Patients with osteoporosis are highly susceptible to fractures that often require implant fixation and stabilization. However, excessive osteoclast activity under osteoporotic conditions accelerates bone resorption at the bone-implant interface, severely compromising implant osseointegration. RANKL-RANK axis is a central regulator of osteoclast function and emerges as a promising target for osteoporosis treatment, yet current therapeutic options primarily rely on reversible ligand neutralization and can be followed by rebound bone loss after treatment discontinuation. Here, we developed a biomimetic titanium implant coating incorporating RANK-targeted micellar lysosome-targeting chimeras (LYTACs) to enhance osseointegration under osteoporotic conditions. Collagen-like peptides (CLPs) were conjugated to bispecific aptamers targeting RANK and the cation-independent mannose-6-phosphate receptor (CI-M6PR) through acid-responsive linkers. The resulting conjugates self-assembled into supramolecular LYTACs (CLP-Apt) and were integrated onto hydroxyapatite-modified titanium surfaces. Hydroxyapatite facilitated mesenchymal stem cell (MSC) recruitment, whereas acidic microenvironmental cues triggered CLP-Apt release. Simultaneous engagement of RANK and CI-M6PR on osteoclasts directed RANK toward lysosomal degradation, thereby suppressing osteoclast-mediated bone resorption while promoting MSC osteogenic differentiation and type H vessel formation. Following lysosomal processing, the released CLPs assembled extracellularly into bone matrix-mimetic fibers that chelated Ca2+ and accelerated new bone formation through a fibrillogenesis-mimetic process. By directly degrading RANK while promoting vascularized bone regeneration, this coating provides a localized strategy to overcome osteoclast-driven implant failure and achieve rapid, robust osseointegration under osteoporotic conditions.
The HPV vaccine, as a key tool for the prevention of cervical cancer and related diseases, has shown a rising trend in its vaccination rate year after year. Along with the increase in its vaccination rate, the related adverse events have also received widespread attention. This study employs real-world data to identify potential reporting signals between HPV vaccination and central nervous system demyelinating diseases using rigorous data analysis. This study is based on the HPV vaccination data of the US Vaccine Adverse Event Reporting System (VAERS) up to January 1, 2025. Four pharmacovigilance methodologies were integratively applied with Bonferroni-adjusted significance testing to detect disproportional reporting signals potentially related to HPV immunization and central nervous system demyelinating diseases. Meanwhile, differences in different population characteristics were assessed by subgroup analysis. In addition, the pattern of change in the incidence of adverse events over time after vaccination was explored using time-to-evocation analysis and Weber distribution analysis. This investigation systematically analyzed 60,840 human papillomavirus (HPV) immunization-associated adverse event reports within the Vaccine Adverse Event Reporting System (VAERS) database, and it was found that non-infectious myelitis and encephalomyelitis showed significant disproportional reporting signals (including transverse myelitis, optic nerve myelitis, acute disseminated encephalomyelitis, and white matter encephalomyelitis). Negative signals were observed for the remaining diseases within the central nervous system demyelinating disease spectrum. Subgroup analysis revealed positive signals for adverse events in female populations and in those within the FDA-recommended vaccination age range. Furthermore, the results of the Weibull distribution analysis exhibited an early-onset pattern, where the incidence of these diseases decreased significantly over time following vaccination. A positive disproportionality reporting signal of non-infectious myelitis and encephalomyelitis following HPV vaccination was observed in the VAERS database. The findings reflect potential reporting differences across populations and time intervals after vaccination. These results highlight the importance of sustained pharmacovigilance and the need for further epidemiological investigations to clarify whether this reporting signal corresponds to a true clinical association.
Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that occupies a key position at the interface between base excision repair (BER) and cellular redox control during inflammation. As the major AP endonuclease in the BER pathway, APE1 maintains the genomic stability by the repairing oxidative DNA lesions that accumulate in chronically inflamed tissues. In addition, its redox effector factor 1 (Ref-1) activity modulates a broad range of transcription factors, thereby influencing inflammatory cytokine production and the cellular response to redox imbalance. Through this combination of DNA repair and redox-signaling functions, APE1 acts as a central hub that couples oxidative DNA damage to inflammatory signaling networks. Dysregulation of APE1 expression or subcellular distribution has been associated with various inflammation-associated diseases, reflecting its broad impact on inflammatory pathology. This review summarizes current understanding of APE1's dual role in inflammation, highlights opportunities and challenges for therapeutic targeting, and discusses its emerging value in the precision monitoring and management of inflammation‑associated diseases.
Although depression and biological aging share dyslipidemia as a common pathological feature, the extent to which dyslipidemia is involved in their association remains unclear. This study aimed to explore the association between depressive symptoms and accelerated biological aging, with a particular focus on whether dyslipidemia, as measured by the lipid accumulation product (LAP), statistically mediates this association. A total of 4,150 American adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) database were included. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and accelerated aging was measured via phenotypic age acceleration (PhenoAgeAccel). Weighted multivariable linear regression, restricted cubic spline (RCS) analyses, subgroup analyses, and interaction tests were conducted to examine the associations between depressive symptoms and PhenoAgeAccel. Mediation analysis was subsequently conducted to assess the statistical mediating role of LAP in this association. Among the 4,150 participants, 375 (9.0
Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) is regarded as the non-invasive gold standard for myocardial tissue characterization. However, its reliance on gadolinium-based contrast agents limits its applicability in patients with renal impairment or contrast allergies. We develop Cine2LGE, a method that simultaneously generates LGE-like images and estimates enhancement probability directly from contrast-free cine MRI. The model was trained and evaluated on a multi-center, multi-manufacturer, multi-disease dataset, and externally tested on an independent dataset. Image quality was assessed by three independent, experienced radiographers. Visualization consistency between LGE-like and real LGE images was evaluated through linear regression, correlation coefficient analysis, and Bland-Altman plots. The accuracy of enhancement probability prediction was assessed using the area under the receiver operating characteristic curve (AUC). The training dataset comprised 6361 paired cine and LGE images from 1189 subjects. The internal test dataset included 777 paired images from 129 subjects, and the external test dataset consisted of 1055 paired images from 198 subjects. Cine2LGE significantly outperformed conventional LGE in terms of image quality (p < 0.05). Strong correlations were observed between Cine2LGE and LGE in the quantification of both hyperintensity (Pearson correlation, 0.732/0.833; p < 0.05) and intermediate-intensity myocardial lesions (Pearson correlation, 0.759/0.712; p < 0.05). The enhancement probability prediction showed robust performance on both internal and external test sets, with AUC values of 0.906 and 0.895, respectively. Cine2LGE offers a viable alternative for patients who cannot undergo conventional LGE imaging, enhancing both the accessibility and clinical utility of cardiac MRI. Question Can contrast-free cine MRI generate LGE-like images and accurately detect myocardial enhancement for patients contraindicated to gadolinium-based contrast agents? Findings Cine2LGE, a diffusion model-based method, generated LGE-like images with superior quality to conventional LGE and achieved high accuracy in predicting enhancement probability from cine MRI. Clinical relevance Cine2LGE shows promise in providing a valuable, contrast-free alternative for patients with LGE contraindications, potentially expanding both the accessibility and clinical utility of cardiac MRI.
