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Abstract Epithelial ovarian cancer (EOC) presents considerable difficulties in prognostication and treatment strategy development. Bevacizumab, an anti-angiogenic medication, has demonstrated potential in enhancing progression-free survival (PFS) in EOC patients. Nevertheless, the identification of individuals at elevated risk of disease progression following treatment remains a challenging task. This study was to develop and validate a deep learning (DL) model using retrospectively collected computed tomography (CT) plain scans of inoperable and recurrent EOC patients receiving bevacizumab treatment diagnosed between January 2013 and January 2024. A total of 525 patients from three different institutions were retrospectively included in the study and divided into training set (N = 400), internal test set (N = 97) and external test set (N = 28). The model’s performance was evaluated using Harrell’s C-index. Patients were categorized into high-risk and low-risk group based on a predetermined cutoff in the training set. Additionally, a multimodal model was evaluated, incorporating the risk score generated by the DL model and the pretreatment level of carbohydrate antigen 125 as input variables. The Net Reclassification Improvement (NRI) metric quantified the reclassification performance of our optimal model in comparison to the International Federation of Gynecology and Obstetrics (FIGO) staging model. The results indicated that DL model achieved a PFS predictive C-index of 0.73 in the internal test set and a C-index of 0.61 in the external test set, along with hazard ratios of 34.24 in the training set (95% CI: 21.7, 54.1; P

Abstract Background Compliance with medication is crucial for the favorable prognosis of children with epilepsy. The objective of this study was to assess the determinants of medication compliance and to construct a predictive model for the risk of non-compliance among pediatric epilepsy patients. Methods The study included children diagnosed with epilepsy and treated at our hospital between February 1 and September 30, 2023. We evaluated the demographic characteristics and medication compliance profiles of these patients. The predictive model’s performance was assessed using the receiver operating characteristic (ROC) curve to determine its sensitivity and specificity. Results A total of 168 children with epilepsy were analyzed. The rate of non-compliance with medication was found to be 32.74% (55 out of 168). Logistic regression identified the educational level of parents (OR = 2.844, 95% CI: 2.182–3.214), monthly household income (OR = 1.945, 95% CI: 1.203–2.422), the number of medications taken (OR = 1.883, 95% CI: 1.314–2.201), and the level of epilepsy knowledge received (OR = 2.517, 95% CI: 1.852–3.009) as significant factors influencing non-compliance (all p

Abstract Background Lung squamous cell carcinoma (LUSCs) is associated with high mortality (20–30%) and lacks of effective treatments. Almost all LUSC exhibit somatic mutations in TP53. Wee1, a tyrosine kinase, regulates the cell cycle at the G2/M checkpoint. In TP53-deficient cells, the dependence on G2/M checkpoints increases. PD0166285 is the first reported drug with inhibitory activity against both Wee1 and PKMYT1. Methods Protein expression was determined by Western blot analysis. Cell proliferation was assessed using cell colony formation and CCK-8 assays. Cell cycle was performed by PI staining with flow cytometry. Apoptosis was evaluated using Annexin V-Phycoerythrin double staining and flow cytometry. DNA damage was detected through comet assay and immunofluorescence assay. In vivo, apoptosis and anti-tumor effects were assessed using the TUNEL assay, a nude mouse model, and immunohistochemistry (IHC). Co-immunoprecipitation assay was used to detect protein–protein interactions. We analyzed Wee1, PKMYT1, and Stat1 expression in pan-cancer studies using the Ualcan public database and assessed their prognostic implications with Kaplan–Meier curves. Result PD0166285, a Wee1 inhibitor, effectively inhibits Wee1 activity, promoting cell entry into a mitotic crisis. Moreover, PD0166285 sensitizes cells to cisplatin, enhancing clinical outcomes. Our study demonstrated that PD016628 regulates the cell cycle through Rad51 and results in cell cycle arrest at the G2/M phase. We observed increased apoptosis in tumor cells treated with PD0166285, particularly when combined with cisplatin, indicating an enhanced apoptotic response. The upregulation of γ-H2AX serves as an indicator of mitotic catastrophe. Co-immunoprecipitation and data analysis revealed that apoptosis in LUSC is mediated through the Stat1 pathway, accompanied by decreased levels of Socs3. Furthermore, IHC staining confirmed significant differences in the expression of Phospho-CDK1 and γ-H2AX in LUSCs, suggesting involvement in DNA damage. Conclusions In summary, our study suggests that PD0166285, an inhibitor of Wee1, sensitizes LUSC cells to cisplatin and modulates DNA damage and apoptosis pathways through Rad51 and Stat1, respectively. These findings highlight the combination of PD0166285 and cisplatin as a promising therapeutic approach for treating LUSC.

Abstract In recent years, the application of real scene 3D technology has become widespread in urban planning and cultural heritage protection. However, there has been relatively little attention paid to the construction of real scene 3D models for special natural landscapes such as caves. Given the global distribution of karst topography and the large number of naturally developed caves with diverse types, unique landscape styles, and significant scientific value, this paper enriches the research in this field. By combining ground-based and aerial remote sensing techniques, and based on 3D laser scanning and photogrammetry, we have successfully constructed a real scene 3D model of the internal structure of a karst cave with a precision better than 4 cm. Utilizing Unmanned Aerial Vehicle (UAV) oblique photography, we established a real scene 3D model of the external karst landform with a precision better than 2 cm. We also integrated the internal and external 3D models of the cave, developing a new, complete, and high-precision method for constructing real scene 3D models of karst cave landscapes. Furthermore, we proposed a method for texture reproduction in the dark environment inside the caves, enhancing the reproduction and visual appeal of the real interior. The establishment of high-precision real scene 3D models can not only serve as an effective tool for scientific research on caves but also, as replicas of the real world, play a crucial role in public dissemination and education, thereby enhancing public understanding of cave geological landscapes.

Abstract Background Our research endeavored to develop a robust predictive signature grounded in super-enhancer-related genes (SERGs), with the dual objectives of forecasting survival outcomes and evaluating the tumor immune microenvironment (TiME) in hepatocellular carcinoma (HCC). Methods HCC RNA-sequencing data were retrieved from The Cancer Genome Atlas (TCGA), and 365 patients were randomly assigned to training or testing sets in 1:1 ratio. SERGs of HCC were downloaded from Super-Enhancer Database (SEdb). On the basis of training set, a SERGs signature was identified, and its prognostic value was confirmed by internal and external validation (GSE14520) sets. We subsequently examined the model for potential functional enrichment and the degree of tumor immune infiltration. Additionally, we carried out in vitro experiments to delve into the biological functions of CBX2 gene. Results An SE-related prognostic model including CBX2, TPX2, EFNA3, DNASE1L3 and SOCS2 was established and validated. According to this risk model, patients in the high-risk group had a significantly worse prognosis, and their immune cell infiltration was significantly different from that of low-risk group. Moreover, the high-risk group exhibited a significant enrichment of tumor-associated pathological pathways. The SERGs signature can generally be utilized to screen HCC patients who are likely to respond to immunotherapy, as there is a positive correlation between the risk score and the Tumor Immune Dysfunction and Exclusion (TIDE) score. Furthermore, the downregulation of the CBX2 gene expression was found to inhibit HCC cell viability, migration, and cell cycle progression, while simultaneously promoting apoptosis. Conclusions We developed a novel HCC prognostic model utilizing SERGs, indicating that patients with high-risk score not only face a poorer prognosis but also may exhibit a diminished therapeutic response to immune checkpoint inhibitors (ICIs). This model is designed to tailor personalized treatment strategies to the individual needs of each patient, thereby improving the overall clinical outcomes for HCC patients. Furthermore, CBX2 is a promising candidate for therapeutic intervention in HCC.

The photocatalytic conversion of soluble U(Ⅵ) to insoluble U(Ⅳ) is regarded as an effective method for the separation of solution uranium. During the photocatalytic reactions, the design of photocatalyst plays a role. As a metal free polymer semiconductor, carbon nitride(CN) has attracted increasing attentions in photo-catalytic reduction of U(Ⅵ) under visible light irradiation due to its low cost, easy preparation, excellent physicochemical stability and adjustable structure. However, the application of carbon nitride in photocatalytic U(Ⅵ) reduction is limited by its low photocatalytic reduction efficiency, which is caused by the poor reactive sites low separation rate of charge carriers, and slow transport efficiency of electrons. This study aimed to evaluate the transformation of U(Ⅵ) in aqueous solution over Y-doped CN(YCN). YCN photocatalysts with different amount of Y3+ were prepared by in situ doping to modify the energy band structure and physicochemical properties of carbon nitride. It was revealed that the presence of Y3+ changed the in-plane periodic topology and inter-layer stacking structure of the tri-s-triazine unit of carbon nitride, resulting in the incomplete polymerization of the tri-s-triazine unit. The doping of Y3+ lead to the formation of porous structure in YCN, which increases the specific surface area and the active sites. Comparing with pristine CN, YCN showes enhanced absorbance for light and increases separation rate of charge carriers. The average fluorescence life is subsequently increased under light irradiation, which is 1.8 times for YCN2 than the pristine CN. The EPR spectra demonstrates that, compared to CN, significantly more \begin{document}$ · {\mathrm{O}}_2^- $\end{document} radicals and less \begin{document}$· {\mathrm{OH}} $\end{document} radicals are generated on YCN2 under light irradiation. The free radical trapping experiments verifies that \begin{document}$ · {\mathrm{O}}_2^- $\end{document} radicals act as the dominant reactive species for the reduction of U(Ⅵ) and the small amount of other radicals do not bring obvious influence. The enhanced generation of \begin{document}$ · {\mathrm{O}}_2^- $\end{document} radicals on YCN2 therefore provides favorable conditions for the photocatalytic reduction of U(Ⅵ). When using methanol as a sacrificial agent, it can remove about 95% of U(Ⅵ) within 20 min for the YCN2-containing system under light. The rate of the photocatalytic reduction of U(Ⅵ) on YCN2(0.112 min−1) is 5.3 times higher than CN(0.021 min−1). Analysis of the products reveals that water-soluble U(Ⅵ) is reduced in the photocatalytic reaction, with approximately 80% U(Ⅳ) and 20% U(Ⅵ). The soluble U(Ⅵ) is mainly reduced to insoluble UO2+x deposited on the surface of YCN by \begin{document}$ { · {\mathrm{O}}_2^- } $\end{document} radicals. This study improves the photocatalytic performance of CN for the reduction of U(Ⅵ) by Y3+ doping.

Abstract Background It is challenging to improve the effects of chemotherapy and reduce its adverse impact on the ovaries. Our previous study suggested that the combination of galaxamide could enhance the antitumor effect of cisplatin (CIS) in HeLa cell xenograft mice. However, their potential effects on ovarian tissues remain unknown. Methods The Hela tumor-bearing female BALB/c mice model was established and randomly divided into three groups: control group (PBS group), CIS group (0.3 mg/kg CIS group) and galaxamide group (0.3 mg/kg CIS + 3 mg/kg galaxamide-treated group). The serum sex hormones levels, ovarian morphology, functional and molecular characterisation were determined and compared with those of the control group. Results The hormonal effects indicated premature ovarian insufficiency (POI) associated with CIS-induced tumor-bearing mice. CIS induces the apoptosis in primordial and developing follicles and subsequently increases follicular atresia, eventually leading to follicle loss. After cotreatment, galaxamide significantly increased anti-Mullerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR) expression and prevented the CIS-induced PI3K pathway, which triggers follicle activation, apoptosis or atresia. Conclusion These findings demonstrate that galaxamide could attenuate CIS-induced follicle loss by acting on the PI3K signaling pathway by stimulating AMH and/or FSHR and thus provides promising therapeutic options for patients with cervical cancer.

Abstract Background Obesity is characterized by excessive fat accumulation, which is related with abnormal pluripotency of mesenchymal stem cells (MSCs). Recently, there is growing evidence that the disorder of maternal vitamin D (VD) intake is a well-known risk factor for long-term adverse health outcomes to their offspring. Otherwise, less is known of its repercussion and underlying mechanisms on the different differentiation potential of MSCs. Methods Four-week-old female C57BL/6J mice were fed with different VD reproductive diets throughout the whole pregnancy and lactation. The characteristics of BMSCs from their seven-day male offspring, VDR knockdown establishment of HuMSCs and HuMSCs under the different VD interventions in vitro were confirmed by flow cytometry, RT-PCR, and immunofluorescence. The roles of VD on their mitochondrial dysfunction and differentiation potential were also investigated. Then their remaining weaned male pups were induced by administrating high-fat-diet (HFD) for 16 weeks and normal fat diet was simultaneously as controls. Their lipid accumulation and adipocytes hypertrophy were determined by histological staining and related gene expressions. Results Herein, it was proved that imbalance of early-life VD intake could significantly aggravate the occurrence of obesity by inducing the adipogenesis through affecting the VD metabolism and related metabolites (P

Abstract PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

Abstract Background It is well-established that thrombus aspiration during primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) indicates a higher thrombus burden and necessitates more intensive antithrombotic therapy. The bidirectional association between adverse events in AMI patients and platelet reactivity is typically observed during dual antiplatelet therapy (DAPT). Objective To investigate platelet reactivity after DAPT in AMI patients with thrombus aspiration performed during PCI. Methods In this retrospective study, we examined 269 consecutive AMI patients who underwent PCI and recorded their demographic, clinical and laboratory data. The platelet reactivity was measured with thromboelastogram (TEM). Results Ultimately, 208 patients were included in this study and divided into a Thrombus Aspiration group (N = 97) and a PCI Alone group (N = 111) based on whether thrombus aspiration was performed or not. The adenosine diphosphate (ADP)-induced platelet inhibition rate in the Thrombus Aspiration group was higher than that in the PCI Alone group (P

Abstract This study spanned 6 years and 4 generations, involving the progressive crossbreeding of South African Kalahari Goat (SK) and Guizhou Black Goat (GB) over three generations, followed by cross fixation F3 with F1 in the fourth generation, accompanied by the use of molecular markers technology to select a high fertility population, resulting in the creation of a hybrid goat, BKF4 (11/16 SK lineage and 5/16 GB lineage). A comparative evaluation of the BKF4 hybrid breed and its parental breeds was conducted. Reproductive and production parameters of GB, SK, and BKF4 goat groups were monitored, including lambing rate (LR), survival rate (SR), daily weight gain at 3 months of age (DWG), and adult body weight (ABW) (n = 110, 106, 112 per group). In addition, dressing percentage (DP) (n = 12 per group) and analyses of amino acids (n = 8, 6, 10 per group) and fatty acids (n = 6 per group) were conducted to evaluate meat quality indicators. Results: (1) Reproductive and production performance: The index of LR reached 199%, significantly higher than GB and SK (p ≤ 0.001), with a SR of 95.0%, markedly higher than SK (p ≤ 0.001); DWG was 276.5 g, ABW reached 56.6 kg and with a dressing percentage (DP) of 54.5%, they are significantly surpassing GB (p ≤ 0.001). (2) Regarding meat quality: pH45-value and crude protein content (CP) increased, while intramuscular fat content increased compared to GB and ash content decreased. The amino acid composition was similar to GB, but the taste was more similar to SK. However, there were some negative impacts on fatty acid composition and functionality. (3) PCA analysis revealed that: BKF4 exhibited superior meat quality compared to GB and SK, influenced by two key factors contributing 83.49% and 16.51% to the explained variance, respectively. The key factors affecting meat quality include intramuscular fat (IMF), nutrient index (NI), PUFAs/MUFAs, n-6FAs, and drip loss (DL).

Abstract Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an epigenetic regulator that plays critical roles in tumours. However, the DNA methylation alteration patterns driven by UHRF1 and the related differentially expressed tumour-related genes remain unclear. In this study, a UHRF1-shRNA MCF-7 cell line was constructed, and whole-genome bisulfite sequencing and RNA sequencing were performed. The DNA methylation alteration landscape was elucidated, and DNA methylation-altered regions (DMRs) were found to be distributed in both gene bodies and adjacent regions. The DMRs were annotated and categorized into 488 hypermethylated/1696 hypomethylated promoters and 1149 hypermethylated/5501 hypomethylated gene bodies. Through an integrated analysis with the RNA sequencing data, 217 methylation-regulated upregulated genes and 288 downregulated genes were identified, and these genes were primarily enriched in nervous system development and cancer signalling pathways. Further analysis revealed 21 downregulated oncogenes and 15 upregulated TSGs. We also showed that UHRF1 silencing inhibited cell proliferation and migration and suppressed tumour growth in vivo. Our study suggested that UHRF1 and the oncogenes or TSGs it regulates might serve as biomarkers and targets for breast cancer treatment.

Abstract Collision-free path planning and task scheduling optimization in multi-region operations of autonomous agricultural robots present a complex coupled problem. In addition to considering task access sequences and collision-free path planning, multiple factors such as task priorities, terrain complexity of farmland, and robot energy consumption must be comprehensively addressed. This study aims to explore a hierarchical decoupling approach to tackle the challenges of multi-region path planning. Firstly, we conduct path planning based on the A* algorithm to traverse paths for all tasks and obtain multi-region connected paths. Throughout this process, factors such as path length, turning points, and corner angles are thoroughly considered, and a cost matrix is constructed for subsequent optimization processes. Secondly, we reformulate the multi-region path planning problem into a discrete optimization problem and employ genetic algorithms to optimize the task sequence, thus identifying the optimal task execution order under energy constraints. We finally validate the feasibility of the multi-task planning algorithm proposed by conducting experiments in an open environment, a narrow environment and a large-scale environment. Experimental results demonstrate the method's capability to find feasible collision-free and cost-optimal task access paths in diverse and complex multi-region planning scenarios.

Abstract Background Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms. Methods We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays. Results CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties. Conclusions Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC. Graphical Abstract

Abstract Electron transfer (ET) is the fundamental redox process of life and element cycling. The ET distance is normally as short as nanometers or micrometers in the subsurface. However, the redox gradient in the subsurface is as long as centimeters or even meters. This gap triggers an intriguing question whether directional long-distance ET from reduced to oxidized zones exists along the redox gradient. By using electron-donating capacity variation as a proxy of ET, we show that ET can last over 10 cm along the redox gradient in sediment columns, through a directional long-distance ET chain from reduced to oxidized zones constituted by a series of short-distance electron hopping reactions. Microbial and chemical processes synergistically mediate the long-distance ET chain, with an estimated flux of 6.73 μmol e−/cm2 per day. This directional long-distance ET represents an overlooked but important “remote” source of electrons for local biogeochemical and environmental processes.

Abstract. Background:. Heterotaxy (HTX) is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease (CHD). The aim of this study was to analyze rare copy number variations (CNVs) in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD. Methods:. Chromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients, and available samples from parents were used to confirm the inheritance pattern. Potential candidate genes in CNVs region were prioritized via the DECIPHER database, and PNPLA4 was identified as the leading candidate gene. To validate, we generated PNPLA4-overexpressing human induced pluripotent stem cell lines as well as pnpla4-overexpressing zebrafish model, followed by a series of transcriptomic, biochemical and cellular analyses. Results:. Seventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients (12.5%). Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort, and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD. PNPLA4 is expressed in the lateral plate mesoderm, which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation, and in the neural crest cell lineage. Through a series of in vivo and in vitro analyses at the molecular and cellular levels, we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production. Conclusions:. Our findings demonstrated a significant association between CNVs and HTX/CHD. Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.

In this study, the discrete element model of YCJ particles was established using reverse engineering reconstruction technology and EDEM software, and physical and virtual simulation experiments were conducted to calibrate the contact parameters. In addition, intrinsic parameters and contact parameters of YCJ during the brittle ripening period were measured directly. The heap angle was obtained through heap stacking experiments using the box extraction method, and MATLAB and Origin were utilized to obtain the heap angle. Factors and their ranges significantly affecting the heap angle were selected through Plackett-Burman experiments and steepest ascent experiments using the heap angle as the evaluation index. The physical heap angle of YCJ particles was 17.45°. The optimal combination of static and dynamic friction coefficients between YCJ particles was determined to be 0.395 and 0.446 through variance analysis and optimization calculations of the response surface optimization experiment. Using the optimal parameter combination for simulated heap stacking experiments, a simulated heap angle of 17.3° was measured, with an error of 0.86% compared to the physical heap angle. The results of physical grading and simulated grading experiments for YCJ particles were validated, and the accuracy error under the same operating conditions was 3.28%, with the particle motion state being basically consistent in physical and simulated experiments. The research results indicate that the particle model of YCJ and the calibrated discrete element simulation parameters are reliable, providing a reference for the calibration of contact parameters for fresh-eating jujubes.

In this paper, we established a $ T1 $ criterion for the boundedness of Laguerre-Calderón-Zygmund operators on BMO$ _{L_{\alpha}}(0, \infty) $ associated with Laguerre operators $ L_\alpha(\alpha > -\frac{1}{2}) $. As applications, we proved the boundedness on BMO$ _{L_{\alpha}}(0, \infty) $ of variation operators for semigroups related to the Laguerre operator $ L_\alpha $.

Abstract Background Chronic low-grade inflammation may mediate the relationship between obesity and diabetes, yet clinical research in this area remains scarce. Thus, this study aimed to explore the mediating role of chronic low-grade inflammation in this relationship using the National Health and Nutrition Examination Survey (NHANES). Methods This study involved 2,482 participants enrolled in the NHANES between 2005 and 2016. Based on the complex sampling survey weights of NHANES, logistic regression models were fitted, adjusting for various covariates to investigate the relationship between BMI, INFLA score, and diabetes. Moreover, weighted quantile sum (WQS) regression models were fitted to analyze the proportional contribution of individual components within the INFLA score. Finally, mediation analysis was conducted to quantitatively assess the magnitude of the mediating effect of the INFLA score on the relationship between BMI and diabetes. Results After adjusting for all potential confounding factors, a significant positive correlation was noted between INFLA score and diabetes [OR (95% CI), 1.038(1.003–1.075), p = 0.035]. Additionally, a significant positive correlation was observed between the high INFLA group and diabetes compared to the low INFLA group [OR (95% CI), 1.599(1.031–2.481), p = 0.037]. WQS regression models revealed that the proportional contributions of C-reactive protein, white blood cell count, platelet count, and neutrophil-to-lymphocyte ratio (NLR) were 55.5%, 34.8%, 8.46%, and 1.19%, respectively. Finally, the results of the mediation analysis indicated that the indirect effect of the INFLA score accounted for 10.20%. Conclusions Chronic low-grade inflammation was associated with diabetes and partially mediates the relationship between obesity and diabetes.

Abstract Background Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4+ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN. Methods Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4+ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry. Results We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4+ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells. Conclusion Our study identified novel aberrant DMPs in CD4+ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.

Abstract Background The aim of this study was to elucidate the histogenesis and genetic underpinnings of fibromatosis-like undifferentiated gastric carcinoma (FLUGC), a rare pathological entity. Method Through a detailed analysis of seven cases, including histopathological evaluation, CTNNB1 gene mutation screening, human epidermal growth factor receptor 2 (HER2) protein level quantification, and HER2 gene amplification assessment to identify the pathological and molecular characteristics of FLUGC. Results Of the seven patients in this study, five were male and two were female (age: 39–73 years). Four patients presented with lesions in the gastric antrum and three had lesions in the lateral curvature of the stomach. Histopathologically, over 90% of the tumor consisted of aggressive fibromatosis-like tissue, including proliferating spindle fibroblasts and myofibroblasts and varying amounts of collagenous fibrous tissues. Undifferentiated cancer cells, accounting for less than 10%, were dispersed among the aggressive fibromatosis-like tissues. These cells were characterized by their small size and were relatively sparse without glandular ducts or nested mass-like structures. Immunophenotyping results showed positive expression of CKpan, CDX2, villin, and p53 in undifferentiated cancer cells; positive expression of vimentin in aggressive fibromatosis-like tissue; positive cytoplasmic expression of β-catenin; and focal cytoplasmic positive expression of smooth muscle actin (SMA). Genetic analysis did not reveal any mutations in the CTNNB1 gene test, nor was there amplification in the HER2 gene fluorescence in situ hybridization (FISH) test. Additionally, the Epstein-Barr encoding region (EBER) of in situ hybridization was negative; and the mismatch repair (MMR) protein was positive. Programmed cell death-1 (PD-1) was

Abstract In this paper, we extend Chandrasekhar’s method of calculating rotating black holes into f(R) theory. We show that the solution with constant Ricci scalar always exists in a general f(R) gravity and derive the Kerr and Kerr-Ads metric by using the analytical mathematical method. Suppose that the spacetime is a 4-dimensional Riemannian manifold with a general stationary axisymmetric metric, we calculate Cartan’s equation of structure and derive the Einstein tensor. In order to reduce the solving difficulty, we fix the gauge freedom to transform the metric into a more symmetric form. We solve the field equations in the two cases of the Ricci scalar $$R=0$$ R = 0 and $$R\ne 0$$ R ≠ 0 . In the case of $$R=0$$ R = 0 , the Ernst’s equations are derived. We give the elementary solution of Ernst’s equations and show the way to obtain more solutions including Kerr metric. In the case of $$R\ne 0$$ R ≠ 0 , we reasonably assume that the solution to the equations consists of two parts: the first is Kerr part and the second is introduced by the Ricci scalar. Giving solution to the second part and combining the two parts, we obtain the Kerr-Ads metric. The calculations are carried out in a general f(R) theory. Furthermore, the whole solving process can be treated as a standard calculation procedure to obtain rotating black holes, which can be applied to other modified gravities.

Abstract Background The purpose of this study was to evaluate the effectiveness of intravascular lithotripsy (IVL) in the treatment of severe coronary artery calcification (CAC) lesions. Methods In this study, we selected patients diagnosed with severe CAC lesions confirmed by coronary angiography (CAG) who were hospitalized in Yulin First People’s Hospital between December 2021 and December 2022 and required percutaneous coronary intervention (PCI). Using a random number table, we divided all patients into the IVL group and the PCI group in the order of interventional therapy. We compared both groups in terms of the surgical success rate, intraoperative manipulation characteristics, procedural complication, and cumulative incidence of major adverse cardiovascular events (MACE). Results (1) There were no differences in the surgical success rate, incidence of MACE, and occurrence of procedural complication between the two groups; (2) Compared with the conventional PCI group, patients in the IVL group used fewer predilatation balloons, and the difference was statistically significant (all P 0.05). Conclusion In this study, we found that IVL was a highly safe and effective procedure in the treatment of severe CAC lesions that did not increase the surgery and radiation time, and it could also reduce the use of predilatation balloons, thus improving the management of CAC lesions. Thus, IVL can be a novel choice in treating severe CAC lesions.

Abstract Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2’s role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and β-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Abstract Background Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient. Methods We screened 10 families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R). Results We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had digenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a digenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, four of the 11 mutations are novel mutations. In addition, we found that COL4A5 mutation relation mRNA levels were significantly decreased in HEK 293 T cell compared to control, while the cellular localization remained the same. Conclusions Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.

Abstract Phage therapy holds promise as an alternative to antibiotics for combating multidrug-resistant bacteria. However, host bacteria can quickly produce progeny that are resistant to phage infection. In this study, we investigated the mechanisms of bacterial resistance to phage infection. We found that Rsm1, a mutant strain of Salmonella enteritidis (S. enteritidis) sm140, exhibited resistance to phage Psm140, which was originally capable of lysing its host at sm140. Whole genome sequencing analysis revealed a single nucleotide mutation at position 520 (C → T) in the rfbD gene of Rsm1, resulting in broken lipopolysaccharides (LPS), which is caused by the replacement of CAG coding glutamine with a stop codon TAG. The knockout of rfbD in the sm140ΔrfbD strain caused a subsequent loss of sensitivity toward phages. Furthermore, the reintroduction of rfbD in Rsm1 restored phage sensitivity. Moreover, polymerase chain reaction (PCR) amplification of rfbD in 25 resistant strains revealed a high percentage mutation rate of 64% within the rfbD locus. We assessed the fitness of four bacteria strains and found that the acquisition of phage resistance resulted in slower bacterial growth, faster sedimentation velocity, and increased environmental sensitivity (pH, temperature, and antibiotic sensitivity). In short, bacteria mutants lose some of their abilities while gaining resistance to phage infection, which may be a general survival strategy of bacteria against phages. This study is the first to report phage resistance caused by rfbD mutation, providing a new perspective for the research on phage therapy and drug-resistant mechanisms.

Abstract Background Limited research has explored the associations of gestational age (GA) and breastfeeding practices with growth and nutrition in term infants. Methods This multicenter cross-sectional study recruited 7299 singleton term infants from well-child visits in Shandong, China, between March 2021 and November 2022. Data on GA, gender, ethnicity, birth weight, parental heights, gestational diabetes and hypertension, age at visit, breastfeeding practices (point-in-time data at visit for infants 4. Linear regression models adjused for covariates explored the impact of GA and breastfeeding practices on LAZ and WLZ, while logistic regression models evaluated their effect on the likelihood of moderate and severe stunting (MSS, LAZ 2). Sensitivity analysis was conducted on normal birth weight infants (2.5–4.0 kg). Results Infants born early-term and exclusively breastfed accounted for 31.1% and 66.4% of the sample, respectively. Early-term birth related to higher WLZ (

Abstract Objective To study the historical global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035. Methods Incidence data were retrieved from the Cancer Incidence in Five Continents (CI5) volumes I-XI, and mortality data were obtained from the latest update of the World Health Organization (WHO) mortality database. We used join-point regression analysis to examine historical incidence and mortality trends and used the package NORDPRED in R to predict the number of deaths and mortality rates by 2035 by country and sex. Results More than 1,089,000 new cases of gastric cancer and 769,000 related deaths were reported in 2020. The average annual percent change (AAPC) in the incidence of gastric cancer from 2003 to 2012 among the male population, South Korea, Japan, Malta, Canada, Cyprus, and Switzerland showed an increasing trend (P > 0.05); among the female population, Canada [AAPC, 1.2; (95%Cl, 0.5–2), P 0.05). AAPC in the mortality of gastric cancer from 2006 to 2015 among the male population, Thailand [3.5 (95%cl, 1.6–5.4), P 0.05); among the male population aged 20–44, Thailand [AAPC, 3.4; (95%cl, 1.3–5.4), P 0.05). It is predicted that the mortality rate in Slovenia and France’s female population will show an increasing trend by 2035. It is predicted that the absolute number of deaths in the Israeli male population and in Chile, France, and Canada female population will increase by 2035. Conclusion In the past decade, the incidence and mortality of gastric cancer have shown a decreasing trend; however, there are still some countries showing an increasing trend, especially among populations younger than 45 years. Although mortality in most countries is predicted to decline by 2035, the absolute number of deaths due to gastric cancer may further increase due to population growth.

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications.

Abstract Programmed Death Receptor 1 (PD-1) inhibitors, when combined with chemotherapy, have exhibited notable effectiveness in enhancing the survival outcomes of patients afflicted with advanced gastric cancer. However, it is important to acknowledge that not all patients derive substantial benefits from this therapeutic approach, highlighting the crucial necessity of identifying efficacious biomarkers to inform immunotherapy interventions. In this study, we sought to investigate the predictive utility of circulating tumor DNA (ctDNA) as a biomarker in a cohort of 30 patients diagnosed with advanced gastric cancer, all of whom underwent first-line treatment involving PD-1 inhibitor administration alongside chemotherapy. We procured peripheral blood samples both at baseline and following the completion of two treatment cycles. Additionally, baseline tissue specimens were collected for the purpose of genomic alteration assessment, employing both 47-gene and 737-gene next-generation sequencing panels for plasma and tumor tissue, respectively. We delineated a ctDNA response as the eradication of maximum variant allele frequencies relative to baseline levels. Notably, the objective response rate among individuals exhibiting a ctDNA response proved significantly superior in comparison to non-responders (P = 0.0073). Furthermore, patients who manifested a ctDNA response experienced markedly prolonged progression-free survival (PFS) and overall survival (OS) when juxtaposed with those devoid of a ctDNA response (median PFS: 15.6 vs. 6.0 months, P = 0.003; median OS: not reached [NR] vs. 9.0 months, P = 0.011). In summation, patients with advanced gastric cancer receiving first-line treatment with PD-1 inhibitors and chemotherapy, dynamic changes in ctDNA can serve as a potential biomarker for predicting treatment efficacy and long-term outcomes.

Abstract This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing radiotherapy or chemoradiotherapy between July 2022 and March 2023. Three groups involved: 108 patients without SARS-CoV-2 infection (non-COVID-19 group), 102 patients beginning treatment 10 days after first SARS-CoV-2 infection (≥ 10 days COVID-19 group), and 137 patients beginning treatment less than 10 days after first SARS-CoV-2 infection (

Abstract Background Lettuce (Lactuca sativa L.) is an economically important vegetable crop worldwide. Lettuce is believed to be domesticated from a single wild ancestor Lactuca serriola and subsequently diverged into two major morphologically distinct vegetable types: leafy lettuce and stem lettuce. However, the role of epigenetic variation in lettuce domestication and divergence remains largely unknown. Results To understand the genetic and epigenetic basis underlying lettuce domestication and divergence, we generate single-base resolution DNA methylomes from 52 Lactuca accessions, including major lettuce cultivars and wild relatives. We find a significant increase of DNA methylation during lettuce domestication and uncover abundant epigenetic variations associated with lettuce domestication and divergence. Interestingly, DNA methylation variations specifically associated with leafy and stem lettuce are related to regulation and metabolic processes, respectively, while those associated with both types are enriched in stress responses. Moreover, we reveal that domestication-induced DNA methylation changes could influence expression levels of nearby and distal genes possibly through affecting chromatin accessibility and chromatin loop. Conclusion Our study provides population epigenomic insights into crop domestication and divergence and valuable resources for further domestication for diversity and epigenetic breeding to boost crop improvement.

Abstract Bitter gourd has numerous health-promoting effects on the human body. However, its use has been greatly limited due to its poor acceptance by consumers, resulting from its strong bitterness. This study investigated the effects of five wall materials, namely, soybean protein isolate, gum arabic, maltodextrin, resistant starch, and a soybean lecithin calcium caseinate mixture, on the physicochemical properties of spray-dried bitter gourd powders. The results showed that all five wall materials reduced the moisture content, water activity, browning degree, agglomeration, and bitterness of the spray-dried bitter gourd powder. Maltodextrin was found to be the most effective at reducing water activity, while soybean protein isolate was best at protecting the colour, and the soybean lecithin calcium caseinate mixture was best at reducing hygroscopicity and masking bitterness. Additionally, all five wall materials improved the preservation of flavonoids, saponins, and vitamin C, with soybean protein isolate being the most effective in improving the total flavonoid retention ratio and the soybean lecithin calcium caseinate mixture being the best in improving the retention ratios of total saponins and vitamin C. The spray-dried bitter gourd powder prepared with soybean protein isolate had the highest antioxidant activity and α-glucosidase inhibitory activity. These results are significant for understanding the relationship between wall materials and the physicochemical properties of spray-dried powder. Additionally, these materials provide bitter gourd product manufacturers with useful guidance for producing high-quality products. Furthermore, the results could provide useful insights for processing fruits with similar product characteristics, thus contributing to the enrichment of food processing knowledge.

Abstract Background Exploration of adaptive evolutionary changes at the genetic level in vaginal microbial communities during different stages of cervical cancer remains limited. This study aimed to elucidate the mutational profile of the vaginal microbiota throughout the progression of cervical disease and subsequently establish diagnostic models. Methods This study utilized a metagenomic dataset consisting of 151 subjects classified into four categories: invasive cervical cancer (CC) (n = 42), cervical intraepithelial neoplasia (CIN) (n = 43), HPV-infected (HPVi) patients without cervical lesions (n = 34), and healthy controls (n = 32). The analysis focused on changes in microbiome abundance and extracted information on genetic variation. Consequently, comprehensive multimodal microbial signatures associated with CC, encompassing taxonomic alterations, mutation signatures, and enriched metabolic functional pathways, were identified. Diagnostic models for predicting CC were established considering gene characteristics based on single nucleotide variants (SNVs). Results In this study, we screened and analyzed the abundances of 18 key microbial strains during CC progression. Additionally, 71,6358 non-redundant mutations were identified, predominantly consisting of SNVs that were further annotated into 25,773 genes. Altered abundances of SNVs and mutation types were observed across the four groups. Specifically, there were 9847 SNVs in the HPV-infected group and 14,892 in the CC group. Furthermore, two distinct mutation signatures corresponding to the benign and malignant groups were identified. The enriched metabolic pathways showed limited similarity with only two overlapping pathways among the four groups. HPVi patients exhibited active nucleotide biosynthesis, whereas patients with CC demonstrated a significantly higher abundance of signaling and cellular-associated protein families. In contrast, healthy controls showed a distinct enrichment in sugar metabolism. Moreover, biomarkers based on microbial SNV abundance displayed stronger diagnostic capability (cc.AUC = 0.87) than the species-level biomarkers (cc.AUC = 0.78). Ultimately, the integration of multimodal biomarkers demonstrated optimal performance for accurately identifying different cervical statuses (cc.AUC = 0.86), with an acceptable performance (AUC = 0.79) in the external testing set. Conclusions The vaginal microbiome exhibits specific SNV evolution in conjunction with the progression of CC, and serves as a specific biomarker for distinguishing between different statuses of cervical disease.

Abstract Background Resident microglia- and peripheric macrophage-mediated neuroinflammation plays a predominant role in the occurrence and development of ischemic stroke. Microglia undergo polarization to M1/M2-like phenotype under stress stimulation, which mediates intracellular inflammatory response. β-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of β-elemene in ischemic stroke from the perspective of balancing microglia M1/M2-like polarization. Methods The middle cerebral artery occlusion (MCAO) model and photothrombotic stroke model were established to explore the regulation effect of β-elemene on the cerebral ischemic injury. The LPS and IFN-γ stimulated BV-2 cells were used to demonstrate the anti-inflammatory effects and potential mechanism of β-elemene regulating M1/M2-like polarization in vitro. Results In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, β-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. β-elemene promoted the phenotype transformation of microglia from M1-like to M2-like, which prevented neurons from oxygen and glucose deprivation/reoxygenation (OGD/R) injury by inhibiting inflammatory factor release, thereby reducing neuronal apoptosis. Mechanically, β-elemene prevented the activation of TLR4/NF-κΒ and MAPK signaling pathway and increased AKT/mTOR mediated-autophagy, thereby promoting M2-like polarization of microglia. Conclusions These results indicated that β-elemene improved cerebral ischemic injury and promoted the transformation of microglia phenotype from M1-like to M2-like, at least in part, through AKT/mTOR-mediated autophagy. This study demonstrated that β-elemene might serve as a promising drug for alleviating ischemic stroke injury.

Abstract Background Developmental dysplasia of the hip (DDH) is a common childhood health complaint, whose etiology is multifactorial. The incidence of DDH is variable and higher in Tibet plateau. Here, we collected plasma samples and studied the metabolomics signatures of DDH. Methods Fifty babies were enrolled: 25 with DDH and 25 age-matched non-DDH healthy controls (HC group). We collected plasma samples, laboratory parameters and conducted untargeted metabolomics profiling. Results There are many differential metabolites among patients with DDH, including 4-β-hydroxymethyl-4-α-methyl-5-α-cholest-7-en-3-beta-ol, β-cryptoxanthin, α-tocopherol, taurocholic acid, glycocholic acid, 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate, arabinosylhypoxanthine, leucyl-hydroxyproline, hypoxanthine. The main differential metabolic pathways focused on primary bile acid biosynthesis, arginine and proline metabolism, phenylalanine metabolism, histidine metabolism, purine metabolism. Conclusions To our knowledge, this is the first report of metabolomics profile in babies with DHH. By combining the α-tocopherol and taurocholic acid, we could achieve the differential diagnosis of DDH.

Biodegradable magnesium (Mg) and its alloys exhibit excellent biocompatibility and mechanical compatibility, demonstrating tremendous potential for applications in orthopedics. However, the rapid degradation rate has limited their clinical application. Polycaprolactone (PCL) is commonly employed as a polymer coating to impede the rapid degradation of Mg. Unfortunately, its long-term anti-corrosion capability and bioactivity are inadequate. To address these issues, polydopamine (PDA)-modified zeolitic imidazolate framework-8 (PZIF-8) bioactive nanoparticles are fabricated and incorporated into the PCL coating. The PZIF-8 particles, featuring catechol motifs, can enhance the compactness of the PCL coating, reduce its defects, and possess biomineralization ability, thereby effectively improving its anti-corrosive and bioactive properties. Moreover, the active substances released from the degradation of the PZIF-8 particles such as Zn2+ and PDA are beneficial for osteogenesis. The corrosion tests indicate that the corrosion current density of PCL-treated sample decreases by more than one order of magnitude and the amount of H2 released decreases from 0.23 ± 0.12 to 0.08 ± 0.08 ml cm−2 after doping with the PZIF-8. Furthermore, the improved corrosion resistance and released PDA and Zn2+ from the coating can promote osteogenic differentiation by up-regulating the expression of alkaline phosphatase activity, related osteogenic genes, and proteins. In addition, in vivo implantation experiments in rabbit femur defects further offer strong evidence that the doping of PZIF-8 nanoparticles accelerates bone reconstruction of the PCL coating. In summary, this work implies a new strategy to fabricate a PCL-based coating on Mg-based implants by introducing the PZIF-8 particles for orthopedic applications.

Abstract Understanding water saturation levels in tight gas carbonate reservoirs is vital for optimizing hydrocarbon production and mitigating challenges such as reduced permeability due to water saturation (Sw) and pore throat blockages, given its critical role in managing capillary pressure in water drive mechanisms reservoirs. Traditional sediment characterization methods such as core analysis, are often costly, invasive, and lack comprehensive spatial information. In recent years, several classical machine learning models have been developed to address these shortcomings. Traditional machine learning methods utilized in reservoir characterization encounter various challenges, including the ability to capture intricate relationships, potential overfitting, and handling extensive, multi-dimensional datasets. Moreover, these methods often face difficulties in dealing with temporal dependencies and subtle patterns within geological formations, particularly evident in heterogeneous carbonate reservoirs. Consequently, despite technological advancements, enhancing the reliability, interpretability, and applicability of predictive models remains imperative for effectively characterizing tight gas carbonate reservoirs. This study employs a novel data-driven strategy to prediction of water saturation in tight gas reservoir powered by three recurrent neural network type deep/shallow learning algorithms—Gated Recurrent Unit (GRU), Recurrent Neural Networks (RNN), Long Short-Term Memory (LSTM), Support Vector Machine (SVM), K-nearest neighbor (KNN) and Decision tree (DT)—customized to accurately forecast sequential sedimentary structure data. These models, optimized using Adam's optimizer algorithm, demonstrated impressive performance in predicting water saturation levels using conventional petrophysical data. Particularly, the GRU model stood out, achieving remarkable accuracy (an R-squared value of 0.9973) with minimal errors (RMSE of 0.0198) compared to LSTM, RNN, SVM, KNN and, DT algorithms, thus showcasing its proficiency in processing extensive datasets and effectively identifying patterns. By achieving unprecedented accuracy levels, this study not only enhances the understanding of sediment properties and fluid saturation dynamics but also offers practical implications for reservoir management and hydrocarbon exploration in complex geological settings. These insights pave the way for more reliable and efficient decision-making processes, thereby advancing the forefront of reservoir engineering and petroleum geoscience.

Abstract Background 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. Methods A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. Results In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. Conclusion OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Abstract Robotic surgery may be an alternative to laparoscopic surgery for gastric cancer (GC). However, randomized controlled trials (RCTs) reporting the differences in survival between these two approaches are currently lacking. From September 2017 to January 2020, 300 patients with cT1-4a and N0/+ were enrolled and randomized to either the robotic (RDG) or laparoscopic distal gastrectomy (LDG) group (NCT03313700). The primary endpoint was 3-year disease-free survival (DFS); secondary endpoints reported here are the 3-year overall survival (OS) and recurrence patterns. The remaining secondary outcomes include intraoperative outcomes, postoperative recovery, quality of lymphadenectomy, and cost differences, which have previously been reported. There were 283 patients in the modified intention-to-treat analysis (RDG group: n = 141; LDG group: n = 142). The trial has met pre-specified endpoints. The 3-year DFS rates were 85.8% and 73.2% in the RDG and LDG groups, respectively (p = 0.011). Multivariable Cox regression model including age, tumor size, sex, ECOG PS, lymphovascular invasion, histology, pT stage, and pN stage showed that RDG was associated with better 3-year DFS (HR: 0.541; 95% CI: 0.314-0.932). The RDG also improved the 3-year cumulative recurrence rate (RDG vs. LDG: 12.1% vs. 21.1%; HR: 0.546, 95% CI: 0.302-0.990). Compared to LDG, RDG demonstrated non-inferiority in 3-year DFS rate.

Abstract A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.

Abstract Background Video double-lumen tube (VDLT) intubation in lateral position is a potential alternative to intubation in supine position in patients undergoing thoracic surgery. This non-inferiority trial assessed the efficacy and safety of VDLT intubation in lateral position. Methods Patients (18–70 yr) undergoing right thoracoscopic lung surgery were randomized to either the left lateral position group (group L) or the supine position group (group S). The VDLT was placed under video larygoscopy. The primary endpoint was the intubation time. Secondary endpoints included VDLT displacement rate, intubation failure rate, the satisfaction of surgeon and nurse, and intubation-related adverse events. Results The analysis covered 80 patients. The total intubation time was 52.0 [20.4]s in group L and 34.3 [13.2]s in group S, with a mean difference of 17.6 s [95% confidence interval (CI): 9.9 s to 25.3 s; P = 0.050], failing to demonstrate non-inferiority with a non-inferiority margin of 10 s. Group L, compared with group S, had significantly lower VDLT displacement rate (P = 0.017) and higher nurse satisfaction (P = 0.026). No intubation failure occurred in any group. Intubation complications (P = 0.802) and surgeon satisfaction (P = 0.415) were comparable between two groups. Conclusions The lateral VDLT intubation took longer time than in the supine position, and non-inferiority was not achieved. The incidence of displacement as the secondary endpoint was lower in the L group, possibly due to changing body positions beforehand. The indication of lateral VDLT intubation should be based on a balance between the safety of airway management and the lower incidence of displacement. Trial registration The study was registered at Chictr.org.cn with the number ChiCTR2200064831 on 19/10/2022.

Abstract Abnormal granulosa cell (GC) death contributes to cyclophosphamide (CTX) induced primary ovarian insufficiency (POI). To investigate the contribution of GCs to POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) were enriched in the ferroptosis-related pathway, which is correlated with upregulated heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed iron overload and disrupted ROS, including cytoROS, mtROS and lipROS homeostasis, were associated with upregulation of HO-1 and could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies a role for ROS in CTX-induced ferroptosis and highlights the effect of HO-1 modulators in improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.

Abstract Whether and how the reactive oxygen species generated by hepatic stellate cells (HSCs) promote immune evasion of hepatocellular carcinoma (HCC) remains mysterious. Therefore, investigating the function of superoxide anion (O2 •−), the firstly generated reactive oxygen species, during the immune evasion become necessary. In this work, we establish a novel in situ imaging method for visualization of O2 •− changes in HSCs based on a new two-photon fluorescence probe TPH. TPH comprises recognition group for O2 •− and HSCs targeting peptides. We observe that O2 •− in HSCs gradually rose, impairing the infiltration of CD8+ T cells in HCC mice. Further studies reveal that the cyclin-dependent kinase 4 is deactivated by O2 •−, and then cause the up-regulation of PD-L1. Our work provides molecular insights into HSC-mediated immune evasion of HCC, which may represent potential targets for HCC immunotherapy.

Abstract Background Effective teaching methods are needed to improve students’ abilities in hand-eye coordination and understanding of cardiac anatomy in echocardiography education. Simulation devices have emerged as innovative teaching tools and exhibited distinctive advantages due to their ability to provide vivid and visual learning experiences. This study aimed to investigate the effect of simulation of sectional human anatomy using ultrasound on students’ learning outcomes and satisfaction in echocardiography education. Methods The study included 18 first-year clinical medical students with no prior echocardiography training. After randomization, they underwent a pre-test to assess basic knowledge. Following this, the students were divided into two groups: traditional teaching (traditional group) and simulation of sectional human anatomy using ultrasound (digital group). Each group received 60 min of instruction. Post-tests were assigned to students at two different time points: immediately after the lecture, and one week later (referred to as post-tests 1, and 2). In addition, anonymous questionnaires were distributed to students after class to investigate their satisfaction with teaching. Results Both groups showed significant improvement in their scores on post-test 1 compared to pre-test (traditional group: from 33.1 ± 8.8 to 48.1 ± 13.1, P = 0.034 vs. digital group: from 35.0 ± 6.7 to 58.0 ± 13.2, P = 0.008). However, there were no significant differences between the two groups in several post-test comparisons. Student satisfaction ratings revealed that the digital group experienced significantly greater satisfaction in areas such as subject interest, teaching style, course alignment, and interaction compared to the traditional group. Additionally, 80% of the digital group strongly endorsed the use of simulation of sectional human anatomy using ultrasound for echocardiography teaching, highlighting its effectiveness. Conclusions Simulation of sectional human anatomy using ultrasound may improve students’ understanding of echocardiography and satisfaction with the course. Our study provides evidence supporting the use of simulation teaching devices in medical education. Further research is needed to explore the long-term impact of this teaching method on students’ learning outcomes and its integration into the medical curriculum. Trial registration http://www.chictr.org.cn (registration number: ChiCTR2300074015, 27/07/2023).

AIM: To assess the performance of macular ganglion cell-inner plexiform layer thickness (mGCIPLT) and 10-2 visual field (VF) parameters in detecting early glaucoma and evaluating the severity of advanced glaucoma. METHODS: Totally 127 eyes from 89 participants (36 eyes of 19 healthy participants, 45 eyes of 31 early glaucoma patients and 46 eyes of 39 advanced glaucoma patients) were included. The relationships between the optical coherence tomography (OCT)-derived parameters and VF sensitivity were determined. Patients with early glaucoma were divided into eyes with or without central 10° of the VF damages (CVFDs), and the diagnostic performances of OCT-derived parameters were assessed. RESULTS: In early glaucoma, the mGCIPLT was significantly correlated with 10-2 VF pattern standard deviation (PSD; with average mGCIPLT: β=-0.046, 95%CI, -0.067 to -0.024, P

Tumorigenesis and metastasis are highly dependent on the interactions between the tumor and the surrounding microenvironment. In 3D matrix, the fibrous structure of the extracellular matrix (ECM) undergoes dynamic remodeling during tumor progression. In particular, during the late stage of tumor development, the fibers become more aggregated and oriented. However, it remains unclear how cancer cells respond to the organizational change of ECM fibers and exhibit distinct morphology and behavior. Here, we used electrospinning technology to fabricate biomimetic ECM with distinct fiber arrangements, which mimic the structural characteristics of normal or tumor tissues and found that aligned and oriented nanofibers induce cytoskeletal rearrangement to promote directed migration of cancer cells. Mechanistically, caveolin-1(Cav-1)-expressing cancer cells grown on aligned fibers exhibit increased integrin β1 internalization and actin polymerization, which promoted stress fiber formation, focal adhesion dynamics and YAP activity, thereby accelerating the directional cell migration. In general, the linear fibrous structure of the ECM provides convenient tracks on which tumor cells can invade and migrate. Moreover, histological data from both mice and patients with tumors indicates that tumor tissue exhibits a greater abundance of isotropic ECM fibers compared to normal tissue. And Cav-1 downregulation can suppress cancer cells muscle invasion through the inhibition of YAP-dependent mechanotransduction. Taken together, our findings revealed the Cav-1 is indispensable for the cellular response to topological change of ECM, and that the Cav-1/YAP axis is an attractive target for inhibiting cancer cell directional migration which induced by linearization of ECM fibers.

This study aimed to simulate cold chain sales temperatures to predict the effects of temperature fluctuations on the physicochemical properties, moisture distribution, microstructure, and flavor of mashed potatoes. The results showed a decline in the hardness and chewability of mashed potatoes alongside the migration of water from bound water states to weakly bound states under freeze-thaw cycles (FTC) conditions. Microstructural analysis indicated that the adhesive forces between proteins and starch granules were weakened, and the structure of mashed potatoes particles was destroyed following FTC. The oxidation and degradation of fat induced by FTC increased the content of key compounds such as octanal and nonanal, thereby contributing to an overall deterioration in the flavor of mashed potatoes. This study elucidates the effects of FTC on water migration, microstructure, and flavor characteristics of mashed potatoes, thereby providing a theoretical foundation for improving the quality of prefabricated frozen mashed potatoes dishes.