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The Chang'e-6 (CE-6) landing area on the far side of the Moon is located in the southern part of the Apollo basin within the South Pole-Aitken (SPA) basin. The statistical analysis of impact craters in this region is crucial for ensuring a safe landing and supporting geological research. Aiming at existing impact crater identification problems such as complex background, low identification accuracy, and high computational costs, an efficient impact crater automatic detection model named YOLOv8-LCNET (YOLOv8-Lunar Crater Net) based on the YOLOv8 network is proposed. The model first incorporated a Partial Self-Attention (PSA) mechanism at the end of the Backbone, allowing the model to enhance global perception and reduce missed detections with a low computational cost. Then, a Gather-and-Distribute mechanism (GD) was integrated into the Neck, enabling the model to fully fuse multi-level feature information and capture global information, enhancing the model's ability to detect impact craters of various sizes. The experimental results showed that the YOLOv8-LCNET model performs well in the impact crater detection task, achieving 87.7% Precision, 84.3% Recall, and 92% AP, which were 24.7%, 32.7%, and 37.3% higher than the original YOLOv8 model. The improved YOLOv8 model was then used for automatic crater detection in the CE-6 landing area (246 km × 135 km, with a DOM resolution of 3 m/pixel), resulting in a total of 770,671 craters, ranging from 13 m to 19,882 m in diameter. The analysis of this impact crater catalogue has provided critical support for landing site selection and characterization of the CE-6 mission and lays the foundation for future lunar geological studies.

Exosomes derived from mesenchymal stem cells (MSCs) offer a promising alternative to traditional cell-based therapies for tissue repair by mitigating risks associated with the transplantation of living cells. However, insufficient osteogenic capacity of exosomes diminishes their potential in bone tissue regeneration. Here, we report novel osteogenically induced exosome mimetics (EMs) integrated into injectable hydrogel carriers for improved bone regeneration. EMs were produced by a serial extrusion of MSCs cultured as spheroids during osteogenic induction. The prepared EMs were chemically anchored on a self-healing hydrogel assembled by guanidinylated hyaluronic acid and silica-rich nanoclays for sustained release of EMs. The administration of hydrogel-integrated EMs into mouse calvarial defects resulted in robust bone tissue regeneration. miRNA sequencing revealed altered expression of specific miRNAs in the EMs related to Wnt/β-catenin and Notch signaling pathways. Our study provides new insights into the development of advanced exosome-based cell-free therapies for bone tissue engineering., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Triboelectric nanogenerators (TENGs) offer a convenient means to convert mechanical energy from human movement into electricity, exhibiting the application prospects in human behavior monitoring. Nevertheless, the present methods to improve the device monitoring effect are limited to the design of a triboelectric material level (control of electron gain and loss ability). As compared with reported work, we improve the monitoring effect of TENG-based tactile sensors by optimizing the structure of the electrode/triboelectric material interface by means of a multiple strains mechanism. Cu@Ni double-clad waste woven fabrics are used as electrodes, which are characterized by a structure with a large number of pores formed between the fibers, greatly increasing the specific surface area of the electrode and generating dynamic strain under differentiated stress fields because of their different elastic modulus. To be exact, the resin layer undergoes elastic deformation under 0.64-4.47 kPa external stress and a new deformation generates at the electrode/triboelectric material interface induced by Cu@Ni double-clad woven fabrics slip under 4.47-63.84 kPa external stress, resulting in the accumulation of triboelectric charges on the PDMS surface. The establishment of multiple strains in triboelectric material further facilitates the generation of distinct triboelectric signal waveforms that are easily distinguishable by its amplitude and peak form. Besides, combined with deep machine learning and the triboelectric effect, in an open setting, the identification accuracy of five distinct behaviors approaches 100%. This provides a new pathway for enhancing identification accuracy of a TENG-based tactile sensor.

As a major contributor to neonatal death and neurological sequelae, hypoxic-ischemic encephalopathy (HIE) lacks a viable medication for treatment. Oxidative stress induced by hypoxic-ischemic brain damage (HIBD) predisposes neurons to ferroptosis due to the fact that neonates accumulate high levels of polyunsaturated fatty acids for their brain developmental needs but their antioxidant capacity is immature. Ferroptosis is a form of cell death caused by excessive accumulation of iron-dependent lipid peroxidation and is closely associated with mitochondria. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. In this study we employed mitophagy agonists and inhibitors to explore the mechanisms by which mitophagy exerted ferroptosis resistance in a neonatal rat HIE model. Seven-days-old neonatal rats were subjected to ligation of the right common carotid artery, followed by exposure to hypoxia for 2 h. The neonatal rats were treated with a mitophagy activator Tat-SPK2 peptide (0.5, 1 mg/kg, i.p.) 1 h before hypoxia, or in combination with mitochondrial division inhibitor-1 (Mdivi-1, 20 mg/kg, i.p.), and ferroptosis inhibitor Ferrostatin-1 (Fer-1) (2 mg/kg, i.p.) at the end of the hypoxia period. The regulation of ferroptosis by mitophagy was also investigated in primary cortical neurons or PC12 cells in vitro subjected to 4 or 6 h of OGD followed by 24 h of reperfusion. We showed that HIBD induced mitochondrial damage, ROS overproduction, intracellular iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by the pretreatment with Tat-SPK2 peptide, and aggravated by the treatment with Mdivi-1 or BNIP3 knockdown. Ferroptosis inhibitors Fer-1 and deferoxamine B (DFO) reversed the accumulation of iron and lipid peroxides caused by Mdivi-1, hence reducing ferroptosis triggered by HI. We demonstrated that Tat-SPK2 peptide-activated BNIP3-mediated mitophagy did not alleviate neuronal ferroptosis through the GPX4-GSH pathway. BNIP3-mediated mitophagy drove the P62-KEAP1-NRF2 pathway, which conferred ferroptosis resistance by maintaining iron and redox homeostasis via the regulation of FTH1, HO-1, and DHODH/FSP1-CoQ10-NADH. This study may provide a new perspective and a therapeutic drug for the treatment of neonatal HIE., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Osteosarcopenia is a geriatric syndrome associated with an increased risk of frailty, falls, fractures, disability, and death. Calf circumference (CC) has been used as a simple and practical skeletal muscle marker to diagnose sarcopenia. This study aimed to explore the relationship of calf circumference and osteoporosis (OP) and hip fractures (HF) in middle-aged and older adults. This is important for screening OP and HF in the community and improving the quality of life of older adults., Methods: This study was based on the National Health and Nutrition Examination Survey (NHANES) 1999-2006. Logistic regression analysis and restricted cubic spline were used to investigate the correlation of CC with OP and HF. The receiver operating characteristic (ROC) curve was utilized to determine the optimal cut-off value for CC. Finally, logistic regression model analysis was applied to test the predictive efficacy of CC., Results: Among 4575 individuals with a mean age of 63.0 ± 11.5 years, the OP group had higher proportions of females (P < 0.001) and non-Hispanic whites (P < 0.001). Logistic regression and RCS demonstrated that lower CC was associated with a greater risk of OP and HF in the female group (P < 0.001). ROC curves showed that CC of 33.65 cm and 33.85 cm were the best cut-off values for predicting OP and HF in middle-aged and older females. Logistic regression analyses found good predictive efficacy for cut-off values of CC in females., Conclusion: In middle-aged and older women, low CC is associated with a higher risk of OP and HF. These findings have important implications for managing osteosarcopenia and associated fractures in older adults., Clinical Trial Number: Not applicable., Competing Interests: Declarations. Ethics approval and consent of participate: Ethics approval and consent of participate All the participants from NHANES 1999–2006 gave documented signed consent. These studies were approved by the ethics reviews from the National Center for Health Statistics (NCHS) Ethics Review Board. The NCHS IRB/ERB protocol number for 1999–2004 was # 98 − 12, 2005–2006 was #2005-06. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Clinical trial number: Not applicable., (© 2024. The Author(s).)

Transient receptor potential canonical 1 (TRPC1) facilitates the proliferation, invasion, and metastasis of thyroid cancer cells through up-regulating vascular endothelial growth factor receptor 2 (VEGFR2), while its clinical role in papillary thyroid carcinoma (PTC) is unknown. This study intended to evaluate the prognostic value of TRPC1 and its correlation with VEGFR2 in PTC patients. In this retrospective study, tumor TRPC1 immunohistochemistry (IHC) score was evaluated in 287 PTC patients who underwent surgical resection and 30 thyroid benign lesion (TBL) patients. Moreover, 50 tumor tissue samples from PTC patients were randomly selected for VEGFR2 IHC score evaluation. Our study showed that tumor TRPC1 IHC score was increased in PTC patients versus TBL patients (P = 0.006). Meanwhile, tumor TRPC1 IHC score was related to extrathyroidal invasion (P = 0.028) and pathological node stage 1 (P = 0.011) in PTC patients. Tumor TRPC1 IHC score > 0 was not related to disease-free survival (DFS) or overall survival (OS) (both P > 0.05); however, tumor TRPC1 IHC score > 3 was linked with shortened DFS (P = 0.005) and OS (P = 0.020) in PTC patients. By time-dependent area under curve (AUC) analyses, tumor TRPC1 IHC score showed good values in estimating relapse and death risks over 7 years with all AUCs above 0.7. Furthermore, tumor TRPC1 IHC score > 3 independently predicted shorter DFS (hazard ratio = 2.948, P = 0.045), but not OS (P > 0.05) in PTC patients. Tumor TRPC1 IHC score was positively associated with tumor VEGFR2 IHC score in PTC patients (P = 0.010). Collectively, TRPC1 links with extrathyroidal and lymph node invasion, elevated disease relapse risk, and increased VEGFR2 in PTC patients.

Objectives: To establish an MRI-based model for microvascular invasion (MVI) prediction in mass-forming intrahepatic cholangiocarcinoma (MF-iCCA) and further evaluate its potential survival and therapeutic benefit., Methods: One hundred and fifty-six pathologically confirmed MF-iCCAs with traditional surgery (121 in training and 35 in validation cohorts), 33 with neoadjuvant treatment and 57 with first-line systemic therapy were retrospectively included. Univariate and multivariate regression analyses were performed to identify the independent predictors for MVI in the traditional surgery group, and an MVI-predictive model was constructed. Survival analyses were conducted and compared between MRI-predicted MVI-positive and MVI-negative MF-iCCAs in different treatment groups., Results: Tumor multinodularity (odds ratio = 4.498, p < 0.001) and peri-tumor diffusion-weighted hyperintensity (odds ratio = 4.163, p < 0.001) were independently significant variables associated with MVI. AUC values for the predictive model were 0.760 [95% CI 0.674, 0.833] in the training cohort and 0.757 [95% CI 0.583, 0.885] in the validation cohort. Recurrence-free survival or progression-free survival of the MRI-predicted MVI-positive patients was significantly shorter than the MVI-negative patients in all three treatment groups (log-rank p < 0.001 to 0.046). The use of neoadjuvant therapy was not associated with improved postoperative recurrence-free survival for high-risk MF-iCCA patients in both MRI-predicted MVI-positive and MVI-negative groups (log-rank p = 0.79 and 0.27). Advanced MF-iCCA patients of the MRI-predicted MVI-positive group had significantly worse objective response rate than the MVI-negative group with systemic therapy (40.91% vs 76.92%, χ 2  = 5.208, p = 0.022)., Conclusion: The MRI-based MVI-predictive model could be a potential biomarker for personalized risk stratification and survival prediction in MF-iCCA patients with varied therapies and may aid in candidate selection for systemic therapy., Key Points: Question Identifying intrahepatic cholangiocarcinoma (iCCA) patients at high risk for microvascular invasion (MVI) may inform prognostic risk stratification and guide clinical treatment decision. Findings We established an MRI-based predictive model for MVI in mass-forming-iCCA, integrating imaging features of tumor multinodularity and peri-tumor diffusion-weighted hyperintensity. Clinical relevance The MRI-based MVI-predictive model could be a potential biomarker for personalized risk stratification and survival prediction across varied therapies and may aid in therapeutic candidate selection for systemic therapy., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is Mengsu Zeng. Conflict of interest: The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. Statistics and biometry: One of the authors (Yunfei Zhang) has significant statistical expertise. Informed consent: Written informed consent was waived by the Institutional Review Board. Ethical approval: Institutional Review Board approval was obtained. Study subjects or cohorts overlap: Not applicable. Methodology: Retrospective Diagnostic or prognostic study Performed at one institution, (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Alantolactone, a sesquiterpene lactone, is isolated from the traditional Chinese medicinal herb Inula helenium L. (Asteraceae). Alantolactone is known as its wide spectrum of biological effects, including antimicrobial, antifungal, antiviral, anthelmintic activities, anti-inflammatory activities, and antiproliferative effects on several cancer cell lines. Thus, it has received extensive attention causing in-depth research in medicinal chemistry and numerous undescribed alantolactone derivatives have been synthesized through different strategies. Herein, recent advances in diverse bioactivities and mechanism of alantolactone including its derivatives were summarized., (© 2024 Wiley‐VCH GmbH.)

Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a vital role in regulating redox homeostasis and reductive biosynthesis. However, if exogenous NADPH can be transported across the plasma membrane has remained elusive. In this study, we present evidence supporting that NADPH can traverse the plasma membranes of cells through a mechanism mediated by the P2X7 receptor (P2X7R). Notably, we observed an augmentation of intracellular NADPH levels in cultured microglia upon exogenous NADPH supplementation in the presence of ATP. The P2X7R-mediated transmembrane transportation of NADPH was validated with P2X7R antagonists, including OX-ATP, BBG, and A-438079, or through P2X7 knockdown, which impeded NADPH transportation into cells. Conversely, overexpression of P2X7 resulted in an enhanced capacity for NADPH transport. Furthermore, transfection of hP2X7 demonstrated the ability to complement NADPH uptake in native HEK293 cells. Our findings provide evidence for the first time that NADPH is transported across the plasma membrane via a P2X7R-mediated pathway. Additionally, we propose an innovative avenue for modulating intracellular NADPH levels. This discovery holds promise for advancing our understanding of the role of NADPH in redox homeostasis and neuroinflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Developing a nomogram integrating MR elastography (MRE)-based tumor stiffness and contrast-enhanced MRI in identifying cytokeratin 19 (CK19) status of hepatocellular carcinoma (HCC) preoperatively., Methods: 120 CK19-negative HCC and 39 CK19-positive HCC patients undergoing curative resection were prospectively evaluated. All received MRE and contrast-enhanced MRI. Clinical and MRI tumor features were compared. Univariate and multivariate logistic regression analyses identified independent predictors for CK19 status. Receiver operating characteristic curve analysis evaluated diagnostic performance. A nomogram was established with calibration and decision curve analysis., Results: Multivariate analysis revealed serum alpha fetoprotein (AFP) level (P < 0.001), targetoid appearance (P = 0.007), and tumor stiffness (P = 0.011) as independent significant variables for CK19-positive HCC. The area under the curve for tumor stiffness was 0.729 (95% CI 0.653, 0.796). Combining these features, a nomogram-based model achieved an area under the curve value of 0.844 (95% CI 0.778, 0.897), with sensitivity, specificity, and accuracy of 76.92%, 85.00%, and 83.02%, respectively. Calibration and decision curve analyses demonstrated good agreement and optimal net benefit., Conclusions: MRE-measured tumor stiffness aids in predicting CK19 status in HCC. The combined nomogram incorporating tumor stiffness, targetoid appearance, and AFP provides a reliable biomarker for CK19-positive HCC., Advances in Knowledge: MRE-measured tumor stiffness can be used to predict CK19 status in HCC. The nomogram, which integrates tumor stiffness, targetoid appearance, and AFP levels, has shown enhanced diagnostic performance. It offers a comprehensive preoperative tool for clinical decision-making, further advancing personalized treatment strategies in HCC management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study aimed to investigate the effect of alveolar ridge preservation (ARP) sealing using reactive soft tissue (RST) or collagen sponge (CS), in combination with deproteinized bovine bone mineral (DBBM), for teeth with bone deficiency., Materials and Methods: In this study, 44 patients were recruited. During ARP therapy, RST or CS was applied for socket sealing. Horizontal and vertical bone dimensions were assessed before extraction (T0) and 6 months after ARP (T2). Modified Masse healing index (HI) was recorded to evaluate the soft tissue healing at 14 days after ARP (T1) and T2. Keratinized mucosa width (KMW) was measured at T0 and T2. Biopsies were collected during implant placement for histological analysis., Results: This study was finished by 40 patients. Horizontal ridge gains at 1, 3, and 5 mm below the crest were comparable in RST (4.37/5.57/4.16 mm) and CS (3.57/4.66/2.97 mm) groups. Similar vertical bone gains at both buccal and lingual sides were observed in RST and CS groups. Notably, the sockets in the RST group exhibited a significantly better early healing score (6) at T1 relative to the CS group (7) (p = 0.003). There was no significant difference in KMW changes as well as new bone proportion between the groups., Conclusions: RST and CS, when combined with DBBM, both effectively reduced ridge resorption in sockets with bone deficiency. RST demonstrated a more favorable effect on the early healing of sockets., Clinical Relevance: RST is a promising socket sealing material in ARP, which reduces bone resorption, and promotes soft tissue healing., Trial Registration: Clinical trial registration Number: ChiCTR2200061459., Competing Interests: Declarations. Patient consent: All patients received verbal and written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To establish an MRI-based predictive model for postoperative recurrence in intrahepatic cholangiocarcinoma (iCCA) and further to evaluate the model utility in treatment direction for neoadjuvant and adjuvant therapies., Materials and Methods: Totally 114 iCCA patients with curative surgery were retrospectively included, including 38 patients in the neoadjuvant treatment, traditional surgery, and adjuvant treatment groups for each. Predictive variables associated with postoperative recurrence were identified using univariate and multivariate Cox regression analyses, and a prognostic model was formulated. Recurrence-free survival (RFS) curves were compared using log-rank test between MRI-predicted high-risk and low-risk iCCAs stratified by the optimal threshold., Results: Tumor multiplicity (hazard ratio (HR) = 1.671 [95%CI 1.036, 2.695], P = 0.035), hemorrhage (HR = 2.391 [95%CI 1.189, 4.810], P = 0.015), peri-tumor diffusion-weighted hyperintensity (HR = 1.723 [95%CI 1.085, 2.734], P = 0.021), and positive regional lymph node (HR = 2.175 [95%CI 1.295, 3.653], P = 0.003) were independently associated with postoperative recurrence; treatment group was not significantly related to recurrence (P > 0.05). Independent variables above were incorporated for the recurrence prediction model, the 1-year and 2-year time-dependent area under the curve values were 0.723 (95%CI 0.631, 0.815) and 0.725 (95%CI 0.634, 0.816), respectively. After risk stratification, the MRI-predicted high-risk iCCA patients had higher cumulative incidences of recurrence and worse RFS than the low-risk patients (P < 0.001 for both). In the MRI-predicted high-risk patients, neoadjuvant therapy was associated with improved all-stage RFS (P = 0.034), and adjuvant therapy was associated with improved RFS after 4 months (P = 0.014)., Conclusions: The MRI-based iCCA recurrence predictive model may serve as a decision-making tool for both personalized prognostication and therapy selection., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: The study was conducted according to the guidelines of the Declaration of Helsinki. It was approved by the Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai, China (protocol code B2021-113R)., (© 2024. Italian Society of Medical Radiology.)

Nanoparticles-based drug delivery system has been a promising approach for the treatment of colorectal cancer (CRC), which can be combined with chemotherapy, targeted therapy and immunotherapy to improve the treatment of CRC. 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is an agonist of the STING signaling pathway activating antitumor immunity. IPI-549 is a small-molecule inhibitor for phosphatidylinositol 3-kinase γ (PI3Kγ), which can induce M1 macrophages polarization to provide pro-inflammatory microenvironment to suppress tumors. Here, we developed a ferric ion-punicalagin network (Fe-PU), which can be not only used as an inducer of ferroptosis, but also serve as a carrier to load cGAMP and IPI-549 to obtain nanohybrid (Fe-PU/CD-IPI). In order to improve the delivery effect and targeted ability to CRC, a cyclic arginine-glycine-aspartic acid peptide linked-bovine serum albumin were utilized to modify Fe-PU/CD-IPI to prepare nanohybrid Fe-PU/CD-IPI@cBSA. The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice., Methods: We engineered Asgr1 knockout mice ( Asgr1 -/- ), Asgr1 and ApoE double-knockout mice ( Asgr1 -/- ApoE -/- ), and ASGR1-overexpressing mice on an ApoE -/- background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury., Results: After being fed a Western diet for 12 weeks, Asgr1 -/- ApoE -/- mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in ApoE -/- mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing ApoE -/- mice. In addition, ASGR1 deficiency exacerbates liver injury in Western diet-induced Asgr1 -/- ApoE -/- mice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-induced Asgr1 -/- mice, while its overexpression mitigates liver injury in Western diet-induced ASGR1-overexpressing ApoE -/- mice., Conclusions: Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed ApoE -/- mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases., Competing Interests: None.

Postoperative complications of radical gastrectomy seriously affect postoperative recovery and require accurate risk prediction. Therefore, this study aimed to develop a prediction model specifically tailored to guide perioperative clinical decision-making for postoperative complications in patients with gastric cancer. A retrospective analysis was conducted on patients who underwent radical gastrectomy at the First Affiliated Hospital of Nanjing Medical University between April 2022 and June 2023. A total of 166 patients were enrolled. Patient demographic characteristics, laboratory examination results, and surgical pathological features were recorded. Preoperative abdominal CT scans were used to segment the visceral fat region of the patients through 3Dslicer, a 3D Convolutional Neural Network (3D-CNN) to extract image features and the LASSO regression model was employed for feature selection. Moreover, an ensemble learning strategy was adopted to train the features and predict postoperative complications of gastric cancer. The prediction performance of the LGBM (Light Gradient Boosting Machine), XGB (XGBoost), RF (Random Forest), and GBDT (Gradient Boosting Decision Tree) models was evaluated through fivefold cross-validation. This study successfully constructed a model for predicting early complications following radical gastrectomy based on the optimal algorithm, LGBM. The LGBM model yielded an AUC value of 0.9232 and an accuracy of 87.28% (95% CI, 75.61-98.95%), surpassing the performance of other models. Through ensemble learning and integration of perioperative clinical data and visceral fat radiomics, a predictive LGBM model was established. This model has the potential to facilitate individualized clinical decision-making and the early recovery of patients with gastric cancer post-surgery., Competing Interests: Declarations. Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (22 November 2022/No. 2022-SR-591). Consent to Participate: The requirement for informed consent was waived. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

The transformation of clinical androgen receptor (AR) antagonists into agonists driven by AR mutations poses a significant challenge in treating prostate cancer (PCa). Novel anti-AR therapeutics combating mutation-induced resistance are required. Herein, by combining structure-based virtual screening and biological evaluation, a high-affinity agonist E10 was first discovered. Then guided by the representative conformation of State 1 at the free energy landscape, the structural optimization of E10 was performed, and pure AR antagonists EL15 (IC 50 = 0.94 μM) and EF2 (IC 50 = 0.30 μM) were successfully identified. Both can antagonize wild-type and variant drug-resistant ARs. Therein, EF2 demonstrated potent inhibition of the AR pathway and effectively suppressed tumor growth in a C4-2B xenograft mouse model following oral administration. Further molecular dynamics simulation and mutagenesis studies revealed atomic insights into the mode of action of EF2 which may serve as a novel lead compound for developing therapeutics against AR-driven PCa.

The gut microbiota plays a crucial role in various physiological functions of the host and can be modulated by numerous factors, including feeding habit or trophic level. In this study, the impact of host feeding habits on the gut microbiota of freshwater fish was explored. Ten fish species, classified into four feeding habit categories (herbivorous, omnivorous, planktivorous, and carnivorous) were sampled from West Lake, a renowned urban scenic lake, and their gut content microbiota was analysed using 16S ribosomal RNA gene sequencing. A total of 2531 operational taxonomic units, belonging to 34 bacterial phyla, were identified, with 33.4% shared across all feeding habits. Firmicutes and Proteobacteria were the predominant phyla. However, at the family level, Peptostreptococcaceae and Clostridiaceae&#95;1 were the most dominant. Microbiota composition diversity was highest in herbivorous fish, followed by omnivores, carnivores, and planktivores. Statistically significant differences in microbiota diversity were found between different feeding categories, except for the omnivores, which did not differ from the carnivores or planktivores. The most abundant predicted metabolic pathways across all feeding habits were similar, with amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and metabolism of other amino acids being dominant. However, comparing the relative abundance of gene functions between different feeding habits revealed notable variations across most comparisons. Co-occurrence network analysis for each feeding habit revealed that all networks were dominated by the strong positive correlation among pairs of bacterial genera abundances, while the basic properties varied, implying differences in gut microbiota interactions based on the feeding habit. In conclusion, these results confirmed that the feeding habit could affect the structure and composition of the gut content microbiota but also changed their functions and interactions., (© 2024 Fisheries Society of the British Isles.)

Group A rotaviruses (RVA) remain one of the dominant pathogens causing diarrhea in children under 5 years of age worldwide, despite a sharp decrease of RVA-associated diarrhea and mortality since the introduction of rotavirus vaccines. The decreased effectiveness of live attenuated rotavirus vaccines, coupled with the emergence of new rotavirus genotypes and the risk of cross-species virus transmission, underscores the necessity to develop more effective and broad-spectrum rotavirus vaccines. In this study, we utilized nanoparticles coupled with the SpyCatcher-SpyTag system to effectively display the truncated VP8-1 protein. The modular display of the monovalent VP8-1 proteins markedly increased the immunogenicity of VP8-1. Furthermore, the bivalent display of VP8-1 proteins from simian rotavirus SA11 and lamb rotavirus LLR on the same particle not only increased immunogenicity against homotypic antigens but also elicited robust heterotypic immune responses and conferred effective protection against a distant heterotypic rotavirus with sequence identities of only 62%-66% in an adult mouse model. Therefore, mosaic VP8 nanoparticles could be considered as a viable strategy for the development of the next-generation broad-spectrum rotavirus vaccine.

Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1 , which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC 50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC 50 = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against AR F876L/T877A and AR W741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles ( F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though mild in early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers, and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine., Approach and Results: Herein, we identified cyclin-dependent kinase-like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related hepatic inflammation, fibrosis, and diabetes. Mechanism-wise, CDKL3 directly phosphorylates forkhead box O (FoxO)1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic CDKL3 is a direct target gene of Hepatocyte nuclear factor 4α (HNF4α). HNF4α is inhibited during MASLD, which leads to diminished CDKL3 expression. The CDKL3-mediated cross talk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression., Conclusions: We unearthed an alternative but critical regulatory path of FoxO1 by the HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment., (Copyright © 2024 American Association for the Study of Liver Diseases.)

The direct photocatalytic reduction of CO 2 in air is the future trend of photocatalyst application. Herein, the 0D carbon nitride quantum dots with nitrogen vacancies (V N -CNQDs) and 2D bismuth-deficient Bi 4 O 5 Br 2 (V Bi -Bi 4 O 5 Br 2 ) are integrated by hydrothermal method. The S-scheme heterostructure of V N -CNQDs/V Bi -Bi 4 O 5 Br 2 composite promotes the separation rate of photogenerated carriers and enhances the redox capacity. The dual defects provide a large number of adsorption and catalytic sites that enhance the ability to capture and reduce CO 2 . The synergistic effect of S-scheme heterostructure and defect engineering enables the efficiency of CO 2 photoreduction to CO with V N -CNQDs/V Bi -Bi 4 O 5 Br 2 to reach 16.89 µmol g -1  h -1 in air and 55.69 µmol g -1  h -1 in V CO2 : V Air = 3:1 condition, which is 17 and 21 times higher than that of Bi 4 O 5 Br 2 , respectively. The dual-defective V N -CNQDs/V Bi -Bi 4 O 5 Br 2 exhibits more lower energy barrier for forming * CO 2 , * COOH, and * CO and is easier to release CO gas. And it exhibits excellent cycling stability for photocatalytic CO 2 reduction to CO. The photocatalytic reduction mechanism of CO 2 to CO in the V N -CNQDs/V Bi -Bi 4 O 5 Br 2 S-scheme heterostructure is further analyzed. This work provides new perspectives for the design of the photocatalysts with defect engineering for efficient photoconversion at low CO 2 concentrations., (© 2024 Wiley‐VCH GmbH.)

Presently, the non-biodegradable polypropylene (PP) patches frequently used for hernia repair can cause fibrous tissue growth and adhesions. This study created a Janus Patch with anti-adhesion and antimicrobial properties to improve hernia repair while promoting tissue repair. The biologically active 4arm-PLGA-BLPD was initially synthesized through the modification of 4arm-PLGA with lysine, followed by the fabrication of a Janus patch using a layer-by-layer electrostatic spinning technique. This patch consisted of three layers: a repair layer composed of 4arm-PLGA-BLPD/PCL fiber membrane, a mechanical layer of 4arm-PLGA/PCL fiber membrane, and an antimicrobial layer of EMO-4arm-PLGA/PCL fiber membrane loaded with Emodin (EMO). The results showed that Janus patch exhibited notable tensile strength and elongation at break, enabling it to offer enhanced mechanical reinforcement for abdominal wall defects. In addition, it slowly releases lysine for repair and inhibits bacterial growth with EMO. In vivo experiments demonstrated that the patch effectively induced neovascularization, reduced collagen ac-cumulation, and stabilized the expression of relevant proteins through the up-regulation of MMP1 and MMP9. This facilitated successful repair of the abdominal wall defect model and prevented adhesions. In summary, the Janus patch offers both practical application and theoretical insight for hernia repair., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Spermatogenesis in eukaryotes is a process that occurs within a very narrow temperature threshold, typically not exceeding 36 °C. SPO11 was isolated from the temperature-sensitive mutant receptor of Saccharomyces cerevisiae and is thought to be the only protein that functions during meiosis. This suggested that SPO11 may be the key protein that influenced the temperature of spermatogenesis not exceeding 36 °C. Elevated temperatures typically damage the spermatogenic cells. Birds have a core body temperature of 41-42 °C, and their testis are located inside their bodies, providing an alternative perspective to investigate the potential impact of temperature threshold on spermatogenesis. The objective of this study was to ascertain whether elevated ambient temperatures affect spermatogenesis in birds and whether SPO11 is the key gene affecting the temperature threshold for spermatogenesis. STRA8, SCP3, SPO11, γ-H2AX, and RAD51 were all crucial components in the process of meiotic initiation, synapsis, DNA double-strand break (DSB) induction, homologous chromosome crossover recombination, and repair of DSB. In this study, 39-day-old Japanese quail were subjected to heat stress (HS) at 38 °C for 8 h per day for 3 (3d HS) and 13 (13d HS) consecutive days and analyzed the expression of meiotic signaling molecules (STRA8, SCP3, SPO11, γ-H2AX, and RAD51) using molecular biology techniques, including Immunohistochemistry (IHC), Western Blot (WB), and Real-time Quantitative Polymerase Chain Reaction (qRT-PCR). We found that spermatogenesis was normal in both groups exposed to HS. Meiotic signaling molecules were expressed normally in the 3d HS group. All detected signaling molecules were normally expressed in the 13d HS group, except for SPO11, which showed a significant increase in expression, indicating that SPO11 was temperature-sensitive. We examined the localized expression of each meiotic signaling molecule in quail testis, explored the temperature sensitivity of SPO11, and determined that quail testis can undergo normal spermatogenesis at ambient temperatures exceeding 36 °C. This study concluded that SPO11 is not the key protein influencing spermatogenesis in birds. These findings enhance our understanding of avian spermatogenesis., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tendon repair remains challenging due to its poor intrinsic healing capacity, and stem cell therapy has emerged as a promising strategy to promote tendon regeneration. Nevertheless, the inflammatory environment following acute tendon injuries disrupts stem cell differentiation, leading to unsatisfied outcomes. Our study recognized the critical role of NF-κB signaling in activating inflammation and suppressing tenogenic differentiation of stem cells after acute tendon injury via multiomics analysis. TPCA-1, a selective inhibitor of IKKβ/NF-κB signaling, efficiently restored the impaired tenogenesis of stem cells in the inflammatory environment. By developing a microsphere-incorporated hydrogel system for stem cell delivery and controlled release of TPCA-1, we successfully engineered a pro-tenogenic niche to initiate tenogenesis for tendon regeneration. Collectively, we recognize NF-κB signaling as a critical target to tailor a pro-tenogenic niche and propose the combined delivery of stem cells and TPCA-1 as a potential strategy for acute tendon injuries., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins. However, the dependency of RSPO-ZNRF3/RNF43-mediated FZD endocytosis and degradation on Wnt stimulation, as well as the specificity of this degradation for different FZD, remains unclear. Here, we demonstrated that Wnt specifically induces FZD5/8 endocytosis and degradation in a ZNRF3/RNF43-dependent manner. ZNRF3/RNF43 selectively targets FZD5/8 for degradation upon Wnt stimulation. RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8. Wnt promotes the interaction between FZD5 and RNF43. We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling, which may provide new insights into regenerative medicine and cancer therapy., Competing Interests: Declaration of interests The authors declare that they have no competing interests.

Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist M17-B15 was identified. M17-B15 showed strong in vitro efficacy against PCa but had poor pharmacokinetic properties in vivo . In this study, through rational design and structure-activity relationship exploration, a series of thiadiazoleamide derivatives represented by N29 (IC 50 = 0.018 μM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity in vitro . Furthermore, N29 effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of N29 facilitated its efficacy via oral administration, significantly inhibiting LNCaP xenograft tumor in vivo , presenting a promising therapeutic application for PCa.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 μM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg -1 ·d -1 , i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE -/- mice (20, 60 mg·kg -1 ·d -1 , i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg -1 ·d -1 , i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Rationale and Objectives: Identifying intrahepatic cholangiocarcinoma (iCCA) patients who are at high risk for early recurrence (ER) can guide personalized treatment strategy and improve survival. This study aimed to investigate the value of preoperative MRI, especially diffusion-weighted imaging, in predicting ER, including in patients receiving neoadjuvant therapy., Materials and Methods: This study included 175 pathologically-confirmed iCCA patients who underwent curative resection (114 men, 61 women; mean age 59.0 ± 9.56 years). MRI features, particularly apparent diffusion coefficient (ADC), were analyzed and compared between ER and non-ER cases. Survival analyses of ER were evaluated using Cox regression and Kaplan-Meier analysis., Results: ER occurred in 54.3% (95/175) of patients. Multivariate logistic regression analysis identified tumor ADC as the only independent predictor of ER (odds ratio = 0.034, P < 0.001), with AUCs of 0.758 (95%CI 0.664, 0.836) in the testing cohort and 0.779 (95%CI 0.622, 0.893) in the validation cohort. The optimal ADC threshold was 1.273 × 10 -3 mm 2 /s. Tumor ADC was comparable to the AJCC 8th staging system in predicting ER (AUC 0.758 vs 0.650 in testing cohort and 0.779 vs 0.661 in validation cohort). Multivariate Cox analysis identified high tumor burden score (HR = 1.109, P = 0.009), non-smooth margin (HR = 2.265, P = 0.008) and tumor ADC (HR = 0.111, P < 0.001) as independent risk factors for ER. Lower ADC values were linked to shorter RFS in both testing and validation cohorts (P < 0.001 and 0.0219), as well as in patients receiving neoadjuvant therapy (P = 0.003)., Conclusion: Preoperative MRI, particularly ADC, can help predict ER in iCCA, regardless of the application of neoadjuvant therapy, comparable to the AJCC 8th staging system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation.

Small bowel strictures remain a debilitating consequence of Crohn's disease and contribute to poor outcomes for patients. Recently, TGFβ has been identified as an important driver of intestinal fibrosis. We studied the localization of TGFβ isoforms in ileal strictures of patients with Crohn's disease using in situ hybridization to understand TGFβ's role in stricture formation. The mucosa of strictures was characterized by higher TGFβ1 while the stricture submucosa showed higher TGFβ3 compared to normal ileum from patients without Crohn's disease (p = 0.02 and p = 0.044, respectively). We correlated these findings with single-cell transcriptomics which demonstrated that TGFβ3 transcripts overall are very rare, which may partially explain why its role in intestinal fibrosis has remained unclear to date. There were no significant differences in fibroblast or B cell TGFβ1 and/or TGFβ3 expression in inflamed vs. noninflamed ileum. We discuss the implications of these findings for therapeutic development strategies to treat patients with fibrostenotic Crohn's disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Dysfunction of dopamine homeostasis (DAH), which is regulated by vesicular monoamine transporter 2 (VMAT2), is a vital cause of dopamine (DA) neurotoxicity and motor deficits in Parkinson's disease (PD). Gastrodin (4-hydroxybenzyl alcohol 4-O-β-D-glucoside; GTD), a natural active compound derived from Gastrodia elata Blume, can be used to treat multiple neurological disorders, including PD. However, whether GTD regulates VMAT2-mediated DAH dysfunction in PD models remains unclear., Purpose: To explore whether GTD confers dopaminergic neuroprotection by facilitating DA vesicle storage and maintaining DAH in PD models., Methods: Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and PC12 cells with 1-methyl-4-phenyl-pyridinium (MPP + ) to induce PD characteristics. Multiple behavioural tests were performed to evaluate the motor functions of the mice. HPLC was used to measure DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Transmission electron microscopy was used to observe synaptic vesicles. Molecular docking and molecular dynamics were used to determine the binding affinity of GTD to the target protein. Reserpine (Res, a VMAT2 inhibitor) and PD0325901 (901, a MEK inhibitor) were employed to investigate the mechanism of GTD. Western blotting and immunohistochemistry were used to assess the expression of the target proteins., Results: GTD attenuated motor deficits and dopaminergic neuronal injury, reversed the imbalance of DAH, and increased VMAT2 levels and vesicle volume in MPTP-induced mice. GTD ameliorated cell damage, ROS release, and dysfunction of DAH in MPP + -induced PC12 cells. Moreover, the neuroprotective effects of GTD were reversed by Res in vitro and in vivo. Furthermore, GTD can activate the MEK/ERK/CREB pathway to upregulate VMAT2 in vitro and in vivo. Interestingly, 901 reversed the effects of GTD on VMAT2 and dopaminergic neuronal impairment., Conclusion: GTD relieved PD-related motor deficits and dopaminergic neuronal impairment by facilitating MEK-depended VMAT2 to regulate DAH, which offers new insights into its therapeutic potential., Competing Interests: Declaration of competing interest All authors declared no conflicts of interest to this work., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

To develop a set of cognitive behavioral therapies (CBTs) to alleviate anxiety in orthopedic surgery (OS) patients, to explore the intervention effects of CBTs on the indicators of anxiety, sleep quality, and pain sensation in OS patients, and to promote them. A total of 68 qualified subjects were selected from among the 103 patients with orthopedic diseases who were hospitalized in the orthopedic department of the hospital between June 2022 and November 2023. According to the different nursing methods, they were divided into a psychological intervention (PI) group and a control intervention group. Among them, 34 patients received hospital-developed CBT for OS in the PI group, and 34 patients received standard orders from the medical staff in the control intervention group. Tools such as self-assessment of anxiety, Athens insomnia scale, state anxiety scale, visual analog pain method, and self-management level scale were utilized to assess the change in anxiety levels, sleep quality, pain perception, and self-management level of the 2 groups of patients before and after the surgery. Following the CBT intervention, patients in the PI group had significantly lower Athens insomnia scale (5.32 ± 0.42), state anxiety scale (38.21 ± 1.12), and visual analog pain method (3.93 ± 1.24) scores than those in the control intervention group. This difference was statistically significant (P < .05). In the meantime, patients in the PI group had a substantially higher correct rate of illness cognition assessment (98.21%) than patients in the control intervention group (65.12%), and this difference was statistically significant (P < .05). The study collated the factors affecting anxiety in OS patients through questionnaire survey and statistical analysis experiment and then formulated a detailed CBT strategy for specific problems. Finally, CBT is a valuable tool for reducing anxiety in OS patients. As such, it deserves to be promoted and used in clinical settings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cartilage maintains the structure and function of joints, with disturbances leading to potential osteoarthritis. N6-methyladenosine (m 6 A), the most widespread post-transcriptional modification in eukaryotes, plays a crucial role in regulating biological processes. While current research has indicated that m 6 A affects the progression of osteoarthritis, its function in the development and homeostasis of articular cartilage remains unclear. Here we report that Mettl3 deficiency in chondrocytes leads to mandibular condylar cartilage morphological alterations, early temporomandibular joint osteoarthritis, and diminished adaptive response to abnormal mechanical stimuli. Mechanistically, METTL3 modulates Lats1 mRNA methylation and facilitates its degradation in an m 6 A-YTHDF2-dependent manner, which subsequently influences the degradation and nuclear translocation of YAP1. Intervention with the Hippo pathway inhibitor XMU-MP-1 alleviates condylar abnormality caused by Mettl3 knockout. Our findings demonstrate the role of METTL3 in cartilage development and homeostasis, offering insights into potential treatment strategies for osteoarthritis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)