Fully Automatic Deep Learning Model for Spine Refracture in Patients with OVCF: A Multi-Center Study.

BACKGROUND: The reaserch of artificial intelligence (AI) model for predicting spinal refracture is limited to bone mineral density, X-ray and some conventional laboratory indicators, which has its own limitations. Besides, it lacks specific indicators related to osteoporosis and imaging factors that can better reflect bone quality, such as computed tomography (CT). OBJECTIVE: To construct a novel predicting model based on bone turn-over markers and CT to identify patients who were more inclined to suffer spine refracture. METHODS: CT images and clinical information of 383 patients (training set = 240 cases of osteoporotic vertebral compression fractures (OVCF), validation set = 63, test set = 80) were retrospectively collected from January 2015 to October 2022 at three medical centers. The U-net model was adopted to automatically segment ROI. Three-dimensional (3D) cropping of all spine regions was used to achieve the final ROI regions including 3D_Full and 3D_RoiOnly. We used the Densenet 121-3D model to model the cropped region and simultaneously build a T-NIPT prediction model. Diagnostics of deep learning models were assessed by constructing ROC curves. We generated calibration curves to assess the calibration performance. Additionally, decision curve analysis (DCA) was used to assess the clinical utility of the predictive models. RESULTS: The performance of the test model is comparable to its performance on the training set (dice coefficients of 0.798, an mIOU of 0.755, an SA of 0.767, and an OS of 0.017). Univariable and multivariable analysis indicate that T_P1NT was an independent risk factor for refracture. The performance of predicting refractures in different ROI regions showed that 3D_Full model exhibits the highest calibration performance, with a Hosmer-Lemeshow goodness-of-fit (HL) test statistic exceeding 0.05. The analysis of the training and test sets showed that the 3D_Full model, which integrates clinical and deep learning results, demonstrated superior performance with significant improvement (p-value < 0.05) compared to using clinical features independently or using only 3D_RoiOnly. CONCLUSION: T_P1NT was an independent risk factor of refracture. Our 3D-FULL model showed better performance in predicting high-risk population of spine refracture than other models and junior doctors do. This model can be applicable to real-world translation due to its automatic segmentation and detection.

The role of minimal residual disease and serum free light chain ratio in the management of multiple myeloma.

Multiple myeloma (MM) denotes a cancerous growth characterized by abnormal proliferation of plasma cells. Growing evidence suggests that the complexity in addressing MM lies in the presence of minimal residual disease (MRD) within the body. MRD assessment is becoming increasingly important for risk assessment in patients with MM. Similarly, the levels of serum free protein light chain and their ratio play a crucial role in assessing the disease burden and changes in MM. In this paper, we review and explore the utilization of MRD and serum free light chain ratio in the treatment of MM, delving into their respective characteristics, advantages, disadvantages, and their interrelation.

miR-let-7a inhibits sympathetic nerve remodeling after myocardial infarction by downregulating the expression of nerve growth factor.

Objective: Sympathetic hyperinnervation following myocardial infarction (MI) is one of the primary causes of ventricular arrhythmias (VAs) after MI. Nerve growth factor (NGF) is a key molecule that induces sympathetic nerve remodeling. Previous studies have confirmed that microRNA (miR)-let-7a interacts with NGF. However, whether miR-let-7a is involved in sympathetic remodeling after MI remains unknown. We aimed to investigate whether miR-let-7a was associated with the occurrence of VA after MI. Methods and results: A rat model of myocardial infarction was established using left coronary artery ligation. miR-let-7a expression levels were analyzed by reverse transcription-quantitative PCR. Western blotting was also used to examine NGF expression levels in vivo and in M1 macrophages in vitro. The relationship between miR-let-7a and NGF levels was investigated using a luciferase reporter assay. The results revealed that the expression of miR-let-7a decreased significantly after MI, while NGF expression was significantly upregulated. In addition, overexpression of miR-let-7a effectively inhibited NGF expression in rats, which was also verified in M1 macrophages. Tyrosine hydroxylase and growth-associated protein 43 immunofluorescence results revealed that the administration of a miR-let-7a overexpression lentivirus to rats inhibited sympathetic remodeling after MI. Programmed electrical stimulation, renal sympathetic nerve activity recording, and heart rate variability measurements showed that miR-let-7a overexpression decreased sympathetic activity. Conclusions: These findings provide novel insights into the molecular mechanisms by which miR-let-7a and NGF contribute to the progression of sympathetic nerve remodeling after MI. Therefore, miR-let-7a may be a promising therapeutic target to reduce the incidence of arrhythmia following MI.

Successful Treatment of Cervical Spondylolysis with Grade-II Spondylolisthesis using Single-Level ACDF: A Case Report.

BACKGROUND Cervical spondylolysis with spondylolisthesis is a rare disorder. According to previous reports, the spondylolisthesis is usually Meyerding Grade I, with only a limited number of cases receiving surgical treatment. We hereby report a special case of cervical spondylolysis with Grade-II spondylolisthesis, treated with single-level anterior cervical discectomy and fusion (ACDF), and present a literature review related to this problem. CASE REPORT Here, we report the case of a 52-year-old man who complained of posterior neck pain and numbness of the bilateral upper limbs. Radiological examination showed bilateral spondylolysis of the C6 and Meyerding Grade-II spondylolisthesis of C6 on C7 with instability. The patient underwent a single-level C6/C7 ACDF surgery. The symptoms of neck pain and bilateral upper-limb numbness were relieved immediately after surgery. The immediate postoperative radiological examination showed successful restoration of sagittal alignment. At 3-month follow-up, the patient had returned to normal life without any symptoms. At 2-year follow-up, computed tomography showed that C6-C7 fusion had been achieved and alignment was maintained. CONCLUSIONS Cervical spondylolysis, as an uncommon spinal disorder, has been regarded as a congenital abnormity, and has unique radiological characteristics. For most of the cases with cervical spondylolysis, even with Grade-II spondylolisthesis, single-level ACDF can achieve good clinical and radiological outcomes.

Bubble thermodynamics in cryogenic fluids under ultrasonic field excitation: Theoretical analysis and numerical calculation.

In the study of cavitation in room-temperature fluids, the heat transfer between gas and liquid in bubble oscillation is usually assumed to be an adiabatic process for simplification. However, this heat transfer and thermodynamic mechanism is not yet understood in cryogenic fluids, especially under small amplitude oscillation conditions excited by ultrasonic field. This article studies bubble thermodynamic model under an external ultrasonic field based on the heat transfer equation for cryogenic fluids. The temperature changes inside bubbles are calculated, and the heat transfer mechanism is briefly analyzed. The results indicate that the heat transfer mechanism of bubbles depends on the relationship between ultrasonic frequency and bubble resonance frequency. By analyzing two special cases of dual-bubble and high-pressure environment, it is believed that heat transfer can be approximated as an adiabatic process under high-pressure conditions with ultrasonic frequency far from the resonance frequency. This conclusion can provide a theoretical basis for subsequent accurate calculation of heat-transfer polytropic coefficient, or void faction measurement in cryogenic two-phase flow.

Nanoscale cellular organization of viral RNA and proteins in SARS-CoV-2 replication organelles.

The SARS-CoV-2 viral infection transforms host cells and produces special organelles in many ways, and we focus on the replication organelles, the sites of replication of viral genomic RNA (vgRNA). To date, the precise cellular localization of key RNA molecules and replication intermediates has been elusive in electron microscopy studies. We use super-resolution fluorescence microscopy and specific labeling to reveal the nanoscopic organization of replication organelles that contain numerous vgRNA molecules along with the replication enzymes and clusters of viral double-stranded RNA (dsRNA). We show that the replication organelles are organized differently at early and late stages of infection. Surprisingly, vgRNA accumulates into distinct globular clusters in the cytoplasmic perinuclear region, which grow and accommodate more vgRNA molecules as infection time increases. The localization of endoplasmic reticulum (ER) markers and nsp3 (a component of the double-membrane vesicle, DMV) at the periphery of the vgRNA clusters suggests that replication organelles are encapsulated into DMVs, which have membranes derived from the host ER. These organelles merge into larger vesicle packets as infection advances. Precise co-imaging of the nanoscale cellular organization of vgRNA, dsRNA, and viral proteins in replication organelles of SARS-CoV-2 may inform therapeutic approaches that target viral replication and associated processes.

Protocol for the Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study: a prospective, observational, multicentre cohort study of acute spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is a catastrophic event with devastating physical, social and occupational consequences for patients and their families. The number of patients with acute SCI in China continues to grow rapidly, but there have been no large prospective cohort studies of patients with acute SCI. This proposed study aims to establish a multicentre, extensive sample cohort of clinical data and biological samples of patients in China, which would aid the systematisation and standardisation of clinical research and treatment of acute SCI, thus reducing the heavy burden of acute SCI on patients and society. METHODS AND ANALYSIS: The Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study is an observational, multicentre cohort study of patients with acute SCI admitted to the Qilu Hospital of Shandong University and other participating centres with prospective collection of their clinical data and biological samples. We aim to recruit 2097 patients in this study. Demographics, disease history, emergency intervention information, motor and sensory examinations, surgical information, medication information and rehabilitation evaluation will be recorded. This will facilitate the development of a prediction model for complications and prognosis of patients with acute SCI and an evaluation of the current management of acute SCI. Among these variables, detailed information on surgical treatment will also be used to assess procedures for acute SCI treatment. Outcome measurements, including the International Standard for Neurological Classification of Spinal Cord Injury examinations, the occurrence of complications and death, will be performed repeatedly during follow-up. We will analyse imaging data and blood samples to develop SCI imaging markers and biomarkers. ETHICS AND DISSEMINATION: This study protocol has been approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres. The findings will be disseminated in peer-reviewed journals and academic conferences.

Three-dimensional architecture of ESCRT-III flat spirals on the membrane.

The endosomal sorting complexes required for transport (ESCRTs) are responsible for membrane remodeling in many cellular processes, such as multivesicular body biogenesis, viral budding, and cytokinetic abscission. ESCRT-III, the most abundant ESCRT subunit, assembles into flat spirals as the primed state, essential to initiate membrane invagination. However, the three-dimensional architecture of ESCRT-III flat spirals remained vague for decades due to highly curved filaments with a small diameter and a single preferred orientation on the membrane. Here, we unveiled that yeast Snf7, a component of ESCRT-III, forms flat spirals on the lipid monolayers using cryogenic electron microscopy. We developed a geometry-constrained Euler angle-assigned reconstruction strategy and obtained moderate-resolution structures of Snf7 flat spirals with varying curvatures. Our analyses showed that Snf7 subunits recline on the membrane with N-terminal motifs α0 as anchors, adopt an open state with fused α2/3 helices, and bend α2/3 gradually from the outer to inner parts of flat spirals. In all, we provide the orientation and conformations of ESCRT-III flat spirals on the membrane and unveil the underlying assembly mechanism, which will serve as the initial step in understanding how ESCRTs drive membrane abscission.

Safety and efficacy of magnesium-rich artificial cerebrospinal fluid for subarachnoid hemorrhage.

Objectives: This study aimed to investigate the efficacy of using a newly formulated magnesium-rich artificial cerebrospinal fluid (MACSF) as an alternative to normal saline (NS) for intraoperative irrigation during aneurysm clipping in improving the prognosis of patients with Aneurysmal subarachnoid hemorrhage (aSAH). Methods: Patients with aSAH who underwent intraoperative irrigation with MACSF or NS during the clipping in the First Affiliated Hospital of Xi 'an Jiaotong University from March 2019 to March 2022 were selected as MACSF group and NS group, respectively. The primary prognostic indicators were the incidence of favorable outcomes (mRS 0-2). The secondary outcome measures included cerebral vasospasm (CVS), mortality, total hospital stay, and intensive care unit (ICU) stay. Safety was evaluated based on the occurrence rates of hypermagnesemia, meningitis, and hydrocephalus. Results: Overall, 34 and 37 patients were enrolled in the MACSF and NS groups, respectively. At 90 days after aSAH onset, the proportion of favorable prognosis in the MACSF group was significantly higher than that in the NS group (p = 0.035). The incidence of CVS within 14 days after surgery was significantly lower in the MACSF group than that in the NS group (p = 0.026). The mortality rate in the MACSF group was significantly lower than in the NS group (p = 0.048). The median lengths of hospital stay (p = 0.008) and ICU stay (p = 0.018) were significantly shorter in the MACSF group than in the NS group. No significant differences were observed in safety measures. Conclusion: Using MACSF as an irrigation fluid for aneurysm clipping can significantly improve the 90-day prognosis of patients with aSAH, which may be related to the reduced incidence of CVS. Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT04358445.

Natural products reverse cancer multidrug resistance.

Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.

Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.

Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy.

Self-organization of embryonic stem cells into a reproducible embryo model through epigenome editing.

Embryonic stem cells (ESCs) can self-organize in vitro into developmental patterns with spatial organization and molecular similarity to that of early embryonic stages. This self-organization of ESCs requires transmission of signaling cues, via addition of small molecule chemicals or recombinant proteins, to induce distinct embryonic cellular fates and subsequent assembly into structures that can mimic aspects of early embryonic development. During natural embryonic development, different embryonic cell types co-develop together, where each cell type expresses specific fate-inducing transcription factors through activation of non-coding regulatory elements and interactions with neighboring cells. However, previous studies have not fully explored the possibility of engineering endogenous regulatory elements to shape self-organization of ESCs into spatially-ordered embryo models. Here, we hypothesized that cell-intrinsic activation of a minimum number of such endogenous regulatory elements is sufficient to self-organize ESCs into early embryonic models. Our results show that CRISPR-based activation (CRISPRa) of only two endogenous regulatory elements in the genome of pluripotent stem cells is sufficient to generate embryonic patterns that show spatial and molecular resemblance to that of pre-gastrulation mouse embryonic development. Quantitative single-cell live fluorescent imaging showed that the emergence of spatially-ordered embryonic patterns happens through the intrinsic induction of cell fate that leads to an orchestrated collective cellular motion. Based on these results, we propose a straightforward approach to efficiently form 3D embryo models through intrinsic CRISPRa-based epigenome editing and independent of external signaling cues. CRISPRa-Programmed Embryo Models (CPEMs) show highly consistent composition of major embryonic cell types that are spatially-organized, with nearly 80% of the structures forming an embryonic cavity. Single cell transcriptomics confirmed the presence of main embryonic cell types in CPEMs with transcriptional similarity to pre-gastrulation mouse embryos and revealed novel signaling communication links between different embryonic cell types. Our findings offer a programmable embryo model and demonstrate that minimum intrinsic epigenome editing is sufficient to self-organize ESCs into highly consistent pre-gastrulation embryo models.

Utilization of Nitrogen-Doped Graphene Quantum Dots to Neutralize ROS and Modulate Intracellular Antioxidant Pathways to Improve Dry Eye Disease Therapy.

Purpose: Patients afflicted with dry eye disease (DED) experience significant discomfort. The underlying cause of DED is the excessive accumulation of ROS on the ocular surface. Here, we investigated the nitrogen doped-graphene quantum dots (NGQDs), known for their ROS-scavenging capabilities, as a treatment for DED. Methods: NGQDs were prepared by using citric acid and urea as precursors through hydrothermal method. The antioxidant abilities of NGQDs were evaluated through: scavenging the ROS both extracellular and intracellular, regulating the nuclear factor-erythroid 2-related factor (Nrf2) antioxidant pathway of human corneal epithelial cells (HCECs) and their transcription of inflammation related genes. Furthermore, NGQDs were modified by Arg-Gly-Asp-Ser (RGDS) peptides to obtain RGDS@NGQDs. In vivo, both the NGQDs and RGDS@NGQDs were suspended in 0.1% Pluronic F127 (w/v) and delivered as eye drops in the scopolamine hydrobromide-induced DED mouse model. Preclinical efficacy was compared to the healthy and DPBS treated DED mice. Results: These NGQDs demonstrated pronounced antioxidant properties, efficiently neutralizing free radicals and activating the intracellular Nrf2 pathway. In vitro studies revealed that treatment of H2O2-exposed HCECs with NGQDs induced a preservation in cell viability. Additionally, there was a reduction in the transcription of inflammation-associated genes. To prolong the corneal residence time of NGQDs, they were further modified with RGDS peptides and suspended in 0.1% Pluronic F127 (w/v) to create RGDS@NGQDs F127 eye drops. RGDS@NGQDs exhibited superior intracellular antioxidant activity even at low concentrations (10 µg/mL). Subsequent in vivo studies revealed that RGDS@NGQDs F127 eye drops notably mitigated the symptoms of DED mouse model, primarily by reducing ocular ROS levels. Conclusion: Our findings underscore the enhanced antioxidant benefits achieved by modifying GQDs through nitrogen doping and RGDS peptide tethering. Importantly, in a mouse model, our novel eye drops formulation effectively ameliorated DED symptoms, thereby representing a novel therapeutic pathway for DED management.

eVAE: Evolutionary Variational Autoencoder.

Variational autoencoders (VAEs) are challenged by the imbalance between representation inference and task fitting caused by surrogate loss. To address this issue, existing methods adjust their balance by directly tuning their coefficients. However, these methods suffer from a tradeoff uncertainty, i.e., nondynamic regulation over iterations and inflexible hyperparameters for learning tasks. Accordingly, we make the first attempt to introduce an evolutionary VAE (eVAE), building on the variational information bottleneck (VIB) theory and integrative evolutionary neural learning. eVAE integrates a variational genetic algorithm (VGA) into VAE with variational evolutionary operators, including variational mutation (V-mutation), crossover, and evolution. Its training mechanism synergistically and dynamically addresses and updates the learning tradeoff uncertainty in the evidence lower bound (ELBO) without additional constraints and hyperparameter tuning. Furthermore, eVAE presents an evolutionary paradigm to tune critical factors of VAEs and addresses the premature convergence and random search problem in integrating evolutionary optimization into deep learning. Experiments show that eVAE addresses the KL-vanishing problem for text generation with low reconstruction loss, generates all the disentangled factors with sharp images, and improves image generation quality. eVAE achieves better disentanglement, generation performance, and generation-inference balance than its competitors. Code available at: https://github.com/amasawa/eVAE.

Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.

Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.

Learning Generalizable Models via Disentangling Spurious and Enhancing Potential Correlations.

Domain generalization (DG) intends to train a model on multiple source domains to ensure that it can generalize well to an arbitrary unseen target domain. The acquisition of domain-invariant representations is pivotal for DG as they possess the ability to capture the inherent semantic information of the data, mitigate the influence of domain shift, and enhance the generalization capability of the model. Adopting multiple perspectives, such as the sample and the feature, proves to be effective. The sample perspective facilitates data augmentation through data manipulation techniques, whereas the feature perspective enables the extraction of meaningful generalization features. In this paper, we focus on improving the generalization ability of the model by compelling it to acquire domain-invariant representations from both the sample and feature perspectives by disentangling spurious correlations and enhancing potential correlations. 1) From the sample perspective, we develop a frequency restriction module, guiding the model to focus on the relevant correlations between object features and labels, thereby disentangling spurious correlations. 2) From the feature perspective, the simple Tail Interaction module implicitly enhances potential correlations among all samples from all source domains, facilitating the acquisition of domain-invariant representations across multiple domains for the model. The experimental results show that Convolutional Neural Networks (CNNs) or Multi-Layer Perceptrons (MLPs) with a strong baseline embedded with these two modules can achieve superior results, e.g., an average accuracy of 92.30% on Digits-DG. Source code is available at https://github.com/RubyHoho/DGeneralization.

Mesoporous bioactive glass scaffolds for the delivery of bone marrow stem cell-derived osteoinductive extracellular vesicles lncRNA promote senescent bone defect repair by targeting the miR-1843a-5p/Mob3a/YAP axis.

Bone repair in elderly patients poses a huge challenge due to the age-related progressive decline in regenerative abilities attributed to the senescence of bone marrow stem cells (BMSCs). Bioactive scaffolds have been applied in bone regeneration due to their various biological functions. In this study, we aimed to fabricate functionalized bioactive scaffolds through loading osteoinductive extracellular vesicles (OI-EVs) based on mesoporous bioactive glass (MBG) scaffolds (1010 particles/scaffold) and to investigate its effects on osteogenesis and senescence of BMSCs. The results suggested that OI-EVs upregulate the proliferative and osteogenic capacities of senescent BMSCs. More importantly, The results showed that loading OI-EVs into MBG scaffolds achieved better bone regeneration. Furthermore, OI-EVs and BMSCs RNAs bioinformatics analysis indicated that OI-EVs play roles through transporting pivotal lncRNA acting as a "sponge" to compete with Mob3a for miR-1843a-5p to promote YAP dephosphorylation and nuclear translocation, ultimately resulting in elevated proliferation and osteogenic differentiation and reduced senescence-related phenotypes. Collectively, these results suggested that the OI-EVs lncRNA ceRNA regulatory networks might be the key point for senescent osteogenesis. More importantly, the study indicated the feasibility of loading OI-EVs into scaffolds and provided novel insights into biomaterial design for facilitating bone regeneration in the treatment of senescent bone defects. STATEMENT OF SIGNIFICANCE: Constructing OI-EVs/MBG delivering system and verification of its bone regeneration enhancement in senescent defect repair. Aging bone repair poses a huge challenge due to the age-related progressive degenerative decline in regenerative abilities attributed to the senescence of BMSCs. OI-EVs/MBG delivering system were expected as promising treatment for senescent bone repair, which could provide an effective strategy for bone regeneration in elderly patients. Clarification of potential OI-EVs lncRNA ceRNA regulatory mechanism in senescent bone regeneration OI-EVs play important roles through transferring lncRNA-ENSRNOG00000056625 sponging miR-1843a-5p that targeted Mob3a to activate YAP translocation into nucleus, ultimately alleviate senescence, promote proliferation and osteogenic differentiation in O-BMSCs, which provides theoretical basis for EVs-mediated therapy in future clinical works.