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miR-29a-3p has been shown to be associated with cardiovascular diseases; however, the effect of miR-29a-3p on endothelial dysfunction is unclear. This study aimed to reveal the effects and mechanisms of miR-29a-3p on endothelial dysfunction. The levels of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin were determined by real-time PCR and immunofluorescence staining to reveal the degree of tumor necrosis factor alpha (TNFα)-induced endothelial dysfunction. A luciferase activity assay and cell transfection with a miR-29a-3p mimic or an inhibitor were used to reveal the underlying mechanisms of miR-29a-3p action. Furthermore, the effects of miR-29a-3p on endothelial dysfunction were assessed in C57BL/6 mice injected with TNFα and/or a miR-29a-3p agomir. The results showed that the expression of TNFα-induced adhesion molecules in vascular endothelial cells (EA.hy926 cells, human aortic endothelial cells [HAECs], and primary human umbilical vein endothelial cells [pHUVECs]) and smooth muscle cells (human umbilical vein smooth muscle cells [HUVSMCs]) was significantly decreased following transfection with miR-29a-3p. This effect was reversed by cotransfection with a miR-29a-3p inhibitor. As a key target of miR-29a-3p, tumor necrosis factor receptor 1 mediated the effect of miR-29a-3p. Moreover, miR-29a-3p decreased the plasma levels of TNFα-induced VCAM-1 (32.62%), ICAM-1 (38.22%), and E-selectin (39.32%) in vivo. These data indicate that miR-29a-3p plays a protective role in TNFα-induced endothelial dysfunction, suggesting that miR-29a-3p is a novel target for the prevention and treatment of atherosclerosis.

The design and fabrication of advanced soft actuators with programmable actuation are highly desirable in constructing intelligent soft robots. In this work, a programmable light‐driven liquid crystalline network (LCN)‐based soft actuator was judiciously designed and prepared by constructing structural anisotropy across the thickness of the film. A three‐dimensional (3D) deformable LCN actuator was realized by polymerization‐induced phase separation of small‐molar‐weight monomers and polymer networks. The resultant anisotropic LCN displays anisotropic microscale nanoporous architecture across the thickness in addition to uniform alignment at the molecular scale. The actuation behaviors of LCN film are tunable by adjusting the size and distribution of nanopores in LCN bulk via changing polymerization conditions and monomer components. More importantly, the nanoporous LCN film can be harnessed as a promising template to achieve diverse light responsiveness by changing the photothermal dyes via a feasible washing and refilling process, demonstrating a reprogrammable light‐driven soft actuator. A programmable soft actuator with a light‐driven liquid crystalline network (LCN) is developed. It features structural anisotropy and tunable actuation via nanopore adjustments. The LCN can be reprogrammed for diverse light responses by changing photothermal dyes, offering a versatile template for soft robotics.

Background/Aims: Atherosclerosis is the primary cause of cardiovascular ischaemic events; arterial stiffness is a characteristic of the atherosclerotic process. MicroRNAs (miRNAs) have been revealed as crucial modulators of atherosclerosis. However, the role of arterial stiffness-related miRNAs in the atherosclerotic process is still unclear. Methods: Four hundred six participants from Northern China were enrolled in this study. Circulating miR-1185 and adhesion molecule levels were measured. Multiple linear regression models were used to evaluate the association of miR-1185 levels with brachial-ankle pulse wave velocity (baPWV) and adhesion molecule levels. A mediation analysis was also performed to examine the mediating effect. Cell adhesion molecule levels were measured in primary human umbilical vein endothelial cells (pHUVECs) and human umbilical vein smooth cells (HUVSMCs) transfected with miR-1185 or co-transfected with a miR-1185 inhibitor. Results: miR-1185 was independently correlated with arterial stiffness. A positive relationship between miR-1185 and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin levels was observed. VCAM- 1 and E-selectin partially mediated the correlation between miR-1185 and arterial stiffness. miR-1185 induced a significant increase in the VCAM-1 and E-selectin levels in pHUVECs and HUVSMCs in vitro. According to our mechanistic analysis, VCAM-1 and E-selectin mediated miR-1185-induced arterial stiffening. Conclusions: miR-1185 modulated the expression of VCAM-1 and E-selectin to promote arterial stiffening, suggesting that miR-1185 plays a crucial role in the development of atherosclerosis and may serve as a novel therapeutic target for atherosclerosis.

Background/Aims: Atherosclerosis is a multifactorial chronic disease and is the main cause of death and impairment in the world. Endothelial injury and apoptosis play a crucial role in the onset and development of atherosclerosis. MicroRNAs (miRNAs) have been proven to be involved in the pathogenesis of atherosclerosis. However, studies of the functional role of apoptosis-related miRNAs in the endothelium during atherogenesis are limited. Methods: Cell injury and apoptosis were measured in five types of cells transfected with miR-1185 or co-transfected with miR-1185 and its inhibitor. Bioinformatics analysis and a luciferase reporter assay were used to confirm the targets of miR-1185. The effects of the targets of miR-1185 on endothelial apoptosis were determined using small-interfering RNA. Results: In this study, we first report that miR-1185 significantly promoted apoptosis in endothelial cells but not in vascular smooth muscle cells and macrophages. A mechanistic analysis showed that ultraviolet irradiation resistance-associated gene (UVRAG) and krev1 interaction trapped gene 1 (KRIT1), targets of miR-1185, mediated miR-1185-induced endothelial cell apoptosis. Conclusion: The results revealed the impact of miR-1185 on endothelial apoptosis, suggesting that miR-1185 may be a potential target for the prevention and treatment of atherosclerosis.

Objective: The dietary index for gut microbiota (DI-GM) is a newly proposed metric for assessing diet quality, and its relationship with biological age is unclear. We hypothesize that consuming foods conducive to a healthy gut microbiota environment may decelerate aging. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2007 to 2018. The DI-GM was calculated by averaging the intakes from two 24-h dietary recall interviews. The biological age indicators were assessed using the Klemera–Doubal Method (KDM), phenotypic age (PA), and homeostasis disorder (HD). Logistic regression, restricted cubic splines (RCS), and mediation analysis were employed to explore the association between DI-GM and KDM, PA, and HD. Results: The study included 20,671 participants. According to the logistic regression model, adjusting for all covariates, a negative association was observed between the DI-GM score and biomarkers of biological aging. Compared to participants in the lowest quartile for DI-GM scores, those in the highest quartile exhibited reduced odds ratio (OR) for all of the biological age indicators, namely biological age assessed via KDM (OR: 0.69, 95% CI: 0.60–0.79), PA (OR: 0.84, 95% CI: 0.73–0.97), and HD (OR: 0.86, 95% CI: 0.76–0.98). Additionally, RCS analysis revealed a nonlinear association between DI-GM and biological age. Mediation analysis showed that the body mass index (BMI) partly mediated the association between DI-GM and biological age. Conclusions: Therefore, we concluded that a higher DI-GM score is associated with a lower risk of accelerated aging, with BMI mediating this association. Future research should validate these findings through the use of longitudinal studies.

Stamping is the earliest and most important process in automobile manufacturing, significantly impacting the overall surface quality of automobiles. Cracking is the most severe quality issue in stamping, but such defects still rely on manual detection, which has low detection efficiency and a high error rate. Furthermore, the difficulty in collecting defect data for stamped parts due to mature production processes leads to challenges in performing fully-supervised defect detection. However, unsupervised detection has limited accuracy and cannot achieve ideal results. In order to address challenges in industrial production lines, this paper proposes an adaptive incremental two-stage framework. In Stage I, to address the issue of insufficient annotated data during the initial stage of project deployment, only normal samples are used for unsupervised anomaly detection to accelerate project landing. In Stage II, to address the limitations of unsupervised detection and fully utilize the defect data collected during project iteration, the framework can fully use the initially annotated seed regions generated in Stage I for weakly supervised semantic segmentation, thereby achieving higher detection accuracy. In practical production applications, the framework adopts an accumulation triggering mechanism, which can expand the training samples through detection feedback of each stage model and continuously improve the defect detection effect using an adaptive training mechanism. To validate the effectiveness of the proposed framework, we conducted extensive experiments on the stamped parts dataset collected from actual automobile production and the public dataset KolektorSDD. Our results surpassed those of state-of-the-art defect detection and localization methods.

Background Rosacea is a chronic inflammatory facial disorder with limited therapeutic options, severely impacting patients' quality of life. The identification of druggable genes plays a crucial role in facilitating the development of effective therapeutic strategies. Methods We conducted Mendelian randomization (MR) and Summary‐based Mendelian randomization (SMR) analyses by integrating data on 5883 druggable genes, cis‐expressed quantitative trait loci (eQTL) from blood and skin tissue (lower leg and suprapubic), and genome‐wide association study (GWAS) data on rosacea to elucidate the causal relationship between druggable genes and rosacea. Robustness was confirmed via heterogeneity/horizontal pleiotropy tests, Steiger filtering, Bayesian colocalization analysis, and the heterogeneity in dependent instruments (HEIDI) analysis. The expression levels of identified druggable genes were validated using the GSE65914 data sets. Further analyses included protein–protein interactions (PPIs), functional enrichment analysis, phenome‐wide association study (PheWAS), drug prediction, and molecular docking. Results MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants. GEO data sets confirmed significant upregulation of IRF1 and downregulation of SLC22A5 in rosacea patients. PPIs and functional enrichment analyses revealed that IRF1 promotes inflammation by regulating immune cell activation and interferon signaling pathways; SLC22A5 regulates membrane transport and metabolic processes, and its dysregulation may lead to lipid homeostasis imbalance. PheWAS analysis indicated no other phenotypes associated with IRF1 and SLC22A5. Drug prediction and molecular docking verified the pharmacological value of IRF1 and SLC22A5. Conclusion This study identified IRF1 and SLC22A5 as potential drug targets for the treatment of rosacea, and their significant therapeutic potential provides a critical foundation for the development of targeted therapies.

PurposeCoronary artery involvement remains the primary focus in the long-term management of Kawasaki disease (KD). However, previous studies suggest that myocardial abnormalities frequently persist beyond coronary artery involvement in KD patients. Yet, their temporal evolution and clinical implications remain poorly characterised. To address this gap, we established the Kawasaki disease cardiac imaging (KDCI) cohort, integrating cardiac magnetic resonance (CMR) with echocardiography, coronary CT angiography (CCTA) and invasive angiography. These multimodal imaging approaches enable comprehensive assessment of cardiac abnormalities and elucidate the role of cardiac imaging in optimising long-term KD management.ParticipantsThe KDCI cohort is a prospective study aiming to enrol 400–500 KD patients diagnosed at West China Second University Hospital from September 2018 to September 2035. To date, 207 participants have been recruited. Participants will perform the multimodal cardiac imaging including echocardiography, CMR, CCTA, invasive angiography and comprehensive laboratory testing under a scheduled protocol in the follow-up.Findings to dateThe KDCI cohort has established baseline characteristics for 207 KD patients. Of those included to date, 72.0% (149/207) received intravenous immunoglobulin (IVIG) treatment, with 26.1% (54/207) demonstrating IVIG resistance, and 37.7% (78/207) exhibiting coronary artery dilatation. Longitudinal follow-up data are available for 80.7% (167/207) of participants, with a median follow-up duration of 2.7 years and a follow-up patient-years of 594 patient-years. Of the 207 patients, 16.9% (35/207) patients experienced endpoint events, encompassing coronary artery thrombosis (8.2%, 17/207), coronary stenosis/obstruction (5.3% 11/207) and clinical myocardial infarction (1.9%, 4/207). Based on the data collected, we have demonstrated the cardiac abnormalities beyond coronary artery involvement in KD by CMR and CCTA.Future planThe KDCI cohort will maintain ongoing recruitment and longitudinal follow-up, with a projected enrolment exceeding 400 participants by 2035. This expansion will yield a median follow-up duration of 10 years, providing robust long-term outcome data. We have implemented standardised protocols for scheduled follow-up assessments and data collection in newly enrolled patients. Furthermore, planned genomic analyses will be incorporated to investigate the molecular pathogenesis and prognostic determinants of KD.

Abstract Context Experimental evidence suggests saturated fatty acids (SFAs) are associated with insulin resistance, but results from epidemiological studies on fasting SFAs-diabetes risk are inconsistent. Objective We investigated SFA (fasting and 2-hour postprandial) profiles and diabetes risk. Design Setting A total of 8940 participants were recruited for the Harbin People’s Health Study in 2008. Serum SFAs (fasting and 2-hour postprandial) at baseline in Chinese men and women without diabetes were profiled, and type 2 diabetes was ascertained using World Health Organization criteria after 4 to 7 years of follow-up. Outcome Associations between 2-hour postprandial SFA (2h-SFA) and diabetes. Results At baseline, incident cases of diabetes were older with a higher body mass index and waist circumference. After a mean follow-up of 6.7 years, 658 incident cases of diabetes occurred. After propensity score computation and inverse probability of treatment weighting (IPTW) estimation, fasting SFAs were unrelated to diabetes risk but IPTW-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the highest tertile of 2-hour postprandial stearic acid (2h-SA), 2-hour postprandial palmitic acid (2h-PA), and 2h-SFA for diabetes risk were 2.50 (2.08 to 3.16), 1.56 (1.23 to 2.02), and 1.70 (1.34 to 2.17), respectively (P-trend < 0.0001). Similarly, 2h-SA/fasting SA, 2h-PA/fasting PA, and 2h-SFA/fasting SFA ratios [IPTW-adjusted OR (95% CI): 2.94 (2.39 to 3.58), 2.31 (1.80 to 2.93), and 2.42 (1.91 to 3.11), respectively; P-trend < 0.0001] predicted the diabetes risk. Conclusions Higher serum 2h-SFA (but not fasting SFA) independently predicted diabetes risk. We prospectively investigated fasting SFA, 2-hour postprandial SFA, and risk of type 2 diabetes. We found that higher 2-hour postprandial SFA was associated with a higher risk of diabetes.

Mutations in RNA-binding proteins (RBPs) localized in ribonucleoprotein (RNP) granules, such as hnRNP A1 and TDP-43, promote aberrant protein aggregation, which is a pathological hallmark of various neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Protein posttranslational modifications (PTMs) are known to regulate RNP granules. In this study, we investigate the function of poly(ADP-ribosyl)ation (PARylation), an important PTM involved in DNA damage repair and cell death, in RNP granule-related neurodegeneration. We reveal that PARylation levels are a major regulator of the assembly-disassembly dynamics of RNP granules containing disease-related RBPs, hnRNP A1 and TDP-43. We find that hnRNP A1 can both be PARylated and bind to PARylated proteins or poly(ADP-ribose) (PAR). We further uncover that PARylation of hnRNP A1 at K298 controls its nucleocytoplasmic transport, whereas PAR-binding via the PAR-binding motif (PBM) of hnRNP A1 regulates its association with stress granules. Moreover, we reveal that PAR not only dramatically enhances the liquid-liquid phase separation of hnRNP A1, but also promotes the co-phase separation of hnRNP A1 and TDP-43 in vitro and their interaction in vivo. Finally, both genetic and pharmacological inhibition of PARP mitigates hnRNP A1- and TDP-43-mediated neurotoxicity in cell and Drosophila models of ALS. Together, our findings suggest a novel and crucial role for PARylation in regulating the dynamics of RNP granules, and that dysregulation in PARylation and PAR levels may contribute to ALS disease pathogenesis by promoting protein aggregation.