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Abstract Background Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it. Methods NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO2, 94% N2 and 1% O2) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo. Results CCK8 assay showed that IC50 of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC50 value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells. Conclusion Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment. Graphical Abstract

Abstract Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and is associated with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the specific mechanism by which OSA induces NAFLD remains unclear. Therefore, effective interventions are lacking. This study aims to investigate the role and mechanism of ferroptosis in OSA‐related NAFLD using clinical data analyses, cell‐based molecular experiments, and animal experiments. Indicators of liver function, lipid accumulation, and ferroptosis are also examined. RNA‐seq, qPCR, western blotting, gene intervention, and E3 ligase prediction using UbiBrowser and co‐IP are used to explore the potential underlying mechanisms. The results show that ferroptosis increases in the liver tissues of patients with OSA. Chronic IH promotes NAFLD progression in mice and is alleviated by a ferroptosis inhibitor Fer‐1. The increased secretion of IL6 by macrophages can promote the expression of MARCH3 in hepatocytes under intermittent conditions, and subsequently promote the ubiquitination and degradation of GPX4 to regulate ferroptosis and lipid accumulation in hepatocytes. Hence, targeted inhibition of MARCH3 may alleviate IH‐induced ferroptosis and lipid accumulation in liver tissues and inhibit the progression of NAFLD.

With the rapid advancements in sequencing technology, an increasing number of genome sequences for medicinal plants have become available. In 2021, TCMPG was introduced as a comprehensive database dedicated to traditional Chinese medicine (TCM) plant genomes, capturing significant attention within the scientific community. To offer invaluable resources to researchers, this database received an upgrade to its latest version, named TCMPG 2.0, accessible at http://cbcb.cdutcm.edu.cn/TCMPG2/. TCMPG 2.0 surpasses its predecessor by adding 114 medicinal plants, 129 genomes, and 159 related herbs. Recognizing the critical role of ingredients in assessing the pharmacological effects of Chinese medicines, TCMPG 2.0 has also amassed data on 13,868 herbal ingredients. Additionally, four practical analytical tools, including Heatmap, Primer3, PlantiSMASH, and CRISPRCasFinder, have been integrated into the toolbox. These valuable enhancements significantly enhance the database's utility for researchers in the field.

Introduction Orthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy.Methods and analysis This is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander’s jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used.Ethics and dissemination This study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications.Trial registration number ChiCTR2300078833.

Abstract Objective Pregnant women experience enormous psychological pressure, particularly during the late trimester. Symptoms of depression in late pregnancy may persist postpartum, increasing the incidence of postpartum depression. This study is aimed to investigate the factors influencing depressive symptoms among pregnant women in their third trimester at a Chinese tertiary hospital and provide information for effective intervention. Methods Pregnant women in their third trimester who visited the Ningbo Women and Children’s Hospital between January 1, 2020 and June 30, 2022 participated in this study. A score of ≥ 13 on the Edinburgh Postnatal Depression Scale (EPDS) was considered as positive for depressive symptom. Potential influencing factors were examined by using an online questionnaire and analyzed using multivariate logistic regression. Results A total of 1196 participants were recruited. The mean EPDS score was 7.12 ± 4.22. The positive screening rate for depressive symptom was 9.9%. Univariate analysis showed that living with partner, annual family income, planned pregnancy, sleep quality, and partner’s drinking habits were related to positive screening for depression(P

Introduction: Dysregulation of iron metabolism is closely associated with the development of obesity and obstructive sleep apnea (OSA), but little is known about the relationship between serum transferrin (TF) level and OSA severity. We aimed to verify this relationship and fit into account for obesity-related confounders among bariatric candidates. Methods: We compared data retrospectively collected in 270 bariatric candidates. A propensity score-matched (PSM) analysis was used to determine the impact of iron metabolism on OSA severity independently of obesity. Univariate analysis was used to evaluate the relationship between serum TF level and the severity of OSA reflected by hypoxia and night awakenings parameters. Serum TF level to predict the severity of OSA was assessed by using univariate and multiple logistic regression model. Results: The preliminary analysis showed that serum ferritin (113 ng/mL [50–203] vs. 79 ng/mL [40–130], p = 0.009) and TF (2.72 g/L [2.46–3.09] vs. 2.65 g/L [2.34–2.93], p = 0.039) level was significantly higher in the moderate/severe OSA group than the no/mild OSA group. After PSM analysis, there were 75 patients in each group and only serum TF level remained significant (p = 0.014). The proportion of patients with combined T2D and hyperlipidemia also remained higher in moderate/severe OSA groups. Univariate analysis showed that the group with higher degree of hypoxia had higher serum TF levels no matter the severity of OSA was grouped by oxygen desaturation index (ODI; 2.79 g/L [2.56–3.06] vs. 2.55 g/L [2.22–2.84], p < 0.001) or minimum oxygen saturation (SpO2nadir; 2.75 g/L [2.50–3.03] vs. 2.56 g/L [2.24–2.92], p = 0.009). Univariate and multiple logistic regression analysis further showed that serum TF level emerged as a significant and independent factor associated with OSA severity especially grouped by ODI (odds ratio: 2.91, 95% CI: 1.36–6.23, p = 0.006). Conclusion: The existence of OSA exacerbates obesity comorbidities, particularly type 2 diabetes and hyperlipidemia. Serum TF level is associated with the severity of OSA independently of obesity and might be a potential identification and therapeutic targets.

Both obesity and obstructive sleep apnea (OSA) can lead to metabolic dysregulation and systemic inflammation. Similar to obesity, increasing evidence has revealed that immune infiltration in the visceral adipose tissue (VAT) is associated with obstructive sleep apnea-related morbidity. However, the pathological changes and potential molecular mechanisms in visceral adipose tissue of obstructive sleep apnea patients need to be further studied. Herein, by bioinformatics analysis and clinical validation methods, including the immune-related differentially expressed genes (IRDEGs) analysis, protein-protein interaction network (PPI), functional enrichment analysis, a devolution algorithm (CIBERSORT), spearman’s correlation analysis, polymerase chain reaction (PCR), Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), we identified and validated 10 hub IRDEGs, the relative mRNA expression of four hub genes (CRP, CD40LG, CCL20, and GZMB), and the protein expression level of two hub genes (CD40LG and GZMB) were consistent with the bioinformatics analysis results. Immune infiltration results further revealed that obstructive sleep apnea patients contained a higher proportion of pro-inflammatory M1 macrophages and a lower proportion of M2 macrophages. Spearman’s correlation analysis showed that CD40LG was positively correlated with M1 macrophages and GZMB was negatively correlated with M2 macrophages. CD40LG and GZMB might play a vital role in the visceral adipose tissue homeostasis of obstructive sleep apnea patients. Their interaction with macrophages and involved pathways not only provides new insights for understanding molecular mechanisms but also be of great significance in discovering novel small molecules or other promising candidates as immunotherapies of OSA-associated metabolic complications.

The abnormality of RNA-binding proteins (RBPs) is closely related to the tumorigenesis and development of esophageal squamous cell carcinoma (ESCC), and has been an area of interest for research recently. In this study, 162 tumors and 11 normal samples are obtained from The Cancer Genome Atlas database, among which 218 differentially expressed RBPs are screened. Finally, a prognostic model including seven RBPs (CLK1, DDX39A, EEF2, ELAC1, NKRF, POP7, and SMN1) is established. Further analysis reveals that the overall survival (OS) rate of the high-risk group is lower than that of the low-risk group. The area under the receiver operating characteristic (ROC) curve (AUC) of the training group and testing group is significant (AUCs of 3 years are 0.815 and 0.694, respectively, AUCs of 5 years are 0.737 and 0.725, respectively). In addition, a comprehensive analysis of seven identified RBPs shows that most RBPs are related to OS in patients with ESCC, among which EEF2 and ELCA1 are differentially expressed at the protein level of ESCC and control tissues. CLK1 and POP7 expressions in esophageal cancer tumor samples are undertaken using the tissue microarray, and show that CLK1 mRNA levels are relatively lower, and POP7 mRNA levels are higher compared with non-cancerous esophageal tissues. Survival analysis reveals that a higher expression of CLK1 predicts a significant worse prognosis, and a lower expression of POP7 predicts a worse prognosis in esophageal cancer. These results suggest that CLK1 may promote tumor progression, and POP7 may hinder the development of esophageal cancer. In addition, gene set enrichment analysis reveals that abnormal biological processes related to ribosomes and abnormalities in classic tumor signaling pathways such as TGF-β are important driving forces for the occurrence and development of ESCC. Our results provide new insights into the pathogenesis of ESCC, and seven RBPs have potential application value in the clinical prognosis prediction of ESCC.

Alternative splicing (AS) is a key mechanism involved in regulating gene expression and is closely related to tumorigenesis. The incidence of thyroid cancer (THCA) has increased during the past decade, and the role of AS in THCA is still unclear. Here, we used TCGA and to generate AS maps in patients with THCA. Univariate analysis revealed 825 AS events related to the survival of THCA. Five prognostic models of AA, AD, AT, ES, and ME events were obtained through lasso and multivariate analyses, and the final prediction model was established by integrating all the AS events in the five prediction models. Kaplan–Meier survival analysis revealed that the overall survival rate of patients in the high-risk group was significantly shorter than that of patients in the low-risk group. The ROC results revealed that the prognostic capabilities of each model at 3, 5, and 8 years were all greater than 0.7, and the final prognostic capabilities of the models were all greater than 0.9. By reviewing other databases and utilizing qPCR, we verified the established THCA gene model. In addition, gene set enrichment analysis showed that abnormal AS events might play key roles in tumor development and progression of THCA by participating in changes in molecular structure, homeostasis of the cell environment and in cell energy. Finally, a splicing correlation network was established to reveal the potential regulatory patterns between the predicted splicing factors and AS event candidates. In summary, AS should be considered an important prognostic indicator of THCA. Our results will help to elucidate the underlying mechanism of AS in the process of THCA tumorigenesis and broaden the prognostic and clinical application of molecular targeted therapy for THCA.

BACKGROUND:Aberrant methylation of DNA plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC). In the current study, we aimed to integrate three cohorts profile datasets to identify abnormally methylated-differentially expressed genes and pathways associated with NPC. METHODS:Data of gene expression microarrays (GSE53819, GSE412452) and gene methylation microarrays (GSE52068) obtained from the GEO database. Aberrantly methylated differentially expressed genes (DEGs) were obtained by GEO2R. The David database was utilized to perform enrichment and functional analysis regarding selected genes. To create a protein-protein interaction (PPI), STRING and Cytoscape software were utilized. The MCODE was used for module analysis of the PPI network. RESULTS:In total, 181 hypomethylation-high expression genes were identified, which were enriched in the biological mechanisms involved in the differentiation of endodermal cell, mitotic nuclear division, mitotic cell cycle process, chromosome segregation and cell cycle phase transition, etc. Pathway enrichment showed ECM-receptor interaction, PI3K-Akt signaling pathway, Focal adhesion, Protein digestion and absorption and Amoebiasis, etc. The top 3 hub genes of PPI network were FANCI, POSTN, and IFIH1. Additionally, 210 hypermethylation-low expression genes were identified, and our data revealed enrichment in biological processes including axoneme assembly, micro tubular formation, assembly of axonemal dynein complex, cilium movement and cilium organization, etc. Pathway analysis indicated enrichment in B cell receptor signaling pathway, Hematopoietic cell lineage, Leukocyte transendothelial migration, Complement and coagulation cascades and Fc gamma R-mediated phagocytosis, etc. The ZMYND10, PACRG and POU2AF1 were identified as the top three hub genes of PPI network. After validation in TCGA and GEPIA database, most hub genes remained significant. Patients with high expression of POSTN found to have shorter overall survival, while in patients with high expression of ZMYND10 and POU2AF1 longer overall survival was identified. CONCLUSIONS:The data revealed novel aberrantly methylated-differentially expressed genes and pathways in NPC by bioinformatics analysis, potentially providing novel insights for the molecular mechanisms governing NPC progression. Hub genes including FANCI, POSTN, IFIH1, ZMYND10, PACRG and POU2AF1 might serve as novel biomarkers for precision diagnosis and providing medical treatment for patient with NPC.

Abstract Background Obstructive sleep apnea-hypopnea syndrome (OSAHS) is prone to being complicated with various cardiovascular, cerebrovascular and metabolic conditions. OSAHS, due to its multifactorial nature, entails individualized and comprehensive treatment. So far, no well-established diagnostic criteria for the disease are available. In recent years, miRNA has been shown to be a sensitive biomarker suggestive of the progression and prognosis of many diseases. In this study, we examined some serum miRNAs in healthy OSAHS (OSAHS patients without complication) and OSAHS with arterial hypertension, with an attempt to understand the potential effects on the disease, improve the diagnosis of OSAHS and find OSAHS-related diagnostic markers. Methods Against various diagnostic criteria, participants were divided into three groups: healthy OSAHS, OSAHS with arterial hypertension and healthy controls. Their serum miRNA profiles were assessed by microarray technology, and then differentially expressed miRNAs were verified by quantitative real-time PCR (qRT-PCR). The receiver operating characteristic (ROC) curves of miRNAs were constructed and the areas under the curve (AUC) were calculated. Meanwhile, the miRNAs were subjected to logistic regression analysis. The target genes were bioinformatically assessed, their functions and signaling pathways further determined and eventually an miRNA-gene network was established. Results Analysis with the miRNA array exhibited that, compared with the control group, 12 differentially expressed miRNAs were found in healthy OSAHS, and 33 were found in OSAHS with arterial hypertension. The expression of miR-126-3p, let-7d-5p, miR-7641 and miR-1233-5p, miR-320b, miR-145-5p, miR-107, miR-26a-5p were validated by using qRT-PCR. Bioinformatics analysis predicted that the potential target genes of these miRNAs might be involved in metabolism, and the regulation of endothelial cells and nervous system. Moreover, the ROC analysis showed that the using miR-145-5p and let-7d-5p in combination can identify the healthy OSAHS, presence of miR-126-3p, miR-26a-5p and miR-107 was well indicative of OSAHS with arterial hypertension. Conclusions A cluster of dysregulation miRNAs have been found to be involved in the development of OSAHS patients. Moreover, these miRNAs might be used to be potential diagnostic and early warning markers.

Abstract Background Inflammatory myofibroblastic tumor (IMT) of the stomach is extremely rare in adults and exhibits a variable biological behavior that ranges from frequently benign lesions to more aggressive variants. Here we report a case of gastric IMT with lymph node metastasis in an adult who had undergone total colectomy for familial adenomatous polyposis (FAP). Case presentation A 37-year-old man presented gradual-onset epigastric discomfort; he had undergone total colectomy for FAP 6 years before. The upper endoscopy revealed diffuse polyposis in the body of stomach and a submucosal protruding tumor of approximately 4.5 × 3.5 cm in the gastric angular incisure, appearing like gastrointestinal stromal tumor. Histology after surgery verified the diagnosis of fundic gland polyposis (FGPs) and gastric IMT with lymph node metastasis. Both the primary IMT tissue and its metastatic lesion but not the FGP or FAP tissue were positive for anaplastic lymphoma kinase (ALK) on immunohistochemical staining. Fluorescent in situ hybridization confirmed the existence of ALK rearrangement in IMT tissues. However, the patient exhibited no abnormalities in microsatellite instability or mismatch repair-system components, including MSH6, MSH2, MLH1 and PMS2, in IMT, FGP or FAP tissue. Conclusions This case allowed for exploring the relationship among IMT, FGP and FAP and indicates that gastric IMT should be considered in the diagnosis of a gastric mass in patients with FAP. ALK may be a useful biomarker in the diagnosis of IMT and its metastatic lesions.

Force feedback gloves allow users to touch and manipulate virtual objects intuitively. Compared with gloves providing active feedback force, gloves with passive feedback force are promising in terms of safety and low weight, but simulating the variable stiffness of virtual objects is more challenging. Addressing this difficulty, we propose a five-fingered glove with passive force feedback employing a variable ratio lever mechanism. The stiffness of the proposed glove is tuned by changing the structural stiffness of this mechanism rather than by applying torque control at each joint of the finger. The switch between free and constrained space is realized in real time by locking/unlocking the revolute joints of the glove using a servo motor. Furthermore, a predictive control mode is proposed to reduce the response time of the control system, and the actual response time is less than the limit of the delay (45 ms) that humans can perceive between visual and haptic stimuli. Experimental results show that the linear stiffness at the fingertip ranges from 0.89 to 619.89 N/m, and the maximum backdrive force of the proposed glove is less than 0.147 N.

Metal-doped nanosized ZnO (nZnO) photocatalyst has been widely used for its typical properties and has thus gained considerable attention. In this study, five types of nZnO (nondoped nZnO, iron- (Fe-) doped nZnO, cobalt- (Co-) doped nZnO, nickel- (Ni-) doped nZnO, and manganese- (Mn-) doped nZnO) materials were prepared through a wet chemical method and then exposed to Daphnia magna (D. magna) at low and high concentrations (50 and 250 μg L−1). Results showed that the different metal-doped nZnOs had a variety of shapes and sizes and exhibited diverse dissolubility. After exposure tests, Zn accumulation, metallothionein (MT), and malondialdehyde (MDA) contents in D. magna under 250 μg L−1 were significantly higher than those in the 50 μg L−1 groups. Compared with nondoped nZnO, Co-doped and Ni-doped nZnO enhanced Zn accumulation in D. magna whereas Mn-doped nZnO reduced such accumulation. MT and MDA contents in metal-doped nZnO (except Ni-nZnO) treatments were lower than those in nondoped nZnO. Zn accumulation showed a negative relationship with dissolved Zn percentage, which can be explained by the swallowing of nZnO particles as an important pathway of D. magna ingestion. Sizes, dissolubility, and physiological functions of doping metals were the influencing factors on metal-doped nZnO biotoxicity to D. magna.

Zinc Oxide Nanoparticles (ZnO NPs) have attracted increasing concerns because of their widespread use and toxic potential. In this study, Zn accumulations in different tissues (gills, liver, muscle, and gut) of goldfish (Carassius auratus) after exposure to ZnO NPs were studied in comparison with bulk ZnO and Zn(2+). And the technique of subcellular partitioning was firstly used on the liver of goldfish to study the hepatic accumulation of ZnO NPs. The results showed that at sublethal Zn concentration (2 mg/L), bioaccumulation in goldfish was tissue-specific and dependent on the exposure materials. Compared with Zn(2+), the particles of bulk ZnO and the ZnO NPs appeared to aggregate in the environmentally contacted tissues (gills and gut), rather than transport to the internal tissues (liver and muscle). The subcellular distributions of liver differed for the three exposure treatments. After ZnO NPs exposure, Zn percentage in metal-rich granule (MRG) increased significantly, and after Zn(2+) exposure, it increased significantly in the organelles. Metallothionein-like proteins (MTLP) were the main target for Zn(2+), while MRG played dominant role for ZnO NPs. The different results of subcellular distributions revealed that metal detoxification mechanisms of liver for ZnO NPs, bulk ZnO, and Zn(2+) were different. Overall, subcellular partitioning provided an interesting start to better understanding of the toxicity of nano- and conventional materials.