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.

Targeting the senescence-related genes MAPK12 and FOS to alleviate osteoarthritis.

Background: The mechanism by which chondrocyte senescence aggravate OA progression has not yet been well elucidated. The aim of this study was to investigate the chondrocyte senescence related gene biosignatures in OA, and to analyze on the underlying mechanisms of senescence in OA. Materials and methods: We intersected osteoarthritis dataset GSE82107 from GEO database and senescence dataset from CellAge database of human senescence-associated genes based on genetic manipulations experiments plus gene expression profilin, and screened out 4 overlapping genes. The hub genes were verified in vitro and in human OA cartilage tissues by qRT-PCR. We further confirmed the function of mitogen-activated protein kinase 12 (MAPK12) and Fos proto-oncogene (FOS) in OA in vitro and in vivo by qRT-PCR, western blotting, Edu staining, immunofluorescence, SA-ß-gal staining, HE, IHC, von frey test, and hot plate. Results: 1458 downregulated and 218 upregulated DEGs were determined from GSE82107, and 279 human senescence-associated genes were downloaded from CellAge database. After intersection assay, we screened out 4 overlapping genes, of which FOS, CYR61 and TNFSF15 were upregulated, MAPK12 was downregulated. The expression of MAPK12 was obviously downregulated, whereas the expression profiles of FOS, CYR61 and TNFSF15 were remarkedly upregulated in H2O2- or IL-1ß-stimulated C28/I2 cells, human OA cartilage tissues, and knee cartilage of aging mice. Furthermore, both MAPK12 over-expression and FOS knock-down can promote cell proliferation and cartilage anabolism, inhibit cell senescence and cartilage catabolism, relieve joint pain in H2O2- or IL-1ß-stimulated C28/I2 cells and mouse primary chondrocytes, destabilization of the medial meniscus (DMM) mice. Conclusion: This study explored that MAPK12 and FOS are involved in the occurrence and development of OA through modulating chondrocyte senescence. They might be biomarkers of OA chondrocyte senescence, and provides some evidence as subsequent possible therapeutic targets for OA. The translational potential of this article: The translation potential of this article is that we revealed MAPK12 and FOS can effectively alleviate OA by regulating chondrocyte senescence, and thus provided potential therapeutic targets for prevention or treatment of OA in the future.

GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease.

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.

Double-layer hollow mesoporous silica nanoparticles for ultrasound-guided photodynamic treatment.

Cervical carcinoma persists as a major global public health burden. While conventional therapeutic modalities inevitably cause ablation of adjacent non-tumorous tissues, photodynamic therapy (PDT) offers a targeted cytotoxic strategy through a photosensitizing agent (PS). However, the hydrophobicity and lack of selective accumulation of promising PS compounds such as zinc(II) phthalocyanine (ZnPc) impedes their clinical translation as standalone agents. The present study sought to incorporate ZnPc within double-layer hollow mesoporous silica nanoparticles (DHMSN) as nanocarriers to enhance aqueous dispersibility and tumor specificity. Owing to their compartmentalized design, the hollow mesoporous silica nanoparticles (HMSN) demonstrated enhanced ultrasonic imaging contrast. Combined with the vaporization of the perfluorocarbon perfluoropentane (PFP), the HMSN-encapsulated ZnPc enabled real-time ultrasound monitoring of PDT treatment.In vivo, the innate thermal energy induced vaporization of the DHMSN-carried PFP to significantly amplify ultrasound signals from the tumor site. Results demonstrated biocompatibility, efficient PFP microbubble generation, and robust photocatalytic activity. Collectively, this investigation establishes ultrasound-guided PDT utilizing multi-layer HMSN as a targeted therapeutic strategy for cervical malignancies with mitigated toxicity.

Spatiotemporal characteristics of tissue derived small extracellular vesicles is associated with tumor relapse and anti-PD-1 response.

Small extracellular vesicles (sEVs) residing at tumor tissues are valuable specimens for biopsy. Tumor heterogeneity is common across all cancer types, but the heterogeneity of tumor tissue-derived sEVs (Ti-sEVs) is undefined. This study aims to discover the spatial distributions of Ti-sEVs in oral squamous cell carcinoma (OSCC) tissues and explore how these vesicle distributions affect the patients' prognosis. Multi-regional sampling enabled us to uncover that Ti-sEVs' accumulation at peritumoral sites correlates with a higher disease-free survival rate, and conversely, sparse peritumoral Ti-sEVs tend to forecast a higher risk of relapse. Of those relapsed patients, Ti-sEVs strongly bind to extracellular matrix and subsequently degrade it for allowing themselves enter the bloodstream rather than staying in situ. In advanced OSCC patients, the quantity and spatial distribution of Ti-sEVs prior to anti-PD-1 treatment, as well as the temporal variance of Ti-sEVs before and after immunotherapy, strongly map the clinical response and can help to distinguish the patients with shrinking tumors from those with growing tumors. Our work elucidates the correlation of spatiotemporal features of Ti-sEVs with patients' therapeutic outcomes and exhibit the potential for using Ti-sEVs as a predictor to forecast prognosis and screen the responders to anti-PD-1 therapy.

In Vitro Glioblastoma Model on a Plate for Localized Drug Release Study from a 3D-Printed Drug-Eluted Hydrogel Mesh.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that has limited treatment options. Current standard therapies, including surgery followed by radiotherapy and chemotherapy, are not very effective due to the rapid progression and recurrence of the tumor. Therefore, there is an urgent need for more effective treatments, such as combination therapy and localized drug delivery systems that can reduce systemic side effects. Recently, a handheld printer was developed that can deliver drugs directly to the tumor site. In this study, the feasibility of using this technology for localized co-delivery of temozolomide (TMZ) and deferiprone (DFP) to treat glioblastoma is showcased. A flexible drug-loaded mesh (GlioMesh) loaded with poly (lactic-co-glycolic acid) (PLGA) microparticles is printed, which shows the sustained release of both drugs for up to a month. The effectiveness of the printed drug-eluting mesh in terms of tumor toxicity and invasion inhibition is evaluated using a 3D micro-physiological system on a plate and the formation of GBM tumoroids within the microenvironment. The proposed in vitro model can identify the effective combination doses of TMZ and DFP in a sustained drug delivery platform. Additionally, our approach shows promise in GB therapy by enabling localized delivery of multiple drugs, preventing off-target cytotoxic effects.

An immobilized composite microbial material combined with slow release agents enhances oil-contaminated groundwater remediation.

Microbial remediation of oil-contaminated groundwater is often limited by the low temperature and lack of nutrients in the groundwater environment, resulting in low degradation efficiency and a short duration of effectiveness. In order to overcome this problem, an immobilized composite microbial material and two types of slow release agents (SRA) were creatively prepared. Three oil-degrading bacteria, Serratia marcescens X, Serratia sp. BZ-L I1 and Klebsiella pneumoniae M3, were isolated from oil-contaminated groundwater, enriched and compounded, after which the biodegradation rate of the Venezuelan crude oil and diesel in groundwater at 15 °C reached 63 % and 79 %, respectively. The composite microbial agent was immobilized on a mixed material of silver nitrate-modified zeolite and activated carbon with a mass ratio of 1:5, which achieved excellent oil adsorption and water permeability performance. The slow release processes of spherical and tablet SRAs (SSRA, TSRA) all fit well with the Korsmeyer-Peppas kinetic model, and the nitrogen release mechanism of SSRA N2 followed Fick's law of diffusion. The highest oil removal rates by the immobilized microbial material combined with SSRA N2 and oxygen SRA reached 94.9 % (sand column experiment) and 75.1 % (sand tank experiment) during the 45 days of remediation. Moreover, the addition of SRAs promoted the growth of oil-degrading bacteria based on microbial community analysis. This study demonstrates the effectiveness of using immobilized microbial material combined with SRAs to achieve a high efficiency and long-term microbial remediation of oil contaminated shallow groundwater.

Development of Novel Silicon Quantum Dots and Their Potential in Improving the Enhanced Oil Recovery of HPAM.

Hydrolyzed polyacrylamide (HPAM) is commonly used in polymer flooding, however, it is prone to viscosity reduction at high temperatures and high salinities, weakening its ability to improve oil recovery. In this work, sulfonated modified silicon quantum dots (S-SiQDs) were synthesized and then added to HPAM to study the improvement of rheological properties and enhanced oil recovery performance of HPAM at high temperatures and salinities. It is found that the S-SiQDs with a concentration of only 0.1 wt % can significantly increase the viscosity of HPAM from 28.5 to 39.6 mPa·s at 60 °C and 10,000 mg/L NaCl. Meanwhile, the HPAM/S-SiQDs hybrid solution always possessed higher viscosity and viscoelastic moduli than HPAM, attributed to the hydrogen bonding between HPAM and S-SiQDs. Notably, HPAM/S-SiQDs still maintained elastic behavior at harsh conditions, indicating that they formed a strong network structure. Through oil displacement experiments, it was found that the oil recovery of HPAM/S-SiQDs was higher (28.3%), while that of HPAM was only 17.2%. Thereafter, the utilization sequence of oil during the displacement process was studied with nuclear magnetic resonance experiments. Ultimately, the oil displacement mechanism of HPAM/S-SiQDs was deeply analyzed, including viscosity thickening and wetting reversal.

Selenium-SelK-GPX4 axis protects nucleus pulposus cells against mechanical overloading-induced ferroptosis and attenuates senescence of intervertebral disc.

Intervertebral disc degeneration (IVDD) is one of the most prevalent spinal degenerative disorders and imposes places heavy medical and economic burdens on individuals and society. Mechanical overloading applied to the intervertebral disc (IVD) has been widely recognized as an important cause of IVDD. Mechanical overloading-induced chondrocyte ferroptosis was reported, but the potential association between ferroptosis and mechanical overloading remains to be illustrated in nucleus pulposus (NP) cells. In this study, we discovered that excessive mechanical loading induced ferroptosis and endoplasmic reticulum (ER) stress, which were detected by mitochondria and associated markers, by increasing the intracellular free Ca2+ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free Ca2+ level elevation and the activation of ER stress are positive feedback processes that promote each other, consistent with the results that the level of ER stress in coccygeal discs of aged Piezo1-CKO mice were significantly lower than that of aged WT mice. Then, we confirmed that selenium supplementation decreased intracellular free Ca2+ level by mitigating ER stress through upregulating Selenoprotein K (SelK) expression. Besides, ferroptosis caused by the impaired production and function of Glutathione peroxidase 4 (GPX4) due to mechanical overloading-induced calcium overload could be improved by selenium supplementation through Se-GPX4 axis and Se-SelK axis in vivo and in vitro, eventually presenting the stabilization of the extracellular matrix (ECM). Our findings reveal the important role of ferroptosis in mechanical overloading-induced IVDD, and selenium supplementation promotes significance to attenuate ferroptosis and thus alleviates IVDD, which might provide insights into potential therapeutic interventions for IVDD.

The circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism.

INTRODUCTION: Osteoarthritis (OA) is a degenerative bone disease associated with ageing, characterized by joint pain, stiffness, swelling and deformation. Currently, pharmaceutical options for the clinical treatment of OA are very limited. Circular RNAs(cirRNAs) have garnered significant attention in OA and related drug development due to their unique RNA sequence characteristics.Therefore,exploring the role of cirRNAs in the occurrence and development of OA is of paramount importance for the development of effective medications for OA. OBJECTIVES: To identify a novel circRNA, circUbqln1, for treating osteoarthritis and elucidate its pathophysiological role and mechanisms in the treatment of OA. METHODS: The circUbqln1 expression and distribution were determined by qRT-PCR and FISH. XBP1 gene knockout(XBP1 cKO) spontaneous OA and DMM model and WT mouse CIOA model were used to explore the role of XBP1 and circUbqln1 in OA.Overexpression or knockdown of circUbqln1 lentivirus was used to observe the impacts of circUbqln1 on primary chondrocytes,C28/I2 and mice in vitro and in vivo.Chromatin immunoprecipitation,luciferase reporter assay,RNA pulldown,mass spectrometry,RNA immunoprecipitation,fluorescence in situ hybridization,and flow cytometry to explore the molecular mechanisms of circUbqln1. RESULTS: It was found that cartilage-specific XBP1 cKO mice exhibited a faster OA progression compared to normal's.Importantly,transcript factor XBP1s has the capacity to impede the biogenesis of circUbqln1,derived from Ubqln1. The circUbqln1 promotes cartilage catabolism and inhibits anabolism, therefore accelerates the occurrence of OA.Mechanismly,circUbqln1 can translocate to the chondrocyte nucleus with the assistance of phosphorylated 14-3-3ζ, upregulate the transcriptional activity of the proline dehydrogenase(Prodh) promoter and PRODH enzyme activity. Consequently, this leads to the promotion of proline degradation and the inhibition of collagen synthesis,ultimately culminating in the impairment of cartilage and its structural integrity. CONCLUSION: CircUbqln1 plays a crucial role in the occurrence and development of OA, indicating that the inhibition of circUbqln1 holds promise as a significant approach for treating OA in the future.

Identification and functional coordination analysis of gene co-expression networks in different tissues of XBP1 cartilage-specific deficient mice.

Abnormal differentiation and proliferation of chondrocytes leads to various diseases related to growth and development. The process of chondrocyte differentiation involves a series of complex cellular and molecular interactions. X-box binding protein 1 (XBP1), an essential molecule of the unfolded protein response (UPR) in Endoplasmic Reticulum (ER) stress, participated in cartilage development and causes other related diseases. We previously reported that XBP1 deficiency in cartilage impacts the function and associated diseases of many different tissues including cartilage. However, how differential expression of genes modulates the roles of cartilage and other tissues when XBP1 is lack of in chondrocytes remains unclear. We aimed to screen for differentially expressed (DE) genes in cartilage, brain, heart, and muscle by high-throughput sequencing in XBP1 cartilage-specific knockout (CKO) mice. Further, gene co-expression networks were constructed by weighted gene co-expression network analysis (WGCNA) algorithm and pivot genes were identified in the above four tissues. Protein detection, Hematoxylin-eosin (HE) staining and immunohistochemistry (IHC) experiments have proved that these differentially co-expressed genes participate in the downstream regulatory pathway of different tissues and affect tissue function.Significantly differentially expressed mRNAs [differentially expressed genes (DEGs)] were identified between XBP1 CKO mice and controls in cartilage, brain, heart, and muscle tissues, including 610, 126, 199 and 219 DEGs, respectively. 39 differentially co-expressed genes were identified in the above four tissues, and they were important pivot genes. Comprehensive analysis discovered that XBP1 deficiency in cartilage influences the difference of co-expressed genes between cartilage and other different tissues. These differentially co-expressed genes participate in downstream regulatory pathways of different tissues and affect tissue functions. Collectively, our conclusions may contribute potential biomarkers and molecular mechanisms for the mutual modulation between cartilage and different tissues and the diagnosis and treatment of diseases caused by abnormalities in different tissues. The analysis also provides meaningful insights for future genetic discoveries.

Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway.

Osteoporosis is a systemic metabolic bone disorder for which inflammatory cytokines play an important role. To develop new osteoporosis treatments, strategies for improving the microenvironment for osteoblast and osteoclast balance are needed. Tumor necrosis factor-α (TNF-α) plays an important role in the initiation and development of osteoporosis. Atsttrin is an engineered protein derived from the growth factor, progranulin (PGRN). The present study investigates whether Atsttrin affects osteoclast formation and osteoblast formation. Here we show Atsttrin inhibits TNF-α-induced osteoclastogenesis and inflammation. Further mechanistic investigation indicates Atsttrin inhibits TNF-α-induced osteoclastogenesis through the TNFR1 signaling pathway. Moreover, Atsttrin rescues TNF-α-mediated inhibition of osteoblastogenesis via the TNFR1 pathway. Importantly, the present study indicates that while Atsttrin cannot directly induce osteoblastogenesis, it can significantly enhance osteoblastogenesis through TNFR2-Akt-Erk1/2 signaling. These results suggest that Atsttrin treatment could potentially be a strategy for maintaining proper bone homeostasis by regulating the osteoclast/osteoblast balance. Additionally, these results provide new insights for other bone metabolism-related diseases.

Prognostic impact of cortactin in patients with hypopharyngeal cancer and its role for tegafur-uracil maintenance after adjuvant chemoradiotherapy.

The prognosis of patients with hypopharyngeal cancer (HPC) remains poor. Our study aims to investigate the prognostic impact of cortactin in patients with HPC and its role for tegafur-uracil (UFUR) maintenance after adjuvant chemoradiotherapy (CRT). Patients who were diagnosed to have HPC and underwent laryngopharyngectomy followed by adjuvant CRT were enrolled into our study. Immunohistochemical staining was performed for cortactin evaluation. Kaplan-Meier curves were depicted for recurrence-free survival (RFS) and overall survival (OS). A total of 157 patients were enrolled into our study. After stratified by cortactin, 53 patients were cortactin (+) and 104 patients were cortactin (-). The median RFS was 86.7 months in cortactin (-) and 10.2 months in cortactin (+) (P < 0.001). The median OS was 93.4 months in cortactin (-) and 16.9 months in cortactin (+) (P < 0.001). Patients were further classified according to UFUR maintenance or not after adjuvant CRT. In cortactin (+) patients, the median RFS and OS were 13.6 months versus 7.0 months (P = 0.006) and 24.0 months versus 10.0 months (P < 0.001) in UFUR (+) and UFUR (-), respectively. In cortactin (-) patients, the median RFS and OS were 96.0 months versus 72.2 months (P = 0.262) and 98.5 months versus 105.0 months (P = 0.665) in UFUR (+) and UFUR (-), respectively. Cortactin has a significantly impact in HPC patients. UFUR maintenance provided survival benefits in patients with cortactin (+) after adjuvant CRT.

Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Elucidating the Cancer Phenotype in Turner Syndrome: A 20-Year Observational Cohort Study.

BACKGROUND/AIM: Turner syndrome confers increased cancer susceptibility; however, large-scale epidemiological evidence is lacking. This study aimed to analyze the incidence and prevalence of various malignancies in patients with Turner syndrome over 20 years of age to inform screening strategies. PATIENTS AND METHODS: We performed a retrospective cohort analysis of 11,502 patients with Turner syndrome from 2000 to 2020 utilizing the TriNetX research network database. The outcomes encompassed the incidence and prevalence of 20 cancers. Stratified analyses were used to evaluate variations in age, sex, and race. RESULTS: Key findings demonstrated markedly elevated risks of breast (1.7%), colon (1.0%), renal (0.4%), gonadoblastoma (0.4%), and other cancers. Significant demographic variations were observed in the incidence of cancers, such as gonadoblastoma, renal, and colon cancer. CONCLUSION: This large real-world study offers novel insights into the spectrum of cancer risk across adulthood in Turner syndrome. Our findings elucidate Turner syndrome's complex cancer phenotype to inform clinical decision-making, prognostication, and tailored screening strategies to ultimately advance patient care.

The antioxidant Glycitin protects against intervertebral disc degeneration through antagonizing inflammation and oxidative stress in nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is a kind of typical degenerative disorder of the skeletal muscle system caused by many factors including aging, abnormal mechanical stress and inflammatory responses. Glycitin is a natural isoflavone extracted from legumes. Previous studies have found that it is anti-inflammatory and promotes wound repair. However, the role of Glycitin in IVDD has not been elucidated. In the present research, we were surprised that Glycitin antagonized the NF-κB pathway activity. In addition, we also found that Glycitin alleviated TNF-α-induced metabolic disorders, extracellular matrix degradation, oxidative stress, inflammation responses, and mitochondrial damage. Furthermore, in in vivo experimental study, we discovered Glycitin attenuated IVDD. The results revealed that Glycitin alleviated the degenerative phenotype of IVDD. According to this research, Glycitin has anti-inflammatory properties that might exert a protective function in IVDD, suggesting a prospective therapeutic approach for IVDD.

Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling.

Background: Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. Objective: This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. Methods: We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Results: Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. Conclusion: These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

Incidence of Pulmonary and Respiratory Conditions in Gaucher Disease from 2000 to 2020: A Multi-institutional Cohort Study.

BACKGROUND/AIM: Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management. PATIENTS AND METHODS: We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020. RESULTS: Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years. CONCLUSION: Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality.

Expression Characterization of ABCDE Class MADS-Box Genes in Brassica rapa with Different Pistil Types.

MADS-box is a vital transcription factor family that functions in plant growth and development. Apart from APETALA2, all genes in the ABCDE model that explain the molecular mechanism of floral organ development belong to the MADS-box family. Carpel and ovule numbers in plants are essential agronomic traits that determine seed yield, and multilocular siliques have great potential for the development of high-yield varieties of Brassica. In this study, ABCDE genes in the MADS-box family from Brassica rapa were identified and characterized. Their tissue-specific expression patterns in floral organs and their differential expression in different pistil types of B. rapa were revealed by qRT-PCR. A total of 26 ABCDE genes were found to belong to the MADS-box family. Our proposed ABCDE model of B. rapa is consistent with that of Arabidopsis thaliana, indicating that ABCDE genes are functionally conserved. These results of qRT-PCR showed that the expression levels of class C and D genes were significantly different between the wild-type (wt) and tetracarpel (tetrac) mutant of B. rapa. Interestingly, the expression of the homologs of class E genes was imbalanced. Therefore, it is speculated that class C, D, and E genes are involved in developing the carpel and ovule of B. rapa. Our findings reveal the potential for the selection of candidate genes to improve yield traits in Brassica crops.

Interferon regulatory factor 3 mediates effective antiviral responses to human coronavirus 229E and OC43 infection.

Interferon regulatory factors (IRFs) are key elements of antiviral innate responses that regulate the transcription of interferons (IFNs) and IFN-stimulated genes (ISGs). While the sensitivity of human coronaviruses to IFNs has been characterized, antiviral roles of IRFs during human coronavirus infection are not fully understood. Type I or II IFN treatment protected MRC5 cells from human coronavirus 229E infection, but not OC43. Cells infected with 229E or OC43 upregulated ISGs, indicating that antiviral transcription is not suppressed. Antiviral IRFs, IRF1, IRF3 and IRF7, were activated in cells infected with 229E, OC43 or severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). RNAi knockdown and overexpression of IRFs demonstrated that IRF1 and IRF3 have antiviral properties against OC43, while IRF3 and IRF7 are effective in restricting 229E infection. IRF3 activation effectively promotes transcription of antiviral genes during OC43 or 229E infection. Our study suggests that IRFs may be effective antiviral regulators against human coronavirus infection.