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Background This study aimed to evaluate the effectiveness and efficiency of PBL–CBL combined teaching in thyroid surgery and make observations from the students’ perspectives, based on their satisfaction with the learning process. Methods We prospectively enrolled 354 fourth-year students majoring in clinical medicine, along with 232 residents, from September 2014 to June 2019. These participants were randomly allocated into either the combined PBL–CBL teaching group or the traditional lecture-based classroom group to attend a course about thyroid nodules. Both pre- and post-class quizzes were conducted. An anonymous questionnaire was also administered to both groups to evaluate the students’ perceptions and experiences. We compared the two teaching methods among all the students as well as with the fourth-year students and residents in subgroups. Results The traditional group’s pre-class quiz scores were significantly higher than the PBL–CBL group’s (as determined by a two-tailed t-test at a 95% confidence interval, T  = 16.483, P  < 0.001). After class, in the PBL–CBL group, the mean total quiz score and the basic knowledge and case analysis scores increased significantly ( P  < 0.001). The PBL–CBL group’s performance improvement was significantly higher than the traditional group’s (increasing from 52.76 to 70.51 vs. from 67.03 to 71.97). Furthermore, the scores for learning motivation, understanding, student–teacher interaction, the final examination, communication skills, clinical thinking skills, self-learning skills, teamwork skills, and knowledge absorption, as measured by the survey, were significantly higher in the PBL–CBL group than in the traditional group ( P  < 0.001). Meanwhile, the survey scores representing the amount of students’ free time the course consumed were significantly lower in the PBL–CBL group than in the traditional group ( P  < 0.001). Conclusions PBL combined with CBL may be an effective method for improving medical students’ and residents’ performance and enhancing their clinical skills.

Single-mode microwave-induced tungsten wire discharge was conducted to investigate discharge phenomena in Ar, N 2 , NO, and their mixtures, as well as the effects of parameters, including diameter and number of tungsten wire, initial NO concentration, total gas flow rate, and microwave power, on NO conversion. The discharge phenomena verified that intense discharge could be observed in pure Ar or N 2 , but the discharge was considerably weakened in gas mixtures. The results of NO conversion showed that the increases of the tungsten wire diameter (0.1–0.12 mm), the tungsten wire number (1–3 wires), and microwave power (400–700 W), or the decreases of the total gas flow rate (2–0.5 L/min), and the initial NO concentration (800–200 ppm) could effectively lead to the increase of NO conversion. A maximum NO conversion of 91.5% can be achieved under the optimal conditions in the examined range. Besides, spectral analysis showed that W, O, and N ions were found in the discharge zone. After reactions, depositions were found on the inner surface of reaction tube, and the results of EDS (energy dispersive X-ray spectrometer) tests show that the depositions were composed of W, O, and N. Therefore, a portion of NO was inferred to be consumed by tungsten ions through the formation of tungsten oxides and tungsten nitrides.

Background USP51 is a deubiquitinase (DUB), that is involved in diverse cellular processes. Accumulating evidence has demonstrated that USP51 contributes to cancer development. However, its impact on non-small cell lung carcinoma (NSCLC) cell malignancy is largely unknown. Methods In this study, we performed bioinformatics analysis on a dataset from The Cancer Genome Atlas to determine the association between USP51 and cell stemness marker expression in NSCLC patients. RT‒qPCR, Western blotting, and flow cytometry were performed to examine the effects of USP51 depletion on stemness marker expression. Colony formation and tumor sphere formation assays were used to assess the stemness of NSCLC cells. A cycloheximide chase time-course assay and a polyubiquitination assay were carried out to analyze the effects of USP51 on the TWIST1 protein level. TWIST1 was overexpressed in USP51 knockdown NSCLC cells to determine whether TWIST1 is required. The effect of USP51 on the in vivo growth of NSCLC cells was tested through subcutaneous injections in mice. Results We found that USP51 deubiquitinates TWIST1, which is significantly upregulated in the tissues of patients with NSCLC and is closely associated with poor prognosis. USP51 expression was positively correlated with the expression of stemness marker CD44, SOX2, NANOG, and OCT4 in NSCLC patients. USP51 depletion attenuated mRNA, protein, and cell surface expression of stemness markers and the stemness of NSCLC cells. Ectopic USP51 expression potentiated the stability of the TWIST1 protein by attenuating its polyubiquitination. In addition, TWIST1 re-expression in NSCLC cells reversed the inhibitory effect of USP51 knockdown on cell stemness. Furthermore, the in vivo results confirmed the suppressive effect of USP51 depletion on NSCLC cell growth. Conclusions Our results show that USP51 maintains the stemness of NSCLC cells by deubiquitinating TWIST1. Knocking it down reduces both cell stemness and growth of NSCLC cells.

Background Radiation-induced damage to reproductive tissues presents a major clinical concern with potentially lasting functional consequences. Methods Here, we investigate the protective function of extracellular vesicles derived from mouse bone marrow mesenchymal stem cells (mBMSCs-EVs) in mitigating ionizing radiation-induced injury in murine epididymal cells (mPC-1). Results We demonstrate that mBMSC-EVs significantly enhance cell viability and reduce apoptosis, oxidative stress, and DNA damage in irradiated mPC-1 cells. Besides, we identify the deubiquitinase USP44 as a key mediator enriched in mBMSC-EVs, which confers radioprotection by stabilizing the RNA-binding protein RBM14 through deubiquitination for mPC-1 cells. Silencing USP44 in mBMSCs or their EVs abrogates these protective effects, leading to impaired DNA repair, increased apoptosis, oxidative stress, and disrupted cell cycle progression. Conversely, RBM14 overexpression partially restores cell survival and function, supporting its downstream role in this pathway. Conclusion Our findings reveal a novel USP44/RBM14 axis mediated by mBMSC-EVs that counteracts radiation injury, and suggest this mechanism as a promising therapeutic approach for protecting reproductive tissues from radiation-induced damage. Notably, these findings are primarily grounded in in vitro experiments utilizing an immortalized epididymal cell line; further in vivo validation and evaluation of clinical translatability are required prior to therapeutic application. Graphical Abstract

Background Clear cell renal cell carcinoma (ccRCC) is the most common malignant urological tumor, and regrettably, and is insensitive to chemotherapy and radiotherapy, resulting in poor patient outcomes. DBF4 plays a critical role in DNA replication and participates in various biological functions, making it an attractive target for cancer treatment. However, its significance in ccRCC has not yet been explored. Methods We utilized external datasets and bioinformatics analyses to investigate the significance of DBF4 in ccRCC. We analysed its expression patterns, prognostic and diagnostic value, and potential mechanisms. We subsequently validated our findings through an immunohistochemistry (IHC) assay of ccRCC clinical samples. We further investigated the impact of DBF4 on the progression of ccRCC cells. Various assays, including assessments of cell proliferation, apoptosis, the cell cycle, cell migration and invasion, and colony formation, and xenograft tumor models were subsequently performed following to the knockdown of DBF4 expression via shRNA. Results Bioinformatics analyses revealed that DBF4 is significantly overexpressed in ccRCC tissues compared with adjacent normal tissues. This overexpression was confirmed by IHC analysis of 75 pairs of clinical ccRCC tumor and adjacent tissues. Kaplan-Meier analysis revealed that high DBF4 expression was associated with a significantly lower five-year overall survival rate. Moreover, DBF4 expression was identified as an independent risk factor in multivariate Cox regression analysis. GO and KEGG pathway enrichment analyses revealed a substantial enrichment of terms associated with cell division, whereas gene set enrichment analysis (GSEA) revealed correlations between increased DBF4 expression and the activation of cell cycle-related pathways. Subsequent in vitro and in vivo experiments demonstrated that DBF4 knockdown in ccRCC cells not only suppressed proliferation and migration in vitro but also significantly inhibited tumor growth in xenograft mice by arresting the cell cycle at the G1/G0 phase, which was mediated by the inhibition of MCM2 phosphorylation and cyclin D1 and CDK4 expression. Conclusion The current study revealed that DBF4 overexpression is a significant factor associated with malignant features and poor prognosis in patients with ccRCC. Therefore, it was proposed that DBF4 could serve as a novel potential prognostic biomarker and molecular target for ccRCC. Clinical trial number Not applicable.

Powdery mildew (PM), caused by the biotrophic fungus Podospharea leucotricha , poses a significant threat to apple production. Salicylic acid (SA) signaling plays a crucial role in enhancing resistance to biotrophic pathogens. While PR1, a defense protein induced by SA, is essential for plant immunity, its excessive accumulation can be detrimental. However, the mechanism of PR1-mediated immune balance remains unclear. This study identified a key transcription factor, WRKY1, which enhances the SA accumulation by modulating the SA biosynthesis gene EPS1 , while simultaneously regulating the WRKY40-NPR3g module to prevent sustained PR1 expression caused by continuous SA accumulation. Specifically, the transcription factor WRKY40 upregulates NPR3g expression, and NPR3g interacts with NPR1 in an SA-dependent manner. Then, two TGA2c variants that interact with NPR1 to activate PR1 expression were identified: canonical TGA2c-1 and alternative splicing of TGA2c-2 with an exon deletion. SA does not influence the NPR1-TGA2c-1 interaction but is essential for the NPR1-TGA2c-2 interaction. Notably, NPR3g reduces PR1 levels by selectively disrupting the NPR1-TGA2c-2 complex through competition for the BTB-POZ domain of NPR1. In conclusion, this study identifies a novel mechanism by which WRKY1 modulates PR1-mediated immune balance to defend against PM.

The stress-responsive genes of Sestrin family are recognized as new tumor suppressor genes in breast carcinoma, however, the function of Sestrin family in human prostate cancer is not clear. Ionizing radiation (IR) is known to induce Sestrin gene expression in breast cancer cells. However, the response of Sestrin to IR has not been reported in PC3 prostate cancer cells. Sestrin2 expression in prostate cancer cell lines (PC3, LNCaP clone FGC, and DU145) was detected by Western blot and real-time PCR. Cell counting kit (CCK-8) was used to detect cellular proliferation. The radiosensitivity of PC3 cells was detected by clonogenic assay. Sestrin2 expression in prostate cancer cell lines (PC3, LNCaP clone FGC, and DU145) is low. In vitro assays indicated that over-expressing Sestrin2 in human prostate cancer PC3 inhibited tumor proliferation. In addition, elevated Sestrin2 expression sensitized PC3 cells to IR. We determined Sestrin2 may function as a tumor suppressor through repressing proliferation, mediating sensitization to IR in PC3 cells.

α -adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α -AR agonists are effective drugs for this condition. However, the lack of high selectivity for α -AR subtype of traditional drugs greatly limits their clinic usage. A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α -AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α -AR over α - and α -ARs. Besides, the affinities are of similar linker length-dependence for each α -AR subtype. Among all the compounds tested, C10 has the highest affinity for α -AR ( Ki=-7.45±0.62), which is 12-fold and 60-fold selective over α -AR and α -AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and \"allosteric\" sites of the α -AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99. The specificity of C10 for the α -AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α -AR subtype selective compounds.

Objectives We aimed to systematically evaluate the prognostic prediction accuracy of radiomics features extracted from pre-treatment imaging in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Radiomics literature on overall survival (OS) prediction of PDAC were all included in this systematic review. A further meta-analysis was performed on the effect size of first-order entropy. Methodological quality and risk of bias of the included studies were assessed by the radiomics quality score (RQS) and prediction model risk of bias assessment tool (PROBAST). Results Twenty-three studies were finally identified in this review. Two (8.7%) studies compared prognosis prediction ability between radiomics model and TNM staging model by C-index, and both showed a better performance of the radiomics. Twenty-one (91.3%) studies reported significant predictive values of radiomics features. Nine (39.1%) studies were included in the meta-analysis, and it showed a significant correlation between first-order entropy and OS (HR 1.66, 95%CI 1.18–2.34). RQS assessment revealed validation was only performed in 5 (21.7%) studies on internal datasets and 2 (8.7%) studies on external datasets. PROBAST showed that 22 (95.7%) studies have a high risk of bias in participants because of the retrospective study design. Conclusion First-order entropy was significantly associated with OS and might improve the accuracy of PDAC prognosis prediction. Existing studies were poorly validated, and it should be noted in future studies. Modification of PROBAST for radiomics studies is necessary since the strict requirements of prospective study design may not be applicable to the demand for a large sample size in the model construction stage. Key Points • Radiomics based on the primary lesion holds great potential for prognosis prediction. First-order entropy was significantly associated with the overall survival of PDAC and might improve the accuracy of current PDAC prognosis prediction. • We strongly recommend that at least an internal validation should be conducted in any radiomics study. Attention should be paid to the complex relationships between radiomics features. • Due to the close relationship between radiomics and big data, the strict requirement of prospective study design in PROABST may not be appropriate for radiomics studies. A balance between study types and sample sizes for radiomics studies needs to be found in the model construction stage.

The mechanism of Fe+NO was calculated by the Density Functional Theory (DFT) with the B3LYP methods combined with the 6-311+G (d, p) basis set. The geometry of reactants, transition states, intermediates and products of two reaction systems were completely optimized, and all the transition states were verified by the vibration analysis and intrinsic reaction coordinate (IRC) calculations. The “Two State Reactivity (TSR)” was used to analyze the reaction mechanisms; Results showed that the reaction system preferentially involves low-spin state entrance channel and the high-spin state exit channel. In the reaction channel, the crossing point appears, which would effectively reduce the activation energy and increase the release of reaction heat, play a significant and beneficial role in the kinetic and thermodynamic aspects of this catalytic reaction.