading and release rate. In addition, blood compatibility and cytotoxicity of such microspheres are also evaluated. Cur-Ga-CS microspheres present high entrapment rate of (55.84 ± 0.34) % for Ga and (42.68 ± 0.11) % for Cur, possibly attributed to surface positive charge (21.76 ± 2.46) mV. Strikingly, Cur-Ga-CS microspheres exhibit slowly sustainable release for almost 7 days in physiological buffer. Importantly, these microspheres possess negligibly toxic to blood and normal BMSC cells, but strong anti-osteosarcoma effect on U2OS cells. Overall, Cur-Ga-CS microspheres are promising to become a novel anti-osteosarcoma agent or sustainable delivery carrier in biomedical applications.

Fine-mapping and replication of EWAS loci harboring putative epigenetic alterations associated with AD neuropathology in a large collection of human brain tissue samples.

INTRODUCTION: Our previous epigenome-wide association study (EWAS) of Alzheimer's disease (AD) in human brain identified 71 CpGs associated with AD pathology. However, due to low coverage of the Illumina platform, many important CpGs might have been missed. METHODS: In a large collection of human brain tissue samples (N = 864), we fine-mapped previous EWAS loci by targeted bisulfite sequencing and examined their associations with AD neuropathology. DNA methylation was also linked to gene expression of the same brain cortex. RESULTS: Our targeted sequencing captured 130 CpGs (∼1.2 kb), 93 of which are novel. Of the 130 CpGs, 57 sites (only 17 included in previous EWAS) and 12 gene regions (e.g., ANK1, BIN1, RHBDF2, SPG7, PODXL) were significantly associated with amyloid load. DNA methylation in some regions was associated with expression of nearby genes. DISCUSSION: Targeted methylation sequencing can validate previous EWAS loci and discover novel CpGs associated with AD pathology.

Lipidomic profiling in the Strong Heart Study identified American Indians at risk of chronic kidney disease.

Dyslipidemia associates with and usually precedes the onset of chronic kidney disease (CKD), but a comprehensive assessment of molecular lipid species associated with risk of CKD is lacking. Here, we sought to identify fasting plasma lipids associated with risk of CKD among American Indians in the Strong Heart Family Study, a large-scale community-dwelling of individuals, followed by replication in Mexican Americans from the San Antonio Family Heart Study and Caucasians from the Australian Diabetes, Obesity and Lifestyle Study. We also performed repeated measurement analysis to examine the temporal relationship between the change in the lipidome and change in kidney function between baseline and follow-up of about five years apart. Network analysis was conducted to identify differential lipid classes associated with risk of CKD. In the discovery cohort, we found that higher baseline level of multiple lipid species, including glycerophospholipids, glycerolipids and sphingolipids, was significantly associated with increased risk of CKD, independent of age, sex, body mass index, diabetes and hypertension. Many lipid species were replicated in at least one external cohort at the individual lipid species and/or the class level. Longitudinal change in the plasma lipidome was significantly associated with change in the estimated glomerular filtration rate after adjusting for covariates, baseline lipids and the baseline rate. Network analysis identified distinct lipidomic signatures differentiating high from low-risk groups. Thus, our results demonstrated that disturbed lipid metabolism precedes the onset of CKD. These findings shed light on the mechanisms linking dyslipidemia to CKD and provide potential novel biomarkers for identifying individuals with early impaired kidney function at preclinical stages.

PM2.5 Constituents and Onset of Gestational Diabetes Mellitus: Identifying Susceptible Exposure Windows.

Fine particulate matter (PM2.5) has been linked to gestational diabetes mellitus (GDM). However, PM2.5 is a complex mixture with large spatiotemporal heterogeneities, and women with early-onset GDM (i.e., diagnosed before 24th gestation week) have distinct maternal characteristics and a higher risk of worse health outcomes compared with those with late-onset GDM (i.e., diagnosed in or after 24th gestation week). We aimed to examine differential impacts of PM2.5 and its constituents on early- vs. late-onset GDM, and to identify corresponding susceptible exposure windows. We leveraged statewide linked electronic health records and birth records data in Florida in 2012-2017. Exposures to PM2.5 and its constituents (i.e., sulfate [SO4 2-], ammonium [NH4 +], nitrate [NO3 -], organic matter [OM], black carbon [BC], mineral dust [DUST], and sea-salt [SS]) were spatiotemporally linked to pregnant women based on their residential histories. Cox proportional hazards models and multinomial logistic regression were used to examine the associations of PM2.5 and its constituents with GDM and its onsets. Distributed non-linear lag models were implemented to identify susceptible exposure windows. Exposures to PM2.5, SO4 2-, NH4 +, and BC were statistically significantly associated with higher hazards of GDM. Exposures to PM2.5 during weeks 1-12 of gestation were positively associated with GDM. Associations of early-onset GDM with PM2.5 in the 1st and 2nd trimesters, SO4 2- in the 1st and 2nd trimesters, and NO3 - in the preconception and 1st trimester were considerably stronger than observations for late-onset GDM. Our findings suggest there are differential associations of PM2.5 and its constituents with early- vs. late-onset GDM, with different susceptible exposure windows. This study helps better understand the impacts of air pollution on GDM accounting for its physiological heterogeneity.

Characterization of Glycosphingolipids and Their Diverse Lipid Forms through Two-Stage Matching of LC-MS/MS Spectra.

Glycosphingolipids (GSLs) play a key role in various biological and pathological events. Thus, determination of the complete GSL compositions in human tissues is essential for comparative and functional studies of GSLs. In this work, a new strategy was developed for GSL characterization and glycolipidomics analysis based on two-stage matching of experimental and reference MS/MS spectra. In the first stage, carbohydrate fragments, which contain only glycans and thus are conserved within a GSL species, are directly matched to yield a species identification. In the second stage, glycolipid fragments from the matched GSL species, which contain both the lipid and glycans and thus shift due to lipid structural changes, are treated according to lipid rule-based matching to characterize the lipid compositions. This new strategy uses the whole spectrum for GSL characterization. Furthermore, simple databases containing only a single lipid form per GSL species can be utilized to identify multiple GSL lipid forms. It is expected that this method will help accelerate glycolipidomics analysis and disclose new and diverse lipid forms of GSLs.

Design and methodology challenges of environment-wide association studies: A systematic review.

Environment-wide association studies (EWAS) are an untargeted, agnostic, and hypothesis-generating approach to exploring environmental factors associated with health outcomes, akin to genome-wide association studies (GWAS). While design, methodology, and replicability standards for GWAS are established, EWAS pose many challenges. We systematically reviewed published literature on EWAS to categorize scope, impact, types of analytical approaches, and open challenges in designs and methodologies. The Web of Science and PubMed databases were searched through multiple queries to identify EWAS articles between January 2010 and December 2018, and a systematic review was conducted following the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) reporting standard. Twenty-three articles met our inclusion criteria and were included. For each study, we categorized the data sources, the definitions of study outcomes, the sets of environmental variables, and the data engineering/analytical approaches, e.g. neighborhood definition, variable standardization, handling of multiple hypothesis testing, model selection, and validation. We identified limited exploitation of data sources, high heterogeneity in analytical approaches, and lack of replication. Despite of the promising utility of EWAS, further development of EWAS will require improved data sources, standardization of study designs, and rigorous testing of methodologies.

Quercetin suppresses migration and invasion by targeting miR-146a/GATA6 axis in fibroblast-like synoviocytes of rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a systematic autoimmune disease which may lead to joint dysfunction and disability. Aberrant migration and invasion of fibroblast-like synoviocytes (FLSs) is one of the most predominant etiopathogenesis of RA. Quercetin is a bioflavonoid which is implicated in the development of RA, yet its role in regulating the migration and invasion of FLSs is still elusive. The aim of this study is to investigate the impact of quercetin treatment on migration and invasion of FLSs and the underlying mechanism.Methods: Capacity of migration and invasion of FLSs were assessed using transwell assay. Immunofluorescence assay was used to determine the expression of F-actin. The RNA levels of miR-146a and GATA transcription factor 6 (GATA6) were measured using quantitative real-time PCR. Western blot was used to examine the protein level of GATA6. The correlation between miR-146a and GATA6 was validated using luciferase reporter assay.Results: Transwell assay revealed that the migration and invasion of FLSs were significantly inhibited after quercetin treatment, which was also proved by decreased expression of F-actin. The RNA level of miR-146a was decreased in RA tissues and was negatively related to the expression of GATA transcription factor 6 (GATA6). Quercetin treatment elevated the RNA level of miR-146a, but suppressed the expression of GATA6 in FLSs. Further luciferase reporter assay validated that GATA6 is a downstream target of miR-146a. Besides, miR-146a inhibited the migration and invasion of FLSs, and further GATA6 over-expression abrogated the miR-146a-induced inhibition. In addition, specific anti-miR-146a inhibitor abolished quercetin-mediated suppression of migration and invasion of FLSs.Conclusion: Our study suggested that quercetin suppresses the migration and invasion of FLSs via regulating the miR-146a/GATA6 axis.

Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes.

RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (

Targeted metabolomics to understand the association between arsenic metabolism and diabetes-related outcomes: Preliminary evidence from the Strong Heart Family Study.

BACKGROUND: Inorganic arsenic exposure is ubiquitous and both exposure and inter-individual differences in its metabolism have been associated with cardiometabolic risk. A more efficient arsenic metabolism profile (lower MMA%, higher DMA%) has been associated with reduced risk for arsenic-related health outcomes. This profile, however, has also been associated with increased risk for diabetes-related outcomes. OBJECTIVES: The mechanism behind these conflicting associations is unclear; we hypothesized the one-carbon metabolism (OCM) pathway may play a role. METHODS: We evaluated the influence of OCM on the relationship between arsenic metabolism and diabetes-related outcomes (HOMA2-IR, waist circumference, fasting plasma glucose) using metabolomic data from an OCM-specific and P180 metabolite panel measured in plasma, arsenic metabolism measured in urine, and HOMA2-IR and FPG measured in fasting plasma. Samples were drawn from baseline visits (2001-2003) in 59 participants from the Strong Heart Family Study, a family-based cohort study of American Indians aged ≥14 years from Arizona, Oklahoma, and North/South Dakota. RESULTS: In unadjusted analyses, a 5% increase in DMA% was associated with higher HOMA2-IR (geometric mean ratio (GMR)= 1.13 (95% CI: 1.03, 1.25)) and waist circumference (mean difference=3.66 (0.95, 6.38). MMA% was significantly associated with lower HOMA2-IR and waist circumference. After adjustment for OCM-related metabolites (SAM, SAH, cysteine, glutamate, lysophosphatidylcholine 18.2, and three phosphatidlycholines), associations were attenuated and no longer significant. CONCLUSIONS: These preliminary results indicate that the association of lower MMA% and higher DMA% with diabetes-related outcomes may be influenced by OCM status, either through confounding, reverse causality, or mediation.

Telomere Length and Magnetic Resonance Imaging Findings of Vascular Brain Injury and Central Brain Atrophy: The Strong Heart Study.

Telomeres are repeating regions of DNA that cap chromosomes. They shorten over the mammalian life span, especially in the presence of oxidative stress and inflammation. Telomeres may play a direct role in cell senescence, serving as markers of premature vascular aging. Leukocyte telomere length (LTL) may be associated with premature vascular brain injury and cerebral atrophy. However, reports have been inconsistent, especially among minority populations with a heavy burden of illness related to vascular aging. We examined associations between LTL and magnetic resonance imaging in 363 American Indians aged 64-93 years from the Strong Heart Study (1989-1991) and its ancillary study, Cerebrovascular Disease and Its Consequences in American Indians (2010-2013). Our results showed significant associations of LTL with ventricular enlargement and the presence of white matter hyperintensities. Secondary models indicated that renal function may mediate these associations, although small case numbers limited inference. Hypertension and diabetes showed little evidence of effect modification. Results were most extreme among participants who evinced the largest decline in LTL. Although this study was limited to cross-sectional comparisons, it represents (to our knowledge) the first consideration of associations between telomere length and brain aging in American Indians. Findings suggest a relationship between vascular aging by cell senescence and severity of brain disease.