Association analysis of mitochondrial DNA heteroplasmic variants: Methods and application.

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31 % of African Ancestry, mean age of 62, with 58 % women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p < 0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p < 0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

The effectiveness of intravenous zoledronic acid in elderly patients with osteoporosis after rotator cuff repair: a retrospective study.

The aim of this study was to investigate the effect of zoledronic acid (ZA) on postoperative healing and functional rehabilitation in osteoporotic patients with rotator cuff (RC) injury. 96 Patients were divided into three groups according to bone mineral density and ZA use (Group A: normal BMD; Group B: osteoporosis and intravenous ZA use; Group C: osteoporosis, without ZA use). Radiologic, functional and Serological outcomes were evaluated 6 months after surgery. The functional scores in all groups exhibited significant improvement 6 months after surgery. Inter-group comparison showed that Constant Shoulder joint function Score (CSS) of group A not significantly differing from that of group B, the other indicators were significantly better than those of group B and C. There were no significant differences in shoulder forward flexion, abductive Range of Motion between group B and C. Other indicators of group B were significantly improved compared to group C. The retear rate in group C (30.3%, 10/33) was higher than group A (6.1%, 2/33) and group B (13.3%, 4/30). In conclusion, the application of ZA can significantly reduce the rate of RC retear in elderly patients with osteoporosis after surgery, which is significant for postoperative shoulder joint functional rehabilitation.

Exploring Unique Extracellular Vesicles Associated Signatures: Prognostic Insights, Immune Microenvironment Dynamics, and Therapeutic Responses in Pancreatic Adenocarcinoma.

Extracellular vesicles play an important role in the progression of pancreatic adenocarcinoma (PAAD) through the transfer of proteins, mRNAs, and long noncoding RNAs (lncRNAs). However, the intricate interplay between extracellular vesicles-related lncRNAs and the tumor microenvironment (TME) remains poorly elucidated. Consequently, our investigation aimed to delineate the association between extracellular vesicles-related lncRNAs and the PAAD microenvironment. Initially, we identified differentially expressed lncRNAs (DELs) from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project datasets. Subsequently, we validated the expression of these DELs within extracellular vesicles and assessed their prognostic implications in PAAD using the GSE133684 and TCGA datasets. Multiomics data were analyzed comprehensively, including genomic landscape, functional annotation, immune profiles, and therapeutic responses. Differential expression of selected lncRNAs in both cellular and exosomal fractions of PAAD was further confirmed through quantitative polymerase chain reaction (qPCR). Eight DELs were identified from TCGA and GTEx datasets, and two exosomal lncRNAs exhibited a significant correlation with overall survival, warranting further investigation. Specifically, elevated expression of LINC00996 correlated positively with immune infiltration and enhanced response to immunotherapy. Conversely, heightened expression of TRHED-AS1 was associated with compromised immune cell infiltration and diminished responsiveness to immunotherapy. Our study establishes a compelling link between two extracellular vesicles-related gene signatures, prognosis, and immune infiltration in PAAD. Notably, these signatures serve as robust prognostic indicators for PAAD patients, offering valuable insights for the strategic selection of immunotherapeutic interventions.

Decreased histone H3K9 dimethylation in synergy with DNA demethylation of Spi-1 binding site contributes to ADAMTS-5 expression in articular cartilage of osteoarthritis mice.

Osteoarthritis (OA) is defined by articular cartilage degeneration, synovial membrane inflammation, and abnormal bone remodeling. Recent study has discovered that OA development is linked to an aberrant epigenetic modification of OA-related genes. Our previous research showed that DNA demethylation in ADAMTS-5 promoter region had a substantial impact on ADAMTS-5 expression in the mouse OA model. This process facilitated the binding of Spi-1 to ADAMTS-5 promoter. While alterations in histone methylation have been documented during embryonic development and cancer development, there is a paucity of data on the change in OA pathogenesis. Even no data have been reported on the role of histone modifications in ADAMTS-5 activation in OA. Following our previous study on the role of DNA methylation, we aimed to examine the contribution of histone H3K9 dimethylation in ADAMTS-5 activation in OA. Additionally, we aimed to elucidate the molecular mechanisms underlying the cooperative interaction between DNA methylation and histone H3K9 dimethylation. The potential for anti-OA intervention therapy which is based on modulating histone H3K9 dimethylation is also explored. We demonstrated that a reduction in histone H3K9 dimethylation, along with DNA demethylation of the Spi-1 binding site, had a role in ADAMTS-5 activation in the articular cartilage of OA mice. Significantly, the conditional deletion of histone demethylase to be identified as lysine-specific demethylase 1 (LSD1) in articular cartilage could alleviate the degenerative features of OA mice. Our study demonstrates the direct impact of histone H3K9 dimethylation on gene expression, which in turn contributes to OA development. This research enhances our understanding of the underlying causes of OA.

Polyethylene imine-modified photonic crystal microfluidic chip for highly sensitive detection of microbial spores.

To address the lengthy cycles, complex operations, high costs, and insufficient sensitivity of biomarker detection in traditional biological control agents, photonic crystal treated with PEI was developed for highly sensitive detection of Sclerotinia sclerotiorum microbial spores. By incorporating gelatin molecules, photonic crystal is endowed with excellent photothermal stability and high stability in aqueous solutions. The photonic crystal surface is conferred a positive charge by PEI, which can be used to enhance the adsorption of spores. Efficient enrichment of Sclerotinia sclerotiorum and Purpureocillium lilacinum spores is achieved, with coefficients of determination 0.963 and 0.971, respectively. The detection range is from 102 to 106 spores/ml, and the photonic crystal exhibited good reusability. The prepared photonic crystal enables rapid, non-destructive, and accurate quantitative detection of microbial spores.

Agreement Between Apple Watch and Actical Step Counts in a Community Setting: Cross-Sectional Investigation From the Framingham Heart Study.

BACKGROUND: Step counting is comparable among many research-grade and consumer-grade accelerometers in laboratory settings. OBJECTIVE: The purpose of this study was to compare the agreement between Actical and Apple Watch step-counting in a community setting. METHODS: Among Third Generation Framingham Heart Study participants (N=3486), we examined the agreement of step-counting between those who wore a consumer-grade accelerometer (Apple Watch Series 0) and a research-grade accelerometer (Actical) on the same days. Secondarily, we examined the agreement during each hour when both devices were worn to account for differences in wear time between devices. RESULTS: We studied 523 participants (n=3223 person-days, mean age 51.7, SD 8.9 years; women: n=298, 57.0%). Between devices, we observed modest correlation (intraclass correlation [ICC] 0.56, 95% CI 0.54-0.59), poor continuous agreement (29.7%, n=957 of days having steps counts with ≤15% difference), a mean difference of 499 steps per day higher count by Actical, and wide limits of agreement, roughly ±9000 steps per day. However, devices showed stronger agreement in identifying who meets various steps per day thresholds (eg, at 8000 steps per day, kappa coefficient=0.49), for which devices were concordant for 74.8% (n=391) of participants. In secondary analyses, in the hours during which both devices were worn (n=456 participants, n=18,760 person-hours), the correlation was much stronger (ICC 0.86, 95% CI 0.85-0.86), but continuous agreement remained poor (27.3%, n=5115 of hours having step counts with ≤15% difference) between devices and was slightly worse for those with mobility limitations or obesity. CONCLUSIONS: Our investigation suggests poor overall agreement between steps counted by the Actical device and those counted by the Apple Watch device, with stronger agreement in discriminating who meets certain step thresholds. The impact of these challenges may be minimized if accelerometers are used by individuals to determine whether they are meeting physical activity guidelines or tracking step counts. It is also possible that some of the limitations of these older accelerometers may be improved in newer devices.

Silver coated PS microsphere array SERS microfluidic chip for pesticide detection.

Carbendazim and acetamidine are pesticides that widely used to control pests and diseases in oilseed rape. In this paper, a rapid, accurate and reliable method was proposed for the detection of carbendazim and acetamidine with SERS microfluidic chip technology. Ag-ps(Polystyrene microspheres) microsphere SERS substrate was prepared by spin coating and magnetron sputtering deposition of Ag. The enhancement factor of prepared SERS substrate was 2.4 × 1010. The SERS detection working curves were well fitted and the linear parameters R2 were 0.987 and 0.994, respectively. The limit of detection was 0.01 mg/mL. The use of SERS microfluidic chip to detect carbendazim and acetamidine is expected to provide a way for the detection of pesticide residues in crops, which has broad application prospects in the field of food safety.

g-C3N4 modified natural low-grade dolomite-palygorskite: Removal capacity and adsorption mechanism for Gd3.

Rare earth elements (REEs) pose significant environmental challenges due to the wastewater generated during their extraction. Developing efficient adsorbents with simple, economical and eco-friendly methods for removing and recovering REEs from wastewater is highly demanded but full of challenges. This study creates a novel adsorbent (g-C3N4/0.5DPal) for efficient REEs removal and recovery by integrating the low-grade mineral dolomite-palygorskite with g-C3N4 through a "one-pot" calcination method. Characterization techniques including SEM, XRD, FT-IR, XPS, etc., were employed to analyze the structure of the g-C3N4/0.5DPal composite. Batch adsorption experiments focusing on Gd3+ from among the REEs were conducted to evaluate the adsorption performance. The results reveal a remarkable 3.34 times increase in Gd3+ adsorption capacity of g-C3N4/0.5DPal (192.46 mg/g) compared to raw dolomite-palygorskite (57.62 mg/g) at 298 K, highlighting the effectiveness of the modification. The adsorption mechanism involves electrostatic interactions, surface complexation, and cation-π interactions. It is worth noting that g-C3N4 facilitates the conversion of dolomite to calcite during the preparation process, enhancing the Gd3+ adsorption of g-C3N4/0.5DPal. This work offers a promising solution for the removal and recovery of REEs and the high-value utilization of low-grade minerals, addressing both environmental concerns and resource sustainability.

Association of Smartwatch-Based Heart Rate and Physical Activity With Cardiorespiratory Fitness Measures in the Community: Cohort Study.

BACKGROUND: Resting heart rate (HR) and routine physical activity are associated with cardiorespiratory fitness levels. Commercial smartwatches permit remote HR monitoring and step count recording in real-world settings over long periods of time, but the relationship between smartwatch-measured HR and daily steps to cardiorespiratory fitness remains incompletely characterized in the community. OBJECTIVE: This study aimed to examine the association of nonactive HR and daily steps measured by a smartwatch with a multidimensional fitness assessment via cardiopulmonary exercise testing (CPET) among participants in the electronic Framingham Heart Study. METHODS: Electronic Framingham Heart Study participants were enrolled in a research examination (2016-2019) and provided with a study smartwatch that collected longitudinal HR and physical activity data for up to 3 years. At the same examination, the participants underwent CPET on a cycle ergometer. Multivariable linear models were used to test the association of CPET indices with nonactive HR and daily steps from the smartwatch. RESULTS: We included 662 participants (mean age 53, SD 9 years; n=391, 59% women, n=599, 91% White; mean nonactive HR 73, SD 6 beats per minute) with a median of 1836 (IQR 889-3559) HR records and a median of 128 (IQR 65-227) watch-wearing days for each individual. In multivariable-adjusted models, lower nonactive HR and higher daily steps were associated with higher peak oxygen uptake (VO2), % predicted peak VO2, and VO2 at the ventilatory anaerobic threshold, with false discovery rate (FDR)-adjusted P values <.001 for all. Reductions of 2.4 beats per minute in nonactive HR, or increases of nearly 1000 daily steps, corresponded to a 1.3 mL/kg/min higher peak VO2. In addition, ventilatory efficiency (VE/VCO2; FDR-adjusted P=.009), % predicted maximum HR (FDR-adjusted P<.001), and systolic blood pressure-to-workload slope (FDR-adjusted P=.01) were associated with nonactive HR but not associated with daily steps. CONCLUSIONS: Our findings suggest that smartwatch-based assessments are associated with a broad array of cardiorespiratory fitness responses in the community, including measures of global fitness (peak VO2), ventilatory efficiency, and blood pressure response to exercise. Metrics captured by wearable devices offer a valuable opportunity to use extensive data on health factors and behaviors to provide a window into individual cardiovascular fitness levels.

Seismic noise in South China Sea: High-quality time-frequency analysis from 0.01 to 125 Hz.

An efficient and precise time-frequency analysis method for real-time ocean bottom seismometer (RTOBS) data in the South China Sea (SCS) is presented. Overcoming the limitations of conventional methods, the method involves temporal segmentation, unique frequency octaves, and Fourier transforms to generate power spectral density (PSD) and probability density function profiles. The method demonstrates superior precision, computational efficiency, and full-bandwidth (0 to Nyquist) capability compared to traditional techniques, as validated through theoretical and empirical evaluations. Applied to SCS RTOBS data, it unveils temporal PSD variations, shedding light on underwater noise sources like earthquakes, offshore blasting, ship-induced disturbances, and tidal effects. Establishing background noise levels in the SCS supports noise source categorization and ocean environment monitoring. Furthermore, comparing onshore and offshore seismic stations advances interdisciplinary research, fostering a comprehensive understanding of acoustics and seismology in the region.

Smartphone App Designed to Collect Health Information in Older Adults: Usability Study.

BACKGROUND: Studies evaluating the usability of mobile-phone assessments in older adults are limited. OBJECTIVE: This study aims to identify design-based barriers and facilitators to mobile app survey completion among 2 samples of older adults; those in the Framingham Heart Study and a more diverse sample from a hospital-based setting. METHODS: We used mixed methods to identify challenging and beneficial features of the mobile app in participants from the electronic Framingham Heart Study (n=15; mean age of 72 years; 6/15, 40% women; 15/15, 100% non-Hispanic and White) and among participants recruited from a hospital-based setting (n=15; mean age of 71 years; 7/15, 47% women; 3/15, 20% Hispanic; and 8/15, 53% non-White). A variety of app-based measures with different response formats were tested, including self-reported surveys, pictorial assessments (to indicate body pain sites), and cognitive testing tasks (eg, Trail Making Test and Stroop). Participants completed each measure using a think-aloud protocol, while being audio- and video-recorded with a qualitative interview conducted at the end of the session. Recordings were coded for participant usability errors by 2 pairs of coders. Participants completed the Mobile App Rating Scale to assess the app (response range 1=inadequate to 5=excellent). RESULTS: In electronic Framingham Heart Study participants, the average total Mobile App Rating Scale score was 7.6 (SD 1.1), with no significant differences in the hospital-based sample. In general, participants were pleased with the app and found it easy to use. A large minority had at least 1 navigational issue, most committed only once. Most older adults did not have difficulty completing the self-reported multiple-choice measures unless it included lengthy instructions but participants had usability issues with the Stroop and Trail Making Test. CONCLUSIONS: Our methods and results help guide app development and app-based survey construction for older adults, while also giving consideration to sociodemographic differences.

Association of Arterial Stiffness With Mid- to Long-Term Home Blood Pressure Variability in the Electronic Framingham Heart Study: Cohort Study.

BACKGROUND: Short-term blood pressure variability (BPV) is associated with arterial stiffness in patients with hypertension. Few studies have examined associations between arterial stiffness and digital home BPV over a mid- to long-term time span, irrespective of underlying hypertension. OBJECTIVE: This study aims to investigate if arterial stiffness traits were associated with subsequent mid- to long-term home BPV in the electronic Framingham Heart Study (eFHS). We hypothesized that higher arterial stiffness was associated with higher home BPV over up to 1-year follow-up. METHODS: At a Framingham Heart Study research examination (2016-2019), participants underwent arterial tonometry to acquire measures of arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]; forward pressure wave amplitude [FWA]) and wave reflection (reflection coefficient [RC]). Participants who agreed to enroll in eFHS were provided with a digital blood pressure (BP) cuff to measure home BP weekly over up to 1-year follow-up. Participants with less than 3 weeks of BP readings were excluded. Linear regression models were used to examine associations of arterial measures with average real variability (ARV) of week-to-week home systolic (SBP) and diastolic (DBP) BP adjusting for important covariates. We obtained ARV as an average of the absolute differences of consecutive home BP measurements. ARV considers not only the dispersion of the BP readings around the mean but also the order of BP readings. In addition, ARV is more sensitive to measurement-to-measurement BPV compared with traditional BPV measures. RESULTS: Among 857 eFHS participants (mean age 54, SD 9 years; 508/857, 59% women; mean SBP/DBP 119/76 mm Hg; 405/857, 47% hypertension), 1 SD increment in FWA was associated with 0.16 (95% CI 0.09-0.23) SD increments in ARV of home SBP and 0.08 (95% CI 0.01-0.15) SD increments in ARV of home DBP; 1 SD increment in RC was associated with 0.14 (95% CI 0.07-0.22) SD increments in ARV of home SBP and 0.11 (95% CI 0.04-0.19) SD increments in ARV of home DBP. After adjusting for important covariates, there was no significant association between CFPWV and ARV of home SBP, and similarly, no significant association existed between CFPWV and ARV of home DBP (P>.05). CONCLUSIONS: In eFHS, higher FWA and RC were associated with higher mid- to long-term ARV of week-to-week home SBP and DBP over 1-year follow-up in individuals across the BP spectrum. Our findings suggest that higher aortic stiffness and wave reflection are associated with higher week-to-week variation of BP in a home-based setting over a mid- to long-term time span.

Paucatalinone A from Paulownia Catalpifolia Gong Tong Elicits mitochondrial-mediated cancer cell death to combat osteosarcoma.

As the global cancer burden escalates, the search for alternative therapies becomes increasingly vital. Natural products, particularly plant-derived compounds, have emerged as promising alternatives to conventional cancer treatments due to their diverse bioactivities and favorable biosafety profiles. Here, we investigate Paucatalinone A, a newly discovered geranylated flavanone derived from the fruit of Paulownia Catalpifolia Gong Tong, notable for its significant anti-cancer properties. We revealed the capability of Paucatalinone A to induce apoptosis in osteosarcoma cells and deciphered its underlying mechanisms. Our findings demonstrate that Paucatalinone A substantially augments apoptosis, inhibits cell proliferation, and demonstrates a pronounced anti-tumor effect in a murine model of osteosarcoma. Mechanistically, Paucatalinone A disrupts calcium homeostasis and exacerbates intracellular reactive oxygen species accumulation, leading to mitochondrial impairment, cytoskeletal collapse, and caspase-dependent apoptotic cell death. This study underscores the potential of Paucatalinone A in initiating apoptosis in cancer cells and highlights the therapeutic efficacy of plant-derived agents in treating osteosarcoma, offering a viable approach for managing other intractable cancers.

Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p<0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p<0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

A novel injectable hydrogel prepared from phenylboronic acid modified gelatin and oxidized-dextran for bone tissue engineering.

Complicated fractures have always been challenging in orthopaedics. Designing a multifunctional biomaterial that can contribute to the treatment of fractures using a simple operation remains challenging. Here, we developed a trinity hydrogel system consisting of hydrogel prepared from phenylboronic acid modified gelatin and oxidized-dextran, lithium and cobalt co-doped mesoporous bioactive glass nanoparticles (MBGNs), and irisin. This hydrogel material exhibits considerable injectability, fat-to-shape, and self-healing characteristics. In addition, compared to hydrogel prepared from gelatin and oxidized-dextran, the hydrogel material presented a noticeable enhancement in compression stress and adhesion strength towards porcine bone fragments, which enables it more effectively splice bone fragments during surgery. Based on the various interactions between irisin and the hydrogel network, the system exhibited a clear sustained release of irisin. Based on the results of in vitro cell tests, the hydrogel material showed good cytocompatibility. And it also considerably enhanced the in vitro pro-osteogenic and pro-angiogenic capacities of bone marrow mesenchymal stromal cells (BMSCs) and human umbilical vein endothelial cells (HUVECs). In vivo experimental results indicated that this hydrogel considerably improved the repair of cranial defects in rats. The current study provides a feasible strategy for the treatment of bone fractures and stimulation of fracture healing.

DNA demethylation of promoter region orchestrates SPI-1-induced ADAMTS-5 expression in articular cartilage of osteoarthritis mice.

Osteoarthritis (OA) is one of the most prevalent joint diseases in aged people and characterized by articular cartilage degeneration, synovial inflammation, and abnormal bone remodeling. Recent advances in OA research have clearly shown that OA development is associated with aberrant DNA methylation status of many OA-related genes. As one of most important cartilage degrading proteases in OA, a disintegrin and metalloproteinase with thrombospondin motifs subtype 5 (ADAMTS-5) is activated to mediate cartilage degradation in human OA and experimental murine OA models. The pathological factors and signaling pathways mediating ADAMTS-5 activation during OA development are not well defined and have been a focus of intense research. ADAMTS-5 promoter is featured by CpG islands. So far there have been no reports concerning the DNA methylation status in ADAMTS-5 promoter during OA development. In this study, we sought to investigate DNA methylation status in ADAMTS-5 promoter, the role of DNA methylation in ADAMTS-5 activation in OA, and the underlying mechanisms. The potential for anti-OA intervention therapy which is based on modulating DNA methylation is also explored. Our results showed that DNA methyltransferases 1 (Dnmt1) downregulation-associated ADAMTS-5 promoter demethylation played an important role in ADAMTS-5 activation in OA, which facilitated SPI-1 binding on ADAMTS-5 promoter to activate ADAMTS-5 expression. More importantly, OA pathological phenotype of mice was alleviated in response to Dnmt1-induced DNA methylation of ADAMTS-5 promoter. Our study will benefit not only for deeper insights into the functional role and regulation mechanisms of ADAMTS-5 in OA, but also for the discovery of disease-modifying OA drugs on the basis of ADAMTS-5 via modulating DNA methylation status.

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P<0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; P<0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (ß=0.091; P=0.11) or in the reverse direction (ß=-0.012; P=0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (ß=-0.084; P<0.001), but the reverse direction was not significant (P=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (P=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (ß=-0.092; P<0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Association of Depressive Symptom Trajectory With Physical Activity Collected by mHealth Devices in the Electronic Framingham Heart Study: Cohort Study.

BACKGROUND: Few studies have examined the association between depressive symptom trajectories and physical activity collected by mobile health (mHealth) devices. OBJECTIVE: We aimed to investigate if antecedent depressive symptom trajectories predict subsequent physical activity among participants in the electronic Framingham Heart Study (eFHS). METHODS: We performed group-based multi-trajectory modeling to construct depressive symptom trajectory groups using both depressive symptoms (Center for Epidemiological Studies-Depression [CES-D] scores) and antidepressant medication use in eFHS participants who attended 3 Framingham Heart Study research exams over 14 years. At the third exam, eFHS participants were instructed to use a smartphone app for submitting physical activity index (PAI) surveys. In addition, they were provided with a study smartwatch to track their daily step counts. We performed linear mixed models to examine the association between depressive symptom trajectories and physical activity including app-based PAI and smartwatch-collected step counts over a 1-year follow-up adjusting for age, sex, wear hour, BMI, smoking status, and other health variables. RESULTS: We identified 3 depressive symptom trajectory groups from 722 eFHS participants (mean age 53, SD 8.5 years; n=432, 60% women). The low symptom group (n=570; mean follow-up 287, SD 109 days) consisted of participants with consistently low CES-D scores, and a small proportion reported antidepressant use. The moderate symptom group (n=71; mean follow-up 280, SD 118 days) included participants with intermediate CES-D scores, who showed the highest and increasing likelihood of reporting antidepressant use across 3 exams. The high symptom group (n=81; mean follow-up 252, SD 116 days) comprised participants with the highest CES-D scores, and the proportion of antidepressant use fell between the other 2 groups. Compared to the low symptom group, the high symptom group had decreased PAI (mean difference -1.09, 95% CI -2.16 to -0.01) and the moderate symptom group walked fewer daily steps (823 fewer, 95% CI -1421 to -226) during the 1-year follow-up. CONCLUSIONS: Antecedent depressive symptoms or antidepressant medication use was associated with lower subsequent physical activity collected by mHealth devices in eFHS. Future investigation of interventions to improve mood including via mHealth technologies to help promote people's daily physical activity is needed.

Comprehensive analysis of m6A RNA methylation modification patterns and the immune microenvironment in osteoarthritis.

Background: Osteoarthritis (OA) is the most common joint degenerative disease, and so far, there is no effective therapy to prevent or delay its development. Considerable attention is now being given to the impact of m6A RNA methylation modification on the disease immune regulation. However, much remains unknown about the function of m6A modification in OA. Methods: A total of 63 OA and 59 healthy samples were applied to comprehensively examine the m6A regulators mediated RNA methylation modification pattern in OA, and evaluate the impacts of distinct patterns on the characteristics of OA immune microenvironment, including immune infiltration cells, immune responses and human leukocyte antigen (HLAs) genes expression. In addition, we screened out the m6A phenotype-related genes and further explored their potential biological functions. At last, we verified the expression of key m6A regulators and their associations with immune cells, in vitro. Results: Most of m6A regulators was differentially expressed in OA samples compared to the normal tissues. Based on six hub-m6A regulators identified as abnormally expressed in OA samples, we developed a classifier to distinguish OA patients from healthy individuals. We noted that immune characteristics of OA were correlated with m6A regulators. For instance, YTHDF2 had a strongest significantly positive correlation with regulatory T cells (Tregs) and IGFBP2 was strongest negatively associated with dendritic cells (DCs), which were confirmed by the immunohistochemistry (IHC) staining. Two distinct m6A modification patterns were determined: pattern B had higher infiltrating immunocytes and more active immune responses than pattern A, and two patterns differed in the expression of HLA genes. We also identified 1,592 m6A phenotype-related genes that could mediate the OA synovitis and cartilage degradation by the PI3K-Akt signaling pathway. Quantitative real-time polymerase chain reaction (qRT-PCR) results indicated that IGFBP2 was significantly overexpressed, while YTHDF2 mRNA expression was decreased in OA samples, which was consistent with our findings. Conclusion: Our research proves the essential impact of m6A RNA methylation modification on the OA immune microenvironment, and helps to explain the regulatory mechanism behind it, which may open up a new direction for more precise immunotherapy of osteoarthritis.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (ß = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.