Formation mechanism of co-axial grain boundaries in a Mg alloy

Due to the insufficient slip systems in hexagonal close-packed structure,twinning is frequently activated to support stable plastic deformation of Mg alloy.In this work,we found four typical twin-like interfaces with misorientations of 102°,109°,142°and 149°,respectively,which had not only a shared[1120]zone axis of neighboring grains,but also overlapped diffraction spots similar to twins.However,highresolution transmission electron microscope(HRTEM)analysis revealed that the interfaces in real space deviated from the supposed twinning planes in reciprocal space,i.e.their overlapped diffraction spots.We clarified that the incoherent interfaces were co-axial grain boundaries(CGBs).Additionally,a special angle ofθ,close to 90°,between the interface and one side of basal plane,was frequently formed in CGBs.We proposed that interaction of multiple twinning contributes to the formation of CGBs,and theθis formed due to alternative tensile and compression twinning under a uniaxial loading.

A green cross-linking method for the preparation of renewable threedimensional graphene sponges for efficient adsorption of Congo red dye

Graphene-based materials possess significant potential for the treatment of dye wastewater due to their exceptional adsorption properties toward stubborn pollutants.However,their utilization is hindered by high preparation costs,low yields,environmental pollution during synthesis,and challenges in regenerating the adsorbent.This study proposes a novel approach to address these limitations by developing nitrogen-doped three-dimensional(3D)polyvinyl alcohol(PVA)crosslinked graphene sponges(N-PGA)using a cross-linking method with ammonium carbonate.This method offers a relatively mild,environmentally friendly approach.Ammonium carbonate serves as both a reducing and modifying agent,facilitating the formation of the intrinsic structure of N-PGA and acting as a nitrogen source.Meanwhile,PVA is utilized as the cross-linking agent.The results demonstrate that N-PGA exhibits a favorable internal 3D hierarchical porous structure and possesses robust mechanical properties.The measured specific surface area(BET)of N-PGA was as high as406.538 m^(2)·g^(-1),which was favorable for its efficient adsorption of Congo red(CR)dye molecules.At an initial concentration of 50 mg·L^(-1),N-PGA achieved an impressive removal rate of 89.6%and an adsorption capacity of 112 mg·g^(-1)for CR dye.Furthermore,it retained 79%of its initial adsorption capacity after 10 cycles,demonstrating excellent regeneration performance.In summary,the synthesized N-PGA displays remarkable efficacy in the adsorption of CR dye in wastewater,opening up new possibilities for utilizing 3D porous graphene nanomaterials as efficient adsorbents in wastewater treatment.

Prediction and driving factors of forest fire occurrence in Jilin Province,China

Forest fires are natural disasters that can occur suddenly and can be very damaging,burning thousands of square kilometers.Prevention is better than suppression and prediction models of forest fire occurrence have developed from the logistic regression model,the geographical weighted logistic regression model,the Lasso regression model,the random forest model,and the support vector machine model based on historical forest fire data from 2000 to 2019 in Jilin Province.The models,along with a distribution map are presented in this paper to provide a theoretical basis for forest fire management in this area.Existing studies show that the prediction accuracies of the two machine learning models are higher than those of the three generalized linear regression models.The accuracies of the random forest model,the support vector machine model,geographical weighted logistic regression model,the Lasso regression model,and logistic model were 88.7%,87.7%,86.0%,85.0%and 84.6%,respectively.Weather is the main factor affecting forest fires,while the impacts of topography factors,human and social-economic factors on fire occurrence were similar.

Ligand modulation of active center to promote lead-free Cs_(2)AgInCl_(6)photocatalytic CO_(2)reduction

Metal halide perovskites(MHP)are potential candidates for the photocatalytic reduction of CO_(2)due to their long photogenerated carrier lifetime and charge diffusion length.However,the conventional long-chain ligand impedes the adsorption and activation of CO_(2)molecules in practical applications.Here,a ligand modulation technology is employed to enhance the photocatalytic CO_(2)reduction activity of lead-free Cs_(2)AgInCl_(6)microcrystals(MCs).The Cs_(2)AgInCl_(6)MCs passivated by Oleic acid(OLA)and Octanoic acid(OCA)are used for photocatalytic CO_(2)reduction.The results show that the surface defects and electronic properties of Cs_(2)AgInCl_(6)MCs can be adjusted through ligand modulation.Compared with the OLA-Cs_(2)AgInCl_(6),the OCA-Cs_(2)AgInCl_(6)catalyst demonstrated a significant improvement in the catalytic yield of CO and CH_(4).The CO and CH_(4)catalytic yields of OCA-Cs_(2)AgInCl_(6)reached 171.88 and34.15μmol g^(-1)h^(-1)which were 2.03 and 12.98 times higher than those of OLA-Cs_(2)AgInCl_(6),and the total electron consumption rate of OCA-Cs_(2)AgInCl_(6)was 615.2μmol g^(-1)h^(-1)which was 3.25 times higher than that of OLA-Cs_(2)AgInCl_(6).Furthermore,in situ diffuse reflectance infrared Fourier transform spectra revealed the enhancement of photocatalytic activity in Cs_(2)AgInCl_(6)MCs induced by ligand modulation.This study illustrates the potential of lead-free Cs_(2)AgInCl_(6)MCs for efficient photocatalytic CO_(2)reduction and provides a ligand modulation strategy for the active promotion of MHP photocatalysts.

Preoperative controlling nutritional status as an optimal prognostic nutritional index to predict the outcome for colorectal cancer

BACKGROUND The controlling nutritional status(CONUT)score effectively reflects a patient’s nutritional status,which is closely related to cancer prognosis.This study invest-igated the relationship between the CONUT score and prognosis after radical surgery for colorectal cancer,and compared the predictive ability of the CONUT score with other indexes.AIM To analyze the predictive performance of the CONUT score for the survival rate of colorectal cancer patients who underwent potentially curative resection.METHODS This retrospective analysis included 217 patients with newly diagnosed colorectal.The CONUT score was calculated based on the serum albumin level,total lymphocyte count,and total cholesterol level.The cutoff value of the CONUT score for predicting prognosis was 4 according to the Youden Index by the receiver operating characteristic curve.The associations between the CONUT score and the prognosis were performed using Kaplan-Meier curves and Cox regression analysis.RESULTS Using the cutoff value of the CONUT score,patients were stratified into CONUT low(n=189)and CONUT high groups(n=28).The CONUT high group had worse overall survival(OS)(P=0.013)and relapse-free survival(RFS)(P=0.015).The predictive performance of CONUT was superior to the modified Glasgow prognostic score,the prognostic nutritional index,and the neutrophil-to-lymphocyte ratio.Meanwhile,the predictive performances of CONUT+tumor node metastasis(TNM)stage for 3-year OS[area under the receiver operating characteristics curve(AUC)=0.803]and 3-year RFS(AUC=0.752)were no less than skeletal muscle mass index(SMI)+TNM stage.The CONUT score was negatively correlated with SMI(P<0.01).CONCLUSION As a nutritional indicator,the CONUT score could predict long-term outcomes after radical surgery for colorectal cancer,and its predictive ability was superior to other indexes.The correlation between the CONUT score and skeletal muscle may be one of the factors that play a predictive role.

Exploration of cardiac rehabilitation nursing for elderly patients with myocardial infarction based on individualized cardiac rehabilitation

BACKGROUND Myocardial infarction is a high-risk condition prevalent among the elderly population,often leading to adverse clinical manifestations such as reduced cardiopulmonary function,anxiety,and depression post-surgery.Consequently,cardiac rehabilitation holds immense importance in mitigating these complications.AIM To evaluate the effect of individualized cardiac rehabilitation on blood pressure variability(BPV)and baroreflex sensitivity(BRS)in elderly patients with myocardial infarction.METHODS A cohort of 74 elderly patients diagnosed with myocardial infarction and admitted to our hospital between January 2021 and January 2022 were subjected to random selection.Subsequently,all patients were divided into two groups,namely the research group(n=37)and the control group(n=37),utilizing the number table method.The control group received conventional drug treatment and nursing guidance intervention,while the study group underwent individualized cardiac rehabilitation in addition to the interventions received by the control group.All patients were continuously intervened for 12 wk,and the BPV of these two groups in the 1st wk(T0),the 4th wk(T1)and the 12th wk(T2)were compared,BRS,changes in cardiopulmonary function measures,and adverse cardiovascular events.RESULTS Of 24 h diastolic BPV,24 h systolic BPV,carbon dioxide ventilation equivalent slope of the research group were lower than those of the control group at T1 and T2,BRS,peak heart rate and systolic blood pressure product,1 min heart rate recovery were higher than those of the control group,and the incidence of adverse events in the research group was lower than that of the control group,the difference was statistically significant(P<0.05).CONCLUSION In this study,we found that after individualized cardiac rehabilitation in elderly patients with myocardial infarction,BPV and BRS can be effectively improved,cardiac function is significantly enhanced,and a better prognosis is obtained.

Meta-analysis of the clinical efficacy of the Gamma3 nail vs Gamma3U-blade system in the treatment of intertrochanteric fractures

BACKGROUND The traditional Gamma3 nail is a mainstream treatment for femoral intertrochanteric fractures.Literature reports that the Gamma3U-blade system can increase the stability of the Gamma3 nail and reduce complication incidence.However,comparative studies between the Gamma3U-blade and Gamma3 systems are limited;hence,this meta-analysis was performed to explore the clinical efficacy of these two surgical methods.AIM To investigate the clinical efficacy of Gamma3 and Gamma3 U-blade for intertrochanteric fractures.METHODS A computerized search for Chinese and English literature published from 2010 to 2022 was conducted in PubMed,Cochrane,CNKI,Wanfang,and VIP databases.The search keywords were gamma 3,gamma 3 U blade,and intertrochanteric fracture.Additionally,literature tracking was performed on the references of published literature.The data were analyzed using Revman 5.3 software.Two individuals checked the inputs for accuracy.Continuous variables were described using mean difference and standard deviation,and outcome effect sizes were expressed using ratio OR and 95%confidence interval(CI).High heterogeneity was considered at(P<0.05,I2>50%),moderate heterogeneity at I2 from 25%to 50%,and low heterogeneity at(P≥0.05,I2<50%).RESULTS Following a comprehensive literature search,review,and analysis,six articles were selected for inclusion in this study.This selection comprised five articles in English and one in Chinese,with publication years spanning from 2016 to 2022.The study with the largest sample size,conducted by Seungbae in 2021,included a total of 304 cases.Statistical analysis:A total of 1063 patients were included in this meta-analysis.The main outcome indicators were:Surgical time:The Gamma3U blade system had a longer surgical time compared to Gamma3 nails(P=0.006,I2=76%).Tip-apex distance:No statistical significance or heterogeneity was observed(P=0.65,I2=0%).Harris Hip score:No statistical significance was found,and low heterogeneity was detected(P=0.26,I2=22%).Union time:No statistical significance was found,and high heterogeneity was detected(P=0.05,I2=75%).CONCLUSION Our study indicated that the Gamma3 system reduces operative time compared to the Gamma3 U-blade system in treating intertrochanteric fractures.Both surgical methods proved to be safe and effective for this patient group.These findings may offer valuable insights and guidance for future surgical protocols in hip fracture patients.

Gα_s signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling

How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Gαs that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia(FD) or progressive osseous heteroplasia(POH) that shows craniofacial hyperostosis or craniosynostosis, respectively. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Gαsregulates Hh signaling in a ligand-independent manner. We further show that Gαscontrols intramembranous ossification by regulating both Hh and Wnt/β-catenin signaling. In addition, Gαsactivation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases.

NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts

The adaptor protein NUMB is involved in asymmetric division and cell fate determination and recognized as an antagonist of Notch.Previous studies have proved that Notch activation in osteoblasts contributes to a high bone mass. In this study, however, an osteopenic phenotype was found in 9-week-old mice using osteoblastic specific Col1a1–2.3-Cre to ablate both Numb and its homologue Numbl. The trabecular bone mass decreased dramatically while the cortical bone mass was unaffected. Here, the Notch signal was not activated,while the tensin homologue deleted on human chromosome 10(PTEN), which dephosphorylates phosphatidylinositide 3-kinases, was elevated, attenuating protein kinase B(Akt). The ubiquitination assay revealed that NUMB may physiologically promote PTEN ubiquitination in the presence of neural precursor cell-expressed developmentally downregulated protein 4–1. In addition, the deficiency of Numb/Numbl also activated the Hedgehog pathway through GLI1. This process was found to improve the ratio of the receptor activator of nuclear factor-k B ligand to osteoprotegerin, which enhanced the differentiation of osteoclasts and bone resorption. In conclusion, this study provides an insight into new functons of NUMB and NUMBL on bone homeostasis.

microRNA Expression in Rat Apical Periodontitis Bone Lesion

Apical periodontitis, dominated by dense inflammatory infiltrates and increased osteoclast activities, can lead to alveolar bone destruction and tooth loss. It is believed that miRNA participates in regulating various biological processes, osteoclastogenesis included. This study aims to investigate the differential expression of miRNAs in rat apical periodontitis and explore their functional target genes. Microarray analysis was used to identify differentially expressed miRNAs in apical periodontitis. Bioinformatics technique was applied for predicting the target genes of differentially expressed miRNAs and their biological functions. The result provided us with an insight into the potential biological effects of the differentially expressed miRNAs and showed particular enrichment of target genes involved in the MAPK signaling pathways. These findings may highlight the intricate and specific roles of miRNA in inflammation and osteoclastogenesis, both of which are key aspects of apical periodontitis, thus contributing to the future investigation into the etiology, under- lying mechanism and treatment of apical periodontitis.

Intracardiac,pulmonary cement embolism in a 67-year-old female after cement-augmented pedicle screw instrumentation:A case report and review of literature

BACKGROUND We report a case of Intracardiac,pulmonary,and intravenous cement embolism after cement-augmented pedicle screw instrumentation in treating spondylolisthesis underlying osteoporotic bone,which was successfully managed by conservative treatment.We describe the treatment and outcome of the patient,hoping to shed light on the management of bone cement embolism.CASE SUMMARY A 67-year-old female suffered from progressive low back pain and numbness in lower extremities for 30 years.She was diagnosed with L4 and L5 spondylolisthesis,spinal stenosis,and osteoporosis.The patient underwent spinal canal decompression,an interbody fusion of L4/5 and L5/S1,cement-augmented pedicle screw instrumentation in L4-L5 segments,and regular pedicle screw in S1 segments.Three days postoperatively,a sudden drop in oxygen saturation occurred.Computerized tomography scan confirmed Intracardiac,pulmonary,and intravenous embolism.The patient was treated conservatively by continuous low-flow oxygen inhalation,anti-coagulation,and antibiotic therapy for 1 mo and continued anticoagulation treatment for 6 mo.The patient showed no further symptoms in a 30-mo follow-up.CONCLUSION Intracardiac,pulmonary cement embolism after cement-augmented pedicle screw instrumentation is extremely rare.Careful clinical and radiographic evaluation is required in multiple sites of bone cement embolism.Conservative treatment may be a primary consideration in scattered emboli without life-threatening conditions,but a clinical decision should be made on an individualized basis.

His bundle pacing versus left bundle branch pacing on ventricular function in atrial fibrillation patients referred for pacing:a prospective crossover comparison

BACKGROUND His bundle pacing(HBP)and left bundle branch pacing(LBBP)both provide physiologic pacing which maintain left ventricular synchrony.They both improve heart failure(HF)symptoms in atrial fibrillation(AF)patients.We aimed to assess the intra-patient comparison of ventricular function and remodeling as well as leads parameters corresponding to two pacing modalities in AF patients referred for pacing in intermediate term.METHODS Uncontrolled tachycardia AF patients with both leads implantation successfully were randomized to either modality.Echocardiographic measurements,New York Heart Association(NYHA)classification,quality-of-life assessments and leads parameters were obtained at baseline and at each 6-month follow up.Left ventricular function including the left ventricular endosystolic volume(LVESV),left ventricular ejection fraction(LVEF)and right ventricular(RV)function quantified by tricuspid annular plane systolic excursion(TAPSE)were all assessed.RESULTS Consecutively twenty-eight patients implanted with both HBP and LBBP leads successfully were enrolled(69.1±8.1 years,53.6% male,LVEF 59.2%±13.7%).The LVESV was improved by both pacing modalities in all patients(n=23)and the LVEF was improved in patients with baseline LVEF at less than 50%(n=6).The TAPSE was improved by HBP but not LBBP(n=23).CONCLUSION In this crossover comparison between HBP and LBBP,LBBP was found to have an equivalent effect on LV function and remodeling but better and more stable parameters in AF patients with uncontrolled ventricular rates referred for atrioventricular node(AVN)ablation.HBP could be preferred in patients with reduced TAPSE at baseline rather than LBBP.

CHRM3 is a novel prognostic factor of poor prognosis andpromotes glioblastoma progression via activation of oncogenicinvasive growth factors

Glioblastoma(GBM)is the most aggressive cancer of the brain and has a high mortality rate due to the lack of effective treatment strategy.Clarification of molecular mechanisms of GBM’s characteristic invasive growth is urgently needed to improve the poor prognosis.Single-nuclear sequencing of primary and recurrent GBM samples revealed that levels of M3 muscarinic acetylcholine receptor(CHRM3)were significantly higher in the recurrent samples than in the primary samples.Moreover,immunohistochemical staining of an array of GBM samples showed that high levels of CHRM3 correlated with poor prognosis,consistent with The Cancer Genome Atlas database.Knockdown of CHRM3 inhibited GBM cell growth and invasion.An assay of orthotopic GBM animal model in vivo indicated that inhibition of CHRM3 significantly suppressed GBM progression with prolonged survival time.Transcriptome analysis revealed that CHRM3 knockdown significantly reduced an array of classic factors involved in cancer invasive growth,including MMP1/MMP3/MMP10/MMP12 and CXCL1/CXCL5/CXCL8.Taken together,CHRM3 is a novel and vital factor of GBM progression via regulation of multiple oncogenic genes and may serve as a new biomarker for prognosis and therapy of GBM patients.

Transition-edge sensors using Mo/Au/Au tri-layer films

The proximity effect to reduce the transition temperature of a superconducting film is frequently used in transitionedge sensors. Here, we develop these transition-edge sensors using Mo/Au/Au tri-layer films to detect soft x-rays. They are equipped with an overhanging photon absorber. We reduce the fabrication complexity by integrating the sensor patterning with the tri-layer film formation. We determine the electro-thermal parameters of the sensors through a series of resistance vs. temperature and current vs. voltage measurements. We also demonstrate their energy-resolving capability by using a55Fe radioactive x-ray source. The best energy resolution was approximately 6.66 eV at 5.9 keV, with a theoretical count rate of 500 Hz.

Increasing linear flux range of SQUID amplifier using self-feedback effect

Superconducting quantum interference devices(SQUIDs) are low-noise amplifiers that are essential for the readouts of translation edge sensors(TESs). The linear flux range is an important parameter for SQUID amplifiers, especially those controlled by high-bandwidth digital flux-locked-loop circuits. A large linear flux range conduces to accurately measuring the input signal and also increasing the multiplexing factor in the time-division multiplexed(TDM) readout scheme of the TES array. In this work, we report that the linear flux range of an SQUID can be improved by using self-feedback effect. When the SQUID loop is designed to be asymmetric, a voltage-biased SQUID shows an asymmetric current–flux(I–Φ) response curve. The linear flux range is improved along the I–Φ curve with a shallow slope. The experimental results accord well with the numerical simulations. The asymmetric SQUID will be able to serve as a building block in the development of the TDM readout systems for large TES arrays.

Establishment and Optimization of Ablation Surrogate Model for Thermal Protection Material

The temperature response calculation of thermal protection materials,especially ablative thermal protection materials,usually adopts the ablation model,which is complicated in process and requires a large amount of calculation.Especially in the process of optimization calculation and parameter identification,the ablation model needs to be called many times,so it is necessary to construct an ablation surrogate model to improve the computational efficiency under the premise of ensuring the accuracy.In this paper,the Gaussian process model method is used to construct a thermal protection material ablation surrogate model,and the prediction accuracy of the surrogate model is improved through optimization.

Pure-high-even-order dispersion bound solitons complexes in ultra-fast fiber lasers

Temporal solitons have been the focus of much research due to their fascinating physical properties.These solitons can form bound states,which are fundamentally crucial modes in fiber laser and present striking analogies with their matter molecules counterparts,which means they have potential applications in large-capacity transmission and alloptical information storage.Although traditionally,second-order dispersion has been the dominant dispersion for conventional solitons,recent experimental and theoretical research has shown that pure-high-even-order dispersion(PHEOD)solitons with energy-width scaling can arise from the interaction of arbitrary negative-even-order dispersion and Kerr nonlinearity.Despite these advancements,research on the bound states of PHEOD solitons is currently nonexistent.In this study,we obtained PHEOD bound solitons in a fiber laser using an intra-cavity spectral pulse shaper for high-order dispersion management.Specifically,we experimentally demonstrate the existence of PHEOD solitons and PHEOD bound solitons with pure-quartic,-sextic,-octic,and-decic dispersion.Numerical simulations corroborate these experimental observations.Furthermore,vibrating phase PHEOD bound soliton pairs,sliding phase PHEOD bound soliton pairs,and hybrid phase PHEOD bound tri-soliton are discovered and characterized.These results broaden the fundamental understanding of solitons and show the universality of multi-soliton patterns.

内镜经黏膜下隧道肿瘤切除术治疗食管贲门周围黏膜下肿瘤的疗效分析

目的探讨内镜经黏膜下隧道肿瘤切除术(STER)治疗食管贲门周围黏膜下肿瘤(SMT)的临床效果及安全性。方法收集2012年9月-2018年6月在南京医科大学附属南京医院内镜中心采用STER治疗的50例食管贲门周围SMT患者的临床资料,并进行分析。结果50例患者均完成STER。食管病变33例,贲门周围、胃底病变17例,1例病变为2个瘤体,其他均为单个瘤体。成功切除所有SMT,一次性完整切除率96.0%,手术时间32~115 min,平均(54.0±24.5)min,完整缝合创面所需金属夹4~8枚,平均(5.6±2.1)枚。术后瘤体直径0.8~3.3 cm,平均(1.6±0.4)cm。术后经常规病理及免疫组化染色确诊为平滑肌瘤40例(80.0%),间质瘤7例(14.0%),食管支气管源性囊肿2例(4.0%),钙化性纤维性肿瘤1例(2.0%),切缘均为阴性。4例术中发生穿孔,3例术中发生皮下气肿,3例术后出现发热,均经保守治疗痊愈。住院时间6~15 d,平均(7.8±3.7)d。结论STER对食管贲门周围SMT有较高的完整切除率,且手术创伤小,恢复快,并发症较少,住院时间较短。

Collagen type Ⅱ suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1-SMAD1 interaction

Hypertrophic differentiation is not only the terminal process of endochondral ossification in the growth plate but is also an important pathological change in osteoarthritic cartilage.Collagen type II(COL2A1)was previously considered to be only a structural component of the cartilage matrix,but recently,it has been revealed to be an extracellular signaling molecule that can significantly suppress chondrocyte hypertrophy.However,the mechanisms by which COL2A1 regulates hypertrophic differentiation remain unclear.In our study,a Col2a1 p.Gly1170Ser mutant mouse model was constructed,and Col2a1 loss was demonstrated in homozygotes.Loss of Col2a1 was found to accelerate chondrocyte hypertrophy through the bone morphogenetic protein(BMP)-SMAD1 pathway.Upon interacting with COL2A1,integrinβ1(ITGB1),the major receptor for COL2A1,competed with BMP receptors for binding to SMAD1 and then inhibited SMAD1 activation and nuclear import.COL2A1 could also activate ITGB1-induced ERK1/2 phosphorylation and,through ERK1/2-SMAD1 interaction,it further repressed SMAD1 activation,thus inhibiting BMP-SMAD1-mediated chondrocyte hypertrophy.Moreover,COL2A1 expression was downregulated,while chondrocyte hypertrophic markers and BMP-SMAD1 signaling activity were upregulated in degenerative human articular cartilage.Our study reveals novel mechanisms for the inhibition of chondrocyte hypertrophy by COL2A1 and suggests that the degradation and decrease in COL2A1 might initiate and promote osteoarthritis progression.

Ciliary parathyroid hormone signaling activates transforming growth factor-βto maintain intervertebral disc homeostasis during aging

Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.