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Summary: Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced “on-demand” GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.

Abstract Background Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of cancer cells to radiation. Long non‐coding RNAs (lncRNAs) and N6‐methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A‐modified lncRNAs in ESCC radioresistance remain unclear. Methods Bioinformatics analysis was conducted to identify m6A‐modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification‐mass spectrometry, RNA immunoprecipitation, and co‐immunoprecipitation experiments were performed to explore the mechanism of m6A‐mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models. Results Herein, we identified LNCAROD as a novel METTL3‐mediated lncRNA that enhanced radioresistance in ESCC cells and was post‐transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin‐proteasome degradation of PARP1 protein by facilitating PARP1‐NPM1 interaction, thereby contributing to homologous recombination‐mediated DNA double‐strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity. Conclusion Our findings enhance the understanding of m6A‐modified lncRNA‐driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.

BackgroundModern radiotherapy exemplified by intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), has transformed esophageal cancer treatment. Facing challenges in treating thoracic esophageal cancer near vital organs, this study introduces a regression model-based decision support tool for the optimal selection of radiotherapy techniques.MethodsWe enrolled 106 patients diagnosed with locally advanced thoracic esophageal cancer in this study and designed individualized IMRT and VMAT radiotherapy plans for each patient. Detailed dosimetric analysis was performed to evaluate the differences in dose distribution between the two radiotherapy techniques across various thoracic regions. Single-factor and multifactorial logistic regression analyses were employed to establish predictive models (P1 and P2) and factors such as TLV/PTV ratio. These models were used to predict the compliance and potential advantages of IMRT and VMAT plans. External validation was performed in a validation group of 30 patients.ResultsUsing predictive models, we developed a data-driven decision support tool. For upper thoracic cases, VMAT plans were recommended; for middle/lower thoracic cases, the tool guided VMAT/IMRT choices based on TLV/PTV ratio. Models P1 and P2 assessed IMRT and VMAT compliance. In validation, the tool showed high specificity (90.91%) and sensitivity (78.95%), differentiating IMRT and VMAT plans. Balanced performance in compliance assessment demonstrated tool reliability.ConclusionIn summary, our regression model-based decision support tool provides practical guidance for selecting optimal radiotherapy techniques for thoracic esophageal cancer patients. Despite a limited sample size, the tool demonstrates potential clinical benefits, alleviating manual planning burdens and ensuring precise, individualized treatment decisions for patients.

In this study, Illumina MiSeq sequencing technology was used to analyze the bacterial community structure of Zha-Chili from Xingshan and Baojing. The α-diversity analysis showed that the community diversity and abundance of Zha-Chili in Xingshan were significantly lower than those in Baojing (P

Abstract Background Radiotherapy is one of the main treatments for esophageal squamous cell carcinoma (ESCC), but its efficacy is limited by radioresistance. MicroRNAs play a crucial role in posttranscriptional regulation, which is linked to the cancer response to radiation. Methods We successfully established a radioresistant cell line model by using fractionated irradiation. qRT-PCR was adopted to detect the expression of miR-4443 in human normal esophageal cell lines, tumor cells, and radioresistant cells. Next, CCK-8, colony formation, apoptosis, and cell cycle assays were used to assess the biological effect of miR-4443. Weighted gene coexpression network analysis (WGCNA) was performed to identify potential radiosensitivity-related genes. Additionally, we predicted the probable targets of the miRNA using bioinformatic methods and confirmed them using Western blot. Results miR-4443 was significantly upregulated in radioresistant ESCC cells. Enhancement of miR-4443 further decreased the radiosensitivity of ESCC cells, while inhibition of miR-4443 increased the radiosensitivity of ESCC cells. Notably, miR-4443 modulated radiosensitivity by influencing DNA damage repair, apoptosis, and G2 cycle arrest. By using WGCNA and experimental validation, we identified PTPRJ as a key target for miRNA-4443 to regulate radiosensitivity. The effects of miR-4443 overexpression or inhibition could be reversed by increasing or decreasing PTPRJ expression. Conclusion In this study, miR-4443 is found to promote radiotherapy resistance in ESCC cells by regulating PTPRJ expression, which provides a new perspective and clue to alleviate radioresistance.

Abstract Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Since autophagy-related genes (ARGs) play a key role in the pathogenesis of many tumors, including ESCC, the purpose of this study is to establish an autophagy-related prognostic risk signature based on ARGs expression profile, and to provide a new method for improving prediction of clinical outcomes. We obtained the expression profiles of ESCC from public data (GSE53625) and extracted the portion of ARGs. Differential expression analysis and enrichment analysis were performed to confirm abnormal autophagy-related biological functions. Univariate and multivariate Cox regression analyses were performed on RNA microarray data (GSE53625) to construct a prognostic risk signature associated with autophagy. The performance of the model was evaluated by receiver operating characteristic (ROC) analysis, survival analysis and Brier score. The model was subjected to bootstrap internal validation. The potential molecular mechanism of gene signature was explored by gene set enrichment analysis (GSEA). Spearman correlation coefficient examined the correlation between risk score and immune status and ferroptosis. The expression levels of genes and proteins were validated by qRT-PCR and immunohistochemistry in ESCC cell lines and ESCC tissues. We constructed and validated an autophagy-related prognostic risk signature in 179 patients with ESCC. The long-term survival of patients in high-risk group was lower than that in low-risk group (log-rank, P value

Bone defects that result from trauma, infection, surgery, or congenital malformation can severely affect the quality of life. To address this clinical problem, a phosphoserine-loaded chitosan membrane that consists of chitosan membranes serving as the scaffold support to accommodate endogenous stem cells and phosphoserine is synthesized. The introduction of phosphoserine greatly improves the osteogenic effect of the chitosan membranes via mutual crosslinking using a crosslinker (EDC, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide). The morphology of PS-CS membranes was shown by scanning electron microscopy (SEM) to have an interconnected porous structure. The incorporation of phosphoserine into chitosan membranes was confirmed by energy dispersive spectrum (EDS), Fourier Transforms Infrared (FTIR), and X-ray diffraction (XRD) spectrum. The CCK8 assay and Live/Dead staining, Hemolysis analysis, and cell adhesion assay demonstrated that PS-CS membranes had good biocompatibility. The osteogenesis-related gene expression of BMSCs was higher in PS-CS membranes than in CS membranes, which was verified by alkaline phosphatase (ALP) activity, immunofluorescence staining, and real-time quantitative PCR (RT-qPCR). Furthermore, micro-CT and histological analysis of rat cranial bone defect demonstrated that PS-CS membranes dramatically stimulated bone regeneration in vivo. Moreover, H&E staining of the main organs (heart, liver, spleen, lung, or kidney) showed no obvious histological abnormalities, revealing that PS-CS membranes were no additional systemic toxicity in vivo. Collectively, PS-CS membranes may be a promising candidate for bone tissue engineering.

Ginseng (Panax ginseng) is a perennial herbaceous plant belonging to Panax genus of Araliaceae. Ginsenosides are a kind of important compounds in ginseng and minor ginsenosides are secondary metabolic derivatives of ginsenosides. Studies have shown that minor ginsenosides have many pharmacological effects, such as antioxidant, anti-tumor, anti-platelet aggregation, and neuroprotective effects. However, the therapeutic effects of minor ginsenosides are limited due to poor solubility in water, short half-life, and poor targeting accuracy. In recent years, to improve the application efficiency, the research on the nanocrystallization of minor ginsenosides have attracted extensive attention from researchers. This review focuses on the classification, preparation methods, pharmacological effects, and action mechanisms of minor ginsenoside nanoparticles, as well as existing problems and future direction of relevant research, which provides a reference for the in-depth research of minor ginsenoside nanoparticles.

This study aimed to build up nomogram models to evaluate overall survival (OS) and cancer-specific survival (CSS) in early-onset esophageal cancer (EOEC). Patients diagnosed with esophageal cancer (EC) from 2004 to 2015 were extracted from the Surveillance Epidemiology and End Results (SEER) database. Clinicopathological characteristics of younger versus older patients were compared, and survival analysis was performed in both groups. Independent related factors influencing the prognosis of EOEC were identified by univariate and multivariate Cox analysis, which were incorporated to construct a nomogram. The predictive capability of the nomogram was estimated by the concordance index (C-index), calibration plot, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). A total of 534 younger and 17,243 older patients were available from the SEER database. Younger patients were randomly segmented into a training set (n = 266) and a validation set (n = 268). In terms of the training set, the C-index of the OS nomogram was 0.740 (95% CI: 0.707-0.773), and that of the CSS nomogram was 0.752 (95% CI: 0.719-0.785). In view of the validation set, the C-index of OS and CSS were 0.706 (95% CI: 0.671-0.741) and 0.723 (95% CI: 0.690-0.756), respectively. Calibration curves demonstrated the consistent degree of fit between actual and predicted values in nomogram models. From the perspective of DCA, the nomogram models were more beneficial than the tumor-node-metastasis (TNM) and the SEER stage for EOEC. In brief, the nomogram model can be considered as an individualized quantitative tool to predict the prognosis of EOEC patients to assist clinicians in making treatment decisions.

Maxillofacial bone defects are common medical problems caused by congenital defects, necrosis, trauma, tumor, inflammation, and fractures non-union. Maxillofacial bone defects often need bone graft, which has many difficulties, such as limited autogenous bone supply and donor site morbidity. Bone tissue engineering is a promising strategy to overcome the above-mentioned problems. Osteoimmunology is the inter-discipline that focuses on the relationship between the skeletal and immune systems. The immune microenvironment plays a crucial role in bone healing, tissue repair and regeneration in maxillofacial region. Recent studies have revealed the vital role of immune microenvironment and bone homeostasis. In this study, we analyzed the complex interaction between immune microenvironment and bone regeneration process in oral and maxillofacial region, which will be important to improve the clinical outcome of the bone injury treatment.

Background: Esophageal cancer (ESCA) is a major cause of cancer-related mortality worldwide. Altered fatty acid metabolism is a hallmark of cancer. However, studies on the roles of fatty acid metabolism-related genes (FRGs) in ESCA remain limited. Method: We identified differentially expressed FRGs (DE-FRGs). Then, the DE-FRGs prognostic model was constructed and validated using a comprehensive analysis. Moreover, the correlation between the risk model and clinical characteristics was investigated. A nomogram for predicting survival was established and evaluated. Subsequently, the difference in tumor microenvironment (TME) was compared between two risk groups. The sensitivity of key DE-FRGs to chemotherapeutic interventions and their correlation with immune cells were investigated. Finally, DEGs between two risk groups were measured and the prognostic value of key DE-FRGs in ESCA was confirmed in other databases. Results: A prognostic model was constructed based on seven selected DEG-FRGs. TNM staging and CD8+ T cells were significantly correlated with high-risk groups. Low-risk groups exhibited more infiltrated M0 macrophages, an activation of type II interferon (IFN-γ) responses, and were found to be more suitable for immunotherapy. Seven key DE-FRGs with prognostic value were found to be considerably influenced by different chemotherapy drugs. Conclusion: A prognostic model based on seven DE-FRGs may efficiently predict patient prognosis and immunotherapy response, helping to develop individualized treatment strategies in ESCA.

The ability of human periodontal ligament stem cells (PDLSCs) to differentiate into osteoblasts is significant in periodontal regeneration tissue engineering. In this study, we explored the role and mechanism of circRNA FAT1 (circFAT1) in the osteogenic differentiation of human PDLSCs. The proliferation capacity of PDLSCs was evaluated by EdU and CCK-8 assay. The abilities of circFAT1 and miR-4781-3p in regulating PDLSC differentiation were analyzed by western blot, reverse transcription-polymerase chain reaction (RT-PCR), alkaline phosphatase (ALP), and Alizarin red staining (ARS). A nucleocytoplasmic separation experiment was utilized for circFAT1 localization. A dual-luciferase reporter assay confirmed the binding relationship between miR-4781-3p and circFAT1. It was showed that circFAT1 does not affect the proliferation of PDLSCs. The osteogenic differentiation of PDLSCs was benefited from circFAT1, which serves as a miRNA sponge for miR-4781-3p targeting SMAD5. Both knockdown of circFAT1 and overexpression of miR-4781-3p suppressed the osteogenic differentiation of PDLSCs. Thus, circFAT1 might be considered as a potential target of PDLSCs mediated periodontal bone regeneration.

Pedestrians are some of the most vulnerable road users as they are not protected by safety devices, and must also share the road with vehicles traveling at dangerous speeds, particularly during road crossings. In 2011, the state of Oregon changed their traffic laws to be more accommodating to pedestrians by giving right of way to pedestrians using a crosswalk, regardless if whether the crosswalk is marked or unmarked. This paper estimates a panel logit model to evaluate the efficacy of the law in preventing pedestrian fatalities. Pedestrian fatalities are shown to decrease over time, with smaller likelihood of a fatality outcome in the years following the change in pedestrian crossing laws. To the authors’ knowledge, it is the first time panel logit models have been used in evaluating pedestrian safety. Results indicate that panel logit models are an alternative to using Box-Tiao intervention models to analyze the long term effects of policy changes, as they allow for the consideration of crash exposure factors as well as temporal effects. Keywords: Pedestrians, Panel logit, Traffic laws, Crosswalk

Current PCR-based target enrichment methods for next generation sequencing (NGS) of overlapping amplicons often requires separate PCR reactions and subsequent pooling of amplicons from the different reactions. The study presents a novel method, deemed stem-loop inhibition mediated amplification (SLIMamp), for amplifying overlapping or tiled amplicons in a single multiplex PCR reaction. During a SLIMamp PCR reaction, a stem loop structure formed by the overlapping amplicon suppresses additional amplification of itself by preventing the annealing of the primers. Using the SLIMamp strategy, we designed a next-generation sequencing (NGS) assay to enrich the exon regions of BRCA1 and BRCA2 for sequencing on an Illumina MiSeq system. We used 35 cell line DNAs and 6 patient blood DNAs in the study to evaluate the assay performance. For each sample, all targeted regions were successfully amplified and sequenced with excellent coverage uniformity and specificity. >99% of the total sequencing reads were mapped to the human reference genome (hg19) and >99% of the mapped reads were on the targeted exons. >98% of bases were covered at >0.20x of the mean coverage and >99% are covered at >0.15x of the mean depth. Among 34 independently sequenced samples, all variants were reliably detected with no false positives or false negatives. SLIMamp provides a robust method for single-tube multiplex PCR amplification of numerous, overlapping amplicons that tile for targeted next-generation sequencing.

The converter valve is the core equipment in the HVDC power transmission system, a+-nd its performance has a direct effect on the reliability, stability and efficiency of the whole power system. As the basic unit of HVDC converter valve, the thyristor level needs to be test routinely in order to grasp the state of the converter valve equipment. Therefore, it is urgent to develop a novel synthetic test system for the thyristor level with thyristor control unit (TCU). However, currently there is no specific test scheme for the thyristor level of HVDC converter valve. In this paper, the synthetic test principle, content and methods for the thyristor level with TCU are presented based on the analysis of the thyristor reverse recovery characteristic and the IEC technology standard. And a transient high-voltage pulse is applied to the thyristor level during its reverse recovery period in order to test the characteristics of thyristor level. Then, the synthetic test system for the thyristor level is applied to the converter valve test of ±800 kV HVDC power transmission project, and the practical test result verifies the reasonability and validity of the proposed synthetic test system.