Signatures of TOP1 transcription-associated mutagenesis in cancer and germline.

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.

Splicing factor YBX1 regulates bone marrow stromal cell fate during aging.

Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.

An Investigation of the Energy Harvesting Capabilities of a Novel Three-Dimensional Super-Cell Phononic Crystal with a Local Resonance Structure.

Using the piezoelectric (PZT) effect, energy-harvesting has become possible for phononic crystal (PnC). Low-frequency vibration energy harvesting is more of a challenge, which can be solved by local resonance phononic crystals (LRPnCs). A novel three-dimensional (3D) energy harvesting LRPnC is proposed and further analyzed using the finite element method (FEM) software COMSOL. The 3D LRPnC with spiral unit-cell structures is constructed with a low initial frequency and wide band gaps (BGs). According to the large vibration deformation of the elastic beam near the scatterer, a PZT sheet is mounted in the surface of that beam, to harvest the energy of elastic waves using the PZT effect. To further improve the energy-harvesting performance, a 5 × 5 super-cell is numerically constructed. Numerical simulations show that the present 3D super-cell PnC structure can make full use of the advantages of the large vibration deformation and the PZT effect, i.e., the BGs with a frequency range from 28.47 Hz to 194.21 Hz with a bandwidth of 142.7 Hz, and the maximum voltage output is about 29.3 V under effective sound pressure with a peak power of 11.5 µW. The present super-cell phononic crystal structure provides better support for low-frequency vibration energy harvesting, when designing PnCs, than that of the traditional Prague type.

A Domain Adaption ResNet Model to Detect Faults in Roller Bearings Using Vibro-Acoustic Data.

Intelligent fault diagnosis of roller bearings is facing two important problems, one is that train and test datasets have the same distribution, and the other is the installation positions of accelerometer sensors are limited in industrial environments, and the collected signals are often polluted by background noise. In the recent years, the discrepancy between train and test datasets is decreased by introducing the idea of transfer learning to solve the first issue. In addition, the non-contact sensors will replace the contact sensors. In this paper, a domain adaption residual neural network (DA-ResNet) model using maximum mean discrepancy (MMD) and a residual connection is constructed for cross-domain diagnosis of roller bearings based on acoustic and vibration data. MMD is used to minimize the distribution discrepancy between the source and target domains, thereby improving the transferability of the learned features. Acoustic and vibration signals from three directions are simultaneously sampled to provide more complete bearing information. Two experimental cases are conducted to test the ideas presented. The first is to verify the necessity of multi-source data, and the second is to demonstrate that transfer operation can improve recognition accuracy in fault diagnosis.

The role of autophagy in bone homeostasis.

Autophagy is an evolutionarily conserved intracellular process and is considered one of the main catabolism pathways. In the process of autophagy, cells are digested nonselectively or selectively to recover nutrients and energy, so it is regarded as an antiaging process. In addition to the essential role of autophagy in cellular homeostasis, autophagy is a stress response mechanism for cell survival. Here, we review recent literature describing the pathway of autophagy and its role in different bone cell types, including osteoblasts, osteoclasts, and osteocytes. Also discussed is the mechanism of autophagy in bone diseases associated with bone homeostasis, including osteoporosis and Paget's disease. Finally, we discuss the application of autophagy regulators in bone diseases. This review aims to introduce autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role and therapeutic potential in the pathogenesis of bone diseases such as osteoporosis.

TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

The predictive value of regulatory T cells on glucocorticoid sensitivity in patients with immune thrombocytopenia: a multicentre, prospective clinical study.

Glucocorticoids (GC) are used as the first-line treatment of immune thrombocytopenia (ITP), but 10-20% of patients are insensitive to them. Regulatory T cells (Tregs) can maintain immune tolerance in autoimmune diseases. The present research pooled 55 patients with newly diagnosed ITP and 44 healthy volunteers from seven hospitals. All patients received GC treatment and were divided into GC-sensitive and GC-insensitive groups according to the curative effect after 2 weeks of treatment. The levels of lymphocyte subgroups and Tregs were recorded. As the results indicated, the levels of CD8+ CD25str+ Tregs in the GC-sensitive group were significantly higher than that of the GC-insensitive group (P = 0·005). The optimal critical value of CD8+ CD25str+ Tregs to distinguish GC sensitivity was 0·09%. With GC therapy the level of CD45RO+ /CD8+ CD25str+ Tregs (activated type) decreased after treatment (P = 0·02) and the level of CD45RO- /CD8+ CD25str+ Tregs (initial type) increased slightly (P = 0·11). There were no obvious changes in the level of CD4+ Tregs. These findings support that the level of CD8+ CD25str+ Tregs and its subgroups have a predictive value in judging the sensitivity to GC among patients with ITP. Trial registration: www.chictr.org.cn; ChiCTR-OON-17014165.

A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly lethal malignancy with the 5-year survival rate of less than 7%. Chemotherapy-resistance is a major challenge for SCLC treatment in clinic. In the study, we developed a high-throughput drug screen strategy to identify new drugs that can enhance the sensitivity of chemo-drug cisplatin in SCLC. This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as a sensitizer of cisplatin. Further study validated that auranofin synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant SCLC cells, which was accompanied by the enhanced induction of cell cycle arrest and apoptosis. The synergistic action of auranofin and cisplatin was through ROS overproduction, thereby leading to mitochondrial dysfunction and DNA damage. Furthermore, in vivo study demonstrated that the combination treatment of auranofin and cisplatin dramatically inhibited tumor growth in SCLC. Therefore, our study provides a rational basis for further clinical study to test whether auranofin could enhance the sensitivity of cisplatin-based therapy in SCLC patients.

Resveratrol Reduced Liver Damage After Liver Resection in a Rat Model by Upregulating Sirtuin 1 (SIRT1) and Inhibiting the Acetylation of High Mobility Group Box 1 (HMGB1).

BACKGROUND Liver failure after resection for liver cancer is associated with increased patient mortality. This study aimed to investigate the mechanism of the protective effects of resveratrol, a natural plant-derived compound, on liver injury in a rat model of partial hepatectomy. MATERIAL AND METHODS Adult male Sprague-Dawley (SD) rats (n=60) were divided into the sham group (n=20), the liver resection group (n=20), and the liver resection plus resveratrol-treated group (n=20). Liver resection removed 2/3 of the liver resection; resveratrol was given at a dose of 30 mg/kg/day from one week before surgery until death. Liver injury was assessed by serum liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl-transferase (γ-GT) and total bilirubin, histological examination of the rat liver, and liver cell apoptosis using the TUNEL assay. High mobility group box 1 (HMGB1) expression was measured by enzyme-linked immunoassay (ELISA). Sirtuin 1 (SIRT1) and acetylated HMGB1 (Ac-HMGB1) expression were detected by Western blot. Normal human liver cells and HepG2 liver cancer cells were incubated with acetylated HMGB1, and albumin production and ammonia elimination assays were performed. RESULTS Resveratrol reduced postoperative liver injury as shown by reduced ALT, AST, γ-GT, and total bilirubin levels, maintained liver structure, and reduced cell apoptosis. Resveratrol treatment reduced the expression and acetylation levels of HMGB1 via the SIRT1 signaling pathway. Resveratrol reversed Ac-HMGB1 induced dysfunction in liver cells cultured in vitro. CONCLUSIONS Resveratrol reduced liver damage after liver resection in a rat model by upregulating SIRT1 and reducing the acetylation of HMGB1.

GDF11 Inhibits Bone Formation by Activating Smad2/3 in Bone Marrow Mesenchymal Stem Cells.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-ß superfamily. Recent studies confirmed that GDF11 plays an important role in regulating the regeneration of brain, skeletal muscle, and heart during aging; however, its role in bone metabolism remains unclear. Thus, the aim of this study was to determine the effects of GDF11 on bone metabolism, including bone formation and bone resorption, both in vitro and in vivo. Our results showed that GDF11 inhibited osteoblastic differentiation of bone marrow mesenchymal stem cells in vitro. Mechanistically, GDF11 repressed Runx2 expression by inducing SMAD2/3 phosphorylation during osteoblast differentiation. Moreover, intraperitoneal injection of GDF11 inhibited bone formation and accelerated age-related bone loss in mice. Our results also showed that GDF11 had no effect on osteoclast differentiation or bone resorption both in vitro and in vivo. These results provide a further rationale for the therapeutic targeting of GDF11 for the treatment of age-related osteoporosis.

Predictive factors for prolonged remission after autologous hematopoietic stem cell transplantation in young patients with type 1 diabetes mellitus.

BACKGROUND AIMS: Autologous hematopoietic stem cell transplantation (auto-HSCT) followed by immunoablation is a promising therapy for type 1 diabetes mellitus (T1DM) treatment due to the immunosuppression and immunomodulation mechanisms. Indeed, a considerable number of patients have been able to discontinue insulin use with this treatment. However, nonresponse and relapse occur after auto-HSCT. It is important to select the patients who can potentially benefit from this treatment, but the factors that might influence the therapeutic outcome are unclear. The objective of this study was to explore the predictors for prolonged remission after auto-HSCT therapy. METHODS: The data for this study were extracted from an open-label prospective study, which was performed to treat new-onset T1DM patients with auto-HSCT. The 128 patients were categorized into insulin-free (IF) or insulin-dependent (ID) groups according to their response to treatment during the follow-up. We compared the baseline data of the two groups and explored possible prognostic factors and their odd ratios (ORs) with univariate analysis and multivariate logistic regression. Receiver operating characteristic curves (ROC) were performed to test the model discrimination function. RESULTS: During a follow-up of 28.5 ± 8.3 months, 71 of 128 patients in the IF group discontinued insulin use, whereas 57 of 128 patients in the ID group did not decrease their insulin dose or resumed insulin treatment after a transient remission. Multivariate logistic regression analysis demonstrated that prolonged remission was positively correlated with fasting C-peptide level (OR = 2.60, 95% confidence interval [CI]: 1.16-5.85) but negatively correlated with onset age (OR = 0.36, 95% CI: 0.14-0.88) and tumor necrosis factor-α levels (OR = 0.32, 95% CI: 0.14-0.73). ROC analysis confirmed the combined predictive function of these three variables (AUC = 0.739, 95% CI: 0.655-0.824). CONCLUSIONS: Age and fasting C-peptide and tumor necrosis factor-α levels were identified as possible predictors for prolonged remission following auto-HSCT therapy.

Age-related bone turnover markers and osteoporotic risk in native Chinese women.

BACKGROUND: The rate of bone turnover is closely related to osteoporosis risk. We investigated the correlation between bone turnover markers and BMD at various skeletal sites in healthy native Chinese women, and to study the effect of changes in the levels of bone turnover markers on the risk of osteoporosis. METHODS: A cross-section study of 891 healthy Chinese women aged 20-80 years was conducted. The levels of serum osteocalcin (OC), bone-specific alkaline phosphatase (BAP), serum cross-linked N-terminal telopeptides of type I collagen (sNTX), cross-linked C-terminal telopeptides of type I collagen (sCTX), urinary NTX (uNTX), urinary CTX (uCTX) and total urinary deoxypyridinoline (uDPD) were determined. BMD at the posteroanterior spine and the hip was measured using DXA. RESULTS: Pearson's correlation coefficient found significant negative correlation between bone turnover marker and BMD T-score at different skeletal sites (r = -0.08 to -0.52, all P = 0.038-0.000). After adjustments for age and body mass index, the partial correlation coefficients between the OC, BAP, sNTX, sCTX and uCTX, and the T-scores at various skeletal sites were still significant. After adjustment of height and weight, the correlation coefficients between most BTMs and PA lumbar spine BMD were also significant. Multiple linear regression analysis showed that bone turnover markers were negative determinants of T-scores. BAP and OC accounted for 33.1% and 7.8% of the variations in the T-scores of the PA spine, respectively. Serum OC, BAP, uDPD, and sNTX accounted for 0.4-21.9% of the variations in the femoral neck and total hip T-scores. The bone turnover marker levels were grouped as per quartile intervals, and the T-scores, osteoporosis prevalence and risk were found to markedly and increase with increase in bone turnover marker levels. CONCLUSIONS: This study clarified the relationship between bone turnover markers and osteoporosis risk in native Chinese women. Bone turnover marker levels were found to be important determinants of BMD T-scores. Furthermore, osteoporotic risk significantly increased with increase in the levels of bone turnover markers.

Energy homeostasis in the bone.

The bone serves as an energy reservoir and actively engages in whole-body energy metabolism. Numerous studies have determined fuel requirements and bioenergetic properties of bone under physiological conditions as well as the dysregulation of energy metabolism associated with bone metabolic diseases. Here, we review the main sources of energy in bone cells and their regulation, as well as the endocrine role of the bone in systemic energy homeostasis. Moreover, we discuss metabolic changes that occur as a result of osteoporosis. Exploration in this area will contribute to an enhanced comprehension of bone energy metabolism, presenting novel possibilities to address metabolic diseases.

Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma.

Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing.

Background: Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying mechanism of mechanical regulation of fracture healing is elusive. Methods: We used the lineage-tracing mouse model, conditional knockout depletion mouse model, hindlimb unloading model and single-cell RNA sequencing to analyze the crucial roles of mechanosensitive protein polycystin-1 (PC1, Pkd1) promotes periosteal stem/progenitor cells (PSPCs) osteochondral differentiation in fracture healing. Results: Our results showed that cathepsin (Ctsk)-positive PSPCs are fracture-responsive and mechanosensitive and can differentiate into osteoblasts and chondrocytes during fracture repair. We found that polycystin-1 declines markedly in PSPCs with mechanical unloading while increasing in response to mechanical stimulus. Mice with conditional depletion of Pkd1 in Ctsk+ PSPCs show impaired osteochondrogenesis, reduced cortical bone formation, delayed fracture healing, and diminished responsiveness to mechanical unloading. Mechanistically, PC1 facilitates nuclear translocation of transcriptional coactivator TAZ via PC1 C-terminal tail cleavage, enhancing osteochondral differentiation potential of PSPCs. Pharmacological intervention of the PC1-TAZ axis and promotion of TAZ nuclear translocation using Zinc01442821 enhances fracture healing and alleviates delayed union or nonunion induced by mechanical unloading. Conclusion: Our study reveals that Ctsk+ PSPCs within the callus can sense mechanical forces through the PC1-TAZ axis, targeting which represents great therapeutic potential for delayed fracture union or nonunion.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.

Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

[Relationship of age-related levels of serum sex hormones with bone mineral density decreasing rate in women].

OBJECTIVE: To explore the relationship between the changes of estrogen, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and bone mineral density (BMD) decreasing rate (BDR) at different skeletal regions and examine the effects of hormones levels on BDR. METHODS: An age cross-sectional study was conducted in 694 healthy adult women excluded from diseases and drugs affecting bone metabolism. Their age range was 20-80 years. The serum concentrations of FSH, LH and estradiol (E2) were measured with radioimmunoassay. And BDR was measured with a DXA fan-beam bone densitometer at various skeletal regions including lumbar spine, left hip and left forearm. RESULTS: The serum levels of FSH (r = -0.597 to -0.479, all P < 0.01) and LH r = -0.452 to -0.283, all P < 0.01) were significantly negatively correlated with BDR at various skeletal regions. Meanwhile, the serum level of E2 only had slightly positive correlation with hip and distal forearm (r = 0.077 to 0.122, all P < 0.05). After adjusting age and body mass index (BMI), serum FSH still had markedly negative correlation with BDR at various skeletal regions. However, the correlation coefficients became weak. Multiple line regression stepwise analysis revealed that serum FSH was a negative determinant factor of BDR at various skeletal regions: 20%-32% changes in BDR of various skeletal regions were determined by FSH, while LH only produced very small negative effects (0.6%-0.8%) on BDR of lumbar spine. Serum E2 seemed to be a positive determinant factor of skeletal regions and 2.5%-5.4% changes in BDR were determined by E2. The effects of serum FSH on BDR were approximately 3.8-12.8 folds than those of serum E2. CONCLUSIONS: BDR is correlated with increased FSH in women. The most critical factor for aging-related BDR is FSH in women while a decreased level of estrogen may be secondary.

Metal oxide nanoparticles embedded in porous carbon for sulfur absorption under hydrothermal conditions.

MOx (M = Zn, Cu, Mn, Fe, Ce) nanoparticles (NPs) embedded in porous C with uniform diameter and dispersion were synthesized, with potential application as S-absorbents to protect catalysts from S-poisoning in catalytic hydrothermal gasification (cHTG) of biomass. S-absorption performance of MOx/C was evaluated by reacting the materials with diethyl disulfide at HTG conditions (450 °C, 30 MPa, 15 min). Their S-absorption capacity followed the order CuOx/C > CeOx/C ≈ ZnO/C > MnOx/C > FeOx/C. S was absorbed in the first four through the formation of Cu1.8S, Ce2S3, ZnS, and MnS, respectively, with a capacity of 0.17, 0.12, 0.11, and 0.09 molS molM-1. The structure of MOx/C (M = Zn, Cu, Mn) evolved significantly during S-absorption reaction, with the formation of larger agglomerates and separation of MOx particles from porous C. The formation of ZnS NPs and their aggregation in place of hexagonal ZnO crystals indicate a dissolution/precipitation mechanism. Note that aggregated ZnS NPs barely sinter under these conditions. Cu(0) showed a preferential sulfidation over Cu2O, the sulfidation of the latter seemingly following the same mechanism as for ZnO. In contrast, FeOx/C and CeOx/C showed remarkable structural stability with their NPs well-dispersed within the C matrix after reaction. MOx dissolution in water (from liquid to supercritical state) was modeled and a correlation between solubility and particle growth was found, comforting the hypothesis of the importance of an Ostwald ripening mechanism. CeOx/C with high structural stability and promising S-absorption capacity was suggested as a promising bulk absorbent for sulfides in cHTG of biomass.

Refining the time-frequency characteristic of non-stationary signal for improving time-frequency representation under variable speeds.

Time-frequency ridge not only exhibits the variable process of non-stationary signal with time changing but also provides the information of signal synchronous or non-synchronous components for subsequent detection research. Consequently, the key is to decrease the error between real and estimated ridge in the time-frequency domain for accurate detection. In this article, an adaptive weighted smooth model is presented as a post-processing tool to refine the time-frequency ridge which is based on the coarse estimated time-frequency ridge using newly emerging time-frequency methods. Firstly, the coarse ridge is estimated by using multi-synchrosqueezing transform for vibration signal under variable speed conditions. Secondly, an adaptive weighted method is applied to enhance the large time-frequency energy value location of the estimated ridge. Then, the reasonable smooth regularization parameter associated with the vibration signal is constructed. Thirdly, the majorization-minimization method is developed for solving the adaptive weighted smooth model. Finally, the refined time-frequency characteristic is obtained by utilizing the stop criterion of the optimization model. Simulation and experimental signals are given to validate the performance of the proposed method by average absolute errors. Compared with other methods, the proposed method has the highest performance in refinement accuracy.