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The importance of teaching the Luria-Delbrück experiment to biology students is increasingly recognized by educators, and improved pedagogical methods for teaching the classic experiment have been proposed and tested in the classroom. However, there are still obstacles that impede the proper teaching of the classic experiment. This note proposes two strategies to further improve the teaching of the classic experiment. The first strategy is to be frank with an inherent limitation of the classic experiment, and instructors should explain from a logical point of view why the classic experiment cannot be used to refute the possibility of directed mutation. The second strategy is to emphasize the pioneering work of Delbrück on developing the mutant distribution that enables researchers to estimate microbial mutation rates using data generated by fluctuation experiments, and instructors should shift their attention to the overlooked essential role of the mutant distribution.

Background: Given that students from socio-economically disadvantaged family backgrounds are more likely to suffer from low academic performance, there is an interest in identifying features of academic resilience, which may mitigate the relationship between disadvantaged socio-economic status and academic performance. Aims: This study sought to combine machine learning and explainable artificial intelligence (XAI) technique to identify key features of academic resilience in mathematics learning during COVID-19. Materials and Methods: Based on PISA 2022 data in 79 countries/economies, the random forest model coupled with Shapley additive explanations (SHAP) value technique not only uncovered the key features of academic resilience but also examined the contributions of each key feature. Results: Findings indicated that 35 features were identified in the classification of academically resilient and non-academically resilient students, which largely validated the previous academic resilient framework. Notably, gender differences were shown in the distribution of some key features. Research findings also indicated that resilient students tended to have a stable emotional state, high levels of self-efficacy, low levels of truancy and positive future aspirations. Discussion: This study has established a research paradigm essentially methodological in nature to bridge the gap between psychological theories and big data in the field of educational psychology. Conclusion: To sum up, our study shed light on the issues of education equity and quality from a global perspective in the times of the COVID-19 pandemic.

The era of information and communication technology (ICT) has popularized adolescents' digital reading activities in their daily lives. Most prior studies focused on identifying significant factors that foster digital reading performance. Although educational quality is of great concern, it is crucial to consider the issue of educational equity in the digital world. Our study aims to unfold the mediating roles of ICT-related psychological needs between economic, social, and cultural status (ESCS) and digital reading performance. A multilevel mediation analysis was adopted for 36,490 students from six high-performing Asian regions participating in the Programme for International Student Assessment (PISA). The results indicated that perceived ICT autonomy significantly mediated the relationship in most Asian regions, while perceived ICT competence yielded mixed roles. Interestingly, the suppression effects were detected between ESCS, ICT in social interaction, and digital reading. Our research findings offer fresh insights into narrowing the digital divide in the online reading environment for adolescents.

This study focuses on the different impacts of platform training and learning by doing on gig workers' platform income. Based on survey data of China's delivery riders on the platform in 2020, via quantitative methods combined with the case study, it is found that the platform training is negatively correlated with riders' incomes, while learning by doing is positively correlated with their incomes. Workers with a high level of platform-income dependence earn more than those with an average level of dependence under the same platform training, or learning by doing. Overall, the incomes of the former are significantly lower than those of the latter, where the difference is mainly due to unobservable factors. Both platform training and learning by doing significantly reduce the income gap. In addition, the instrumental variable and the propensity score matching approaches are introduced to handle the endogeneity problem, and robust results are obtained.

Abstract Previous studies have suggested that the presence of human epididymal protein 4 (HE4) in pleural fluid can be used to diagnose malignant pleural effusion (MPE) with moderate accuracy. However, the factors that affect the diagnostic accuracy of HE4 remain unknown. This study aimed to examine how age and sex influence the diagnostic accuracy of HE4. Participants with undiagnosed pleural effusion were prospectively enrolled in two cohorts (Hohhot cohort and Changshu cohort), and the presence of HE4 in their pleural fluid upon admission was determined by an electrochemiluminescence immunoassay. A receiver operating characteristic (ROC) curve with its area under the curve (AUC) was utilized to assess the diagnostic value of HE4 for MPE. Additionally, we conducted subgroup analyses and used a resampling method with different upper age limits to investigate the impacts of age and sex on the diagnostic accuracy of HE4 for MPE. The Hohhot cohort included 86 patients with benign pleural effusions (BPEs) and 66 patients with MPE, whereas the Changshu cohort included 26 patients with MPE and 32 patients with BPE. The diagnostic accuracy of HE4 decreased as age increased in both cohorts. The diagnostic accuracy of HE4 in males did not differ significantly from that in females. Therefore, we conclude that age should be considered when using HE4 in pleural fluid to diagnose MPE.

Abstract Background Long noncoding RNAs (lncRNAs) play a critical role in gastric cancer (GC) progression and metastasis. However, research comprehensively exploring tissue-derived lncRNAs for predicting peritoneal recurrence in patients with GC remains limited. This study aims to investigate the transcriptional landscape of lncRNAs in GC with peritoneal metastasis (PM) and to develop an integrated lncRNA-based score to predict peritoneal recurrence in patients with GC after radical gastrectomy. Methods We analyzed the transcriptome profile of lncRNAs in paired peritoneal, primary gastric tumor, and normal tissue specimens from 12 patients with GC in the Sun Yat-sen University Cancer Center (SYSUCC) discovery cohort. Key lncRNAs were identified via interactive analysis with the TCGA database and SYSUCC validation cohort. A score model was constructed using the LASSO regression model and nomogram COX regression and evaluated using receiver operating characteristic curves. The role of lncRNAs in the PM of GC was then examined through wound healing, Transwell, 3D multicellular tumor spheroid invasion, and peritoneal cavity xenograft tumorigenicity assays in mice. Result Five essential lncRNAs were screened and incorporated into the PM risk score to predict peritoneal recurrence-free survival (pRFS). We developed a comprehensive, integrated nomogram score, including the PM risk score, pT, pN, and tumor size, which could effectively predict the 5-year pRFS with an Area under the curve of 0.79 (95% CI: 0.71-0.88). Subsequently, we demonstrated that one of these lncRNAs, CASC15, promoted the invasion and migration of GC cells in vitro and facilitated the PM of GC cells in vivo, initially verifying that lncRNAs contribute to the PM of GC. Mechanistic analysis demonstrated that CASC15 promoted EMT and metastasis by activating the JNK and p38 pathways. Conclusion A lncRNA-based integrated score was constructed in this study to predict peritoneal recurrence in patients clinically.

Abstract This study addresses the issue of the existence of a considerable number of ancient ceramic fragments within the gene pool of ancient ceramics in Jingdezhen, as well as the limited efficacy of manual restoration techniques. To this end, an ancient ceramic restoration method based on the stitching of ancient ceramic textures through image processing is proposed. By employing the optimal single responsiveness matrix and state transfer equation, coupled with a random sampling strategy to ascertain the precise matching points and a consistency checking mechanism to preclude erroneous matching, the optimal single responsiveness matrix is devised to meticulously transform and stitch ancient ceramic textures. The dynamic programming idea is employed to identify the optimal stitching path, thereby enhancing the quality of the stitching and facilitating the precise, seamless, and natural integration of the ancient ceramic texture. The average peak signal-to-noise ratio of the stitched image of ancient ceramics is 58.7554, and the mean square error is 0.0866, which demonstrates the efficacy of image processing technology in the restoration of ancient ceramics and facilitates the intelligent advancement of cultural protection.

Abstract Nasopharyngeal carcinoma (NPC) is one of the common malignant tumors, and its pathogenesis has not been fully clarified. This study aims to explore the impact of RNA interference on the growth and invasion of NPC cells. Asparaginase and isoaspartyl peptidase 1 (ASRGL1)-short hairpin(sh) RNA expressing lentivirus was used to investigate the effect of ASRGL1 knockdown on NPC cells (C666-1 and SUN-1). The target shASRGL1 gene was determined by mRNA and protein expression in nasopharyngeal carcinoma cells; nasopharyngeal carcinoma cell proliferation viability, migration, invasion, apoptosis, ATP levels, and oxidative stress were examined. The results found that ASRGL1 was found to be highly expressed in NPC tissues and cell lines. shASRGL1 exhibited a high gene expression knockdown efficiency, downregulated the ASRGL1 protein expression in the nasopharyngeal carcinoma cells, suppressed proliferation viability of transfected nasopharyngeal carcinoma cells, inhibited their migration and invasion and ATP levels, promoted nasopharyngeal carcinoma cell apoptosis, ROS, and ferroptosis. shASRGL1 plays a role in protecting against NPC cell growth and invasion.

Abstract Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

Abstract Background The formation of stem cell clones enables close contact of stem cells inside. The gap junctions in such clone spheres establish a microenvironment that allows frequent intercellular communication to maintain self-renewal and functions of stem cells. Nevertheless, the essential gap junction protein for molecular signaling in clones is poorly known. Methods Primary human airway basal cells (hBCs) were isolated from brushing samples through bronchoscopy and then cultured. A tightly focused femtosecond laser was used to excite the local Ca2+ in an individual cell to initiate an internal Ca2+ wave in a clone to screen gap junction proteins. Immunoflourescence staining and clonogenicity assay were used to evaluate self-renewal and functions. RNA and protein levels were assessed by PCR and Western blot. Air–liquid interface assay was conducted to evaluate the differentiation potential. A Naphthalene injury mouse model was used to assess the regeneration potential. Results Herein, we identify Connexin 25 (Cx25) dominates intercellular Ca2+ communications in clones of hBCs in vitro to maintain the self-renewal and pluripotency of them. The self-renewal and in vitro differentiation functions and in vivo regeneration potential of hBCs in an airway damage model are both regulated by Cx25. The abnormal expression of Cx25 is validated in several diseases including IPF, Covid-19 and bronchiectasis. Conclusion Cx25 is essential for hBC clones in maintaining self-renewal and functions of hBCs via gap junctions.

The intensification of electromagnetic (EM) pollution and the development of military detection technology have increased the requirements for EM functional materials. In this study, a molybdenum diselenide@reduced graphene oxide (MoSe2@rGO)-assembled architecture is constructed, where the MoSe2 nanosheets grow uniformly on the rGO sheets. By regulating the contributions of conduction genes and polarization genes, adjustable EM functions of MoSe2@rGO hybrids can be achieved. The reflection loss (RL) of the sample can reach −68.7 dB at a thickness of 2.32 mm, and the maximum effective absorption bandwidth can reach 5.04 GHz. When conduction genes dominate, the MoSe2@rGO hybrids exhibit a 98.7% electromagnetic interference (EMI) shielding efficiency. The design of the EM energy conversion device and the results of the radar cross section (RCS) simulation demonstrate the practical application potential of the material. This work provides inspiration for designing multifunctional EM materials.

Cultivating students' enjoyment of science is one of the significant aims of science education. However, it seems challenging to achieve this goal in most countries or economies. Using the Trends in International Mathematics and Science Study (TIMSS) 2019 Hong Kong data, this study aims to identify multiple configurations of school conditions to develop students' science enjoyment with a School Analytics model. A fuzzy-set Qualitative Comparative Analysis (fsQCA) was employed to capture the potential asymmetric relationships and measure multiple combinations of different conditions. Results indicated that no single school condition was necessary or sufficient for high enjoyment of science (ES). While lacking instructional clarity was a sufficient condition for low enjoyment of science (~ES). Three different configurations resulted in ES and ~ES respectively. The combination of supportive school discipline and high instructional clarity jointly constituted a crucial science learning environment for developing science enjoyment in Hong Kong secondary schools. Under this environment, the effectiveness of science investigation was further discussed to enhance science enjoyment. Our study enlightens educational practitioners to improve students' science enjoyment with multiple combinations of school conditions.

Second language (L2) speakers often experience difficulties in learning words with L2-specific phonemes due to the unfaithful lexical encoding predicted by the fuzzy lexical representations hypothesis. Currently, there is limited understanding of how allophonic variation in the first language (L1) influences L2 phonological and lexical encoding. We report how the Mandarin Chinese L1 phonemic inventory and allophonic variation subject to phonotactic constraints predict phonological encoding problems for novel L2 English words with the /v/-/w/ contrast. L1 English and L1 Chinese participants speaking two varieties of Mandarin Chinese differing as to the presence of [[voiced labiodental approximant]]-[w] allophonic variation for the /w/ phoneme participated in a vocabulary learning task. The novel L2 words with the /v/-/w/ contrast were systematically less robustly encoded than the control words on the day of training and 24 hours later. The degree of fuzziness in lexical representations was jointly predicted by L1 allophonic variation subject to phonotactic constraints and L2 phonological categorization.

Although academic resilience is of great concern to contemporary educational practitioners, there is no consensus on its measurement. Furthermore, protective factors characterized by East Asian societal contexts remain ambiguous. This systematic review aims to offer an overview of the operational definitions, statistical methodology, and protective factors of academic resilience identified in East Asian countries/economies. With a focus on large-scale assessment (LSA) research, three databases (i.e., Web of Science, CNKI, and AiritiLibary) were searched and returned 31 peer-reviewed studies over the last decade. Results indicated that the definition-driven method was commonly adopted in international LSA studies (e.g., Programme for the International Student Assessment) to measure academic resilience, and the research conducted in national/regional LSA (e.g., China Education Panel Survey) tended to use the process-driven approach. Logistic regression was the most frequently data analysis technique utilized in the definition-driven approach, while structural equation modeling and mediation/moderation analyses accounted for the largest proportion of the process-driven methods. Our study shed light on the methodological issues of academic resilience in LSA. Additionally, it highlights the aspiration of educational researchers to identify Asian-specific protective factors from the social-ecological perspective to propose appropriate interventions fostering academic resilience.

Collaborative problem-solving competence (CPSC) is a core skill in the twenty-first century. As an innovative literacy, CPSC was assessed for the first time in the Program for International Student Assessment (PISA) 2015. Our study aims to identify the effects of student's perceptions toward interpersonal relationships on CPSC in PISA 2015. Multiple linear regression was used to examine these effects across Hong Kong, Macao, Taiwan, and the four affluent communities in China. After controlling student's gender and socio-economic status, the results indicated that: (a) Student's external perceptions such as teacher unfairness and disciplinary climate, and student's internal perceptions such as valuing relationships and valuing teamwork significantly predicted CPSC; (b) Disciplinary climate was the strongest predictor among all the external perceptions analyzed; (c) Regarding the internal perceptions, valuing relationships positively predicted CPSC, while valuing teamwork negatively predicted CPSC. These findings enlighten educational practitioners to help students develop their CPSC from the perspective of interpersonal relationships.

Several international large-scale assessments were conducted at the turn of the new century, and during the past two decades the Programme for International Student Assessment (PISA) completed seven cycles of assessment to facilitate practitioners' policy debates and governance. This study reviews PISA-related articles published in English and Chinese. Three literature databases were searched, with a focus on SSCI, CSSCI, and TSSCI journal publications. The frequency of publication was analyzed according to the author's country affiliation, type of journal, and research categories/themes. Findings indicate that research on student-, school- and system-level indicators with a focus on students' learning processes and outcomes as well as critiques of technical matters on PISA were frequent topics in the literature during the past two decades. Issues of equality and equity examined in the publications have implications for enhancing practitioners' capabilities in terms of policy making and governance.

With the rapid growth of education data in large-scale assessment, machine learning techniques are crucial to the interdisciplinary development of education and information. Although data mining tools are increasingly used to predict overall student performance, resilient students in the digital world remain unstudied. Our study aims to comprehensively identify key features in the classification of academically resilient students (ARS) and non-academically resilient students (NRS) in digital reading. With a sample of 11,496 disadvantaged students from seven high-performing Asian economies, data drawn from the Programme for International Student Assessment (PISA) 2018 were analyzed through Support Vector Machine (SVM). Results indicated that 20 key features were selected from 105 contextual features at the individual, home, and school levels, which demonstrated a high predictive ability of the model. Personal experience, especially the use of metacognitive strategies in digital reading and reading enjoyment were predominant features. Interestingly, information and communication technology (ICT) resources and usage showed mixed effects on resilient students. This study provides significant implications for cultivating resilient students in online learning environments.

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways. Methods: Airway trees spanning the proximal–distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments in vitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation. Findings: An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal–distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function. Interpretation: Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways. Funding: National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).

BackgroundOver the past few decades, China has experienced significant demographic and epidemiological changes. The sharp decline in fertility and mortality rates has accelerated population aging, contributing to an increase in the prevalence of chronic diseases. The nutritional condition during early life is associated with the onset of chronic illnesses later in adulthood. However, it remains unclear whether this association also increases the risk of multimorbidity in later adulthood.ObjectivesThis study aimed to systematically evaluate the association between early-life famine exposure and the subsequent development of 14 chronic diseases, as well as multimorbidity, and whether there exists a discrepancy in gender, residence, and famine severity.MethodsData are from the 2018 Wave 4 CHARLS database, a national survey covering 19,816 participants aged 45 years or older. Drawing from our past research on famine in China, we incorporated 3,867 participants, categorizing them into three groups based on their birth years. Considering that climate conditions and population density can influence the intensity of famine, we characterize its severity by establishing a threshold of 50% excess death rate. The 14 chronic diseases assessed by CHARLS were used as the main outcome indicator, with multimorbidity as a secondary outcome indicator. We conducted a stepwise logistic regression analysis to investigate the impact of exposure to famine in early life affects the development of chronic diseases in adulthood, presenting the findings as ORs and 95% CIs. Additionally, we assess multiple moderating factors such as gender, residence, and famine severity to evaluate the outcomes.ResultsOf the 3,867 participants included, the prevalence of each chronic disease ranged from 1.1% (Psychiatric disease) to 10.7% (Hypertension). Overall, 27.0% of participants reported being affected by at least one chronic disease, while 9.6% indicated they had suffered from two or more chronic conditions. Early-life exposure to famine makes it more likely to develop diabetes in later adulthood OR (95% CI) of 1.85 (1.26 to2.72), stroke OR (95% CI) of 1.96 (1.17 to 3.29), kidney disease OR (95% CI) of 1.91 (1.07 to 3.40), and multimorbidity OR (95% CI) of 1.39 (1.08 to 1.80), compared to those who did not face such conditions. The moderating effects analysis revealed that less severe famine exposure during toddlerhood was associated with an increased risk of multimorbidity in adulthood OR (95% CI) of 1.43 (1.01 to 2.03). Males exposed to famine during toddlerhood had a higher risk of multimorbidity in adulthood OR (95% CI) of 2.26 (1.29 to 3.98). Compared to the unexposed group, rural residents who experienced famine exposure in their early life are at a higher risk of developing multimorbidity by about 1.5 times in adulthood.ConclusionExperiencing famine in early childhood increases susceptibility to developing chronic diseases in later adulthood, with the risk of diabetes, stroke, and kidney disease nearly doubling. The association of multimorbidity in later adulthood varies according to the severity of the famine, gender, and residential area.

Large language models (LLMs) are rapidly advancing medical artificial intelligence, offering revolutionary changes in health care. These models excel in natural language processing (NLP), enhancing clinical support, diagnosis, treatment, and medical research. Breakthroughs, like GPT-4 and BERT (Bidirectional Encoder Representations from Transformer), demonstrate LLMs’ evolution through improved computing power and data. However, their high hardware requirements are being addressed through technological advancements. LLMs are unique in processing multimodal data, thereby improving emergency, elder care, and digital medical procedures. Challenges include ensuring their empirical reliability, addressing ethical and societal implications, especially data privacy, and mitigating biases while maintaining privacy and accountability. The paper emphasizes the need for human-centric, bias-free LLMs for personalized medicine and advocates for equitable development and access. LLMs hold promise for transformative impacts in health care.

Introduction and Objectives: Primary biliary cholangitis (PBC) may progress to clinically significant portal hypertension (CSPH) before the development of cirrhosis. This study aimed to investigate CSPH incidence as well as the clinicopathological characteristics and predictive value of these features for the prognosis of patients with PBC, especially at early histologic stage. Patients and Methods: Patients diagnosed with PBC between January 2013 and April 2022 were retrospectively enrolled. The prognostic value of baseline clinicopathological characteristics for long-term outcomes in PBC patients with CSPH was assessed using Kaplan–Meier survival analysis and COX regression analysis. Results: Among 280 patients with PBC, 104 underwent liver biopsy and 68 were at early histologic stage. CSPH was present in 47.2 % of participants with 20.6 % at early histologic stage. CSPH was a risk factor for predicting the liver transplant-free survival in PBC patients (hazard ratio [HR], 6.78; 95 % CI, 2.94–15.63), especially those at early stage. Perisinusoidal fibrosis and nodular regenerative hyperplasia (NRH) were common histopathological features in PBC patients with CSPH at the early stages. Fibrous septa formation in the hepatic lobules (HR, 4.85; 95 % CI, 1.51–15.52) and cholestasis (HR, 7.70; 95 % CI, 2.56–23.18) were independent predictors of adverse outcomes. Conclusions: CSPH indicates an increased risk of adverse outcomes in PBC patients, especially those in early histologic stage. Perisinusoidal fibrosis and NRH are valuable histological features of CSPH in patients with early-stage PBC. Identification of clinicopathological features and assessment of portal hypertension (especially at early stage), contribute to the development of personalized strategies.

Abstract This review explores the mechanisms underlying alcohol‐induced oesophageal carcinogenesis, including DNA damage, oxidative stress, and nutritional deficiencies. Alcohol metabolism primarily involves alcohol dehydrogenase (ADH) converting ethanol to acetaldehyde, which can cause DNA damage, inhibit repair mechanisms, and form DNA adducts thus inhibiting DNA replication. Plus, it delves into the epidemiological evidence, genetic susceptibility, epigenetic modifications, biomarkers, and preventive strategies associated with alcohol‐related oesophageal cancers. Consumption of alcohol increases the risk of gastroesophageal reflux disease thus compromising mucosal integrity of the oesophagus as dysregulation of cytokines such as IL‐18, TNFA, GATA3, TLR4, and CD68 expands the intercellular spaces of epithelial cells. Genetic variants, such as ADH1B rs1229984 and ALDH2 rs671, significantly influence susceptibility to alcohol‐related oesophageal cancers, with these variations affecting acetaldehyde metabolism and cancer risk. Understanding these factors is crucial for early detection, effective treatment, and the development of targeted prevention strategies. Biomarkers, such as miRNA and metabolite markers, offer non‐invasive methods for early detection, while advanced endoscopic techniques provide better diagnostic accuracy. Pharmacological interventions, such as statins and proton pump inhibitors, also show potential for reducing cancer progression in high‐risk individuals. Despite advances, late‐stage oesophageal cancer diagnoses are still common, highlighting the need for better screening and prevention. Further research, including this study, should aim to improve early detection, personalise prevention, and explore new treatments to reduce cases and enhance outcomes in alcohol‐related oesophageal cancers.

ABSTRACT Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) strains present a significant global public health threat due to their high mortality rates. This study investigated the genomic characteristics of seven ST11-K1 CR-hvKP isolates harboring highly homologous KPC-2-encoding multidrug-resistance plasmids. The strains were isolated from a Chinese tertiary hospital between 2017 and 2020. Whole-genome sequencing and bioinformatic analysis revealed various antibiotic resistance genes (ARGs) and virulence determinants. The blaKPC-2-bearing plasmids that contain multiple antibiotic-resistance genes were also identified in these strains. ISfinder and Orifinder were applied to identify insertion sequences (IS) and conjugation-related factors among these blaKPC-2-bearing plasmids. The blaKPC-2 was highly consistent in seven blaKPC-2-bearing plasmids (ISKpn6-blaKPC-2-ISKpn27-ISYps3-IS26). In addition, we found a region composed of ISIR, Tn5393, and IS26. It was located upstream of the blaCTX-M-15 gene and presented in six blaKPC-2-bearing plasmids, with pCR-hvKP221-KPC-P3 as an exception. Conjugation experiments demonstrated the horizontal transfer of resistance plasmids pCR-hvKP128-KPC-P1 and pCR-hvKP132-KPC-P1 across species. Notably, pLVPK-like virulence plasmids carrying virulence gene clusters pCR-hvKP173-Vir-P1, and pCR-hvKP221-Vir-P1 were also detected. A fusional plasmid pCR-hvKP221-Vir-P2, which carries virulence gene clusters and ARGs, was also identified. Five CR-hvKP strains displayed enhanced biofilm formation and high virulence in vivo infection models. Phylogenetic and single nucleotide polymorphism (SNP) analyses indicated a close genetic relationship among the isolates, suggesting a subclade. These findings highlight the complex genetic profiles and potential transmission mechanisms of CR-hvKP strains.IMPORTANCEWe reported seven CR-hvKP strains all carried a highly homologous blaKPC-2 integrated IncFⅡ-resistant plasmid, and two strains harbored virulence plasmids. Conjugation experiments confirmed the transferability of these plasmids, indicating a potential for resistance spread. Phylogenetic analysis clarified the relationship among the CR-hvKP isolates. This study provides insights into the phenotypic and genomic characteristics of seven ST11-K1 CR-hvKP strains. The high prevalence and potential for local outbreaks emphasize the need for effective control measures.

BackgroundThe inflammatory response is associated with cardiac repair and ventricular remodeling after myocardial infarction (MI). The key inflammation regulatory factor thymic stromal lymphopoietin (TSLP) plays a critical role in various diseases. However, its role in cardiac repair after MI remains uncertain. In this study, we elucidated the biological function and mechanism of action of TSLP in cardiac repair and ventricular remodeling following MI.Method and ResultWild-type and TSLP receptor (TSLPR)-knockout (Crlf2-/-) mice underwent MI induction via ligation of the left anterior descending artery. TSLP expression was upregulated in the infarcted heart, with a peak observed on day 7 post-MI. TSLP expression was enriched in the cardiomyocytes of infarcted hearts and the highest expression of TSLPR was observed in dendritic cells. Crlf2-/- mice exhibited reduced survival and worsened cardiac function, increased interstitial fibrosis and cardiomyocyte cross-sectional area, and reduced CD31+ staining, with no change in the proportion of apoptotic cardiomyocytes within the border zone. Mechanistically, reduced Treg cell counts but increased myeloid cell infiltration and an increased ratio of Ly6Chigh/Ly6Clow monocyte were observed in the ani hearts of Crlf2-/- mice. Further, TSLP regulated CD4+ T cell activation and proliferation at baseline and after MI, with a greater impact on Treg cells than on conventional T cells. RNA-seq analysis revealed significant downregulation of genes involved in T cell activation and TCR signaling in the infarcted heart of Crlf2-/- mice compared with their WT counterparts.ConclusionCollectively, our data indicate a critical role for TSLP in facilitating cardiac repair and conferring protection against MI, primarily through regulating CD4+ T cell responses, which may provide a potential novel therapeutic approach for managing heart failure after MI.

Crayfish, as a new consumer trend, has become one of the most popular freshwater aquatic foods in China, and its processed product output has been increasing year by year. In this study, the effect of multi-frequency power ultrasound (MFPU) pretreatment in various working modes including mono-, dual- and tri-frequency on the enzymatic hydrolysis and Maillard reaction of crayfish was investigated. Additionally, the underlying mechanism was also explored. Results showed that the degree of hydrolysis (DH) of crayfish was 23.89 %, while it increased to 40.78 % after MFPU pretreatment at 20/40 kHz dual-frequency, indicating that MFPU pretreatment significantly (p

Stigma maydis (SM) possesses remarkable nutritional value due to the presence of health-protective chemical constituents in it. Despite its commercial uses, there is a lack of information on changes in the nutritional profile of SM during Shenke 601 waxy corn development by following four different maturity stages (silking stage; blister stage; milky stage; dough stage). In this study, the ideal times for the development of seven active compounds (polysaccharides, saponin, rutin, luteolin, quercetin, kaempferol and chlorogenic acid) were at the silking stage. The total flavonoid and total phenol content increased as the SM matured. Except for the above-mentioned active compounds, the content of major nutritional components of dough stage was higher than that of three other stages. The extract of Stigma maydis exhibited good α-amylase, α-glucosidase and pancreatic lipase inhibition activities. The ethanolic SM extracts showed better inhibitory effects than aqueous SM extracts with a dose–effect relationship. The hypoglycemic activity of ethanolic extract was higher than that of aqueous extract at each stage. This provided an important basis for the application of SM.

ABSTRACTThe evasive tactics of Treponema pallidum pose a major challenge in combating and eradicating syphilis. Natural killer (NK) cells mediate important effector functions in the control of pathogenic infection, preferentially eliminating targets with low or no expression of major histocompatibility complex (MHC) class I. To clarify T. pallidum’s mechanisms in evading NK-mediated immunosurveillance, experiments were performed to explore the cross-talk relations among T. pallidum, NK cells, and platelets. T. pallidum adhered to, activated, and promoted particle secretion of platelets. After preincubation with T. pallidum, platelets expressed and secreted high levels of MHC class I, subsequently transferring them to the surface of T. pallidum, potentially inducing an immune phenotype characterized by the “pseudo-expression” of MHC class I on the surface of T. pallidum (hereafter referred to a “pseudo-expression” of MHC class I). The polA mRNA assay showed that platelet-preincubated T. pallidum group exhibited a significantly higher copy number of polA transcript than the T. pallidum group. The survival rate of T. pallidum mirrored that of polA mRNA, indicating that preincubation of T. pallidum with platelets attenuated NK cell lethality. Platelets pseudo-expressed the MHC class I ligand on the T. pallidum surface, facilitating binding to killer cell immunoglobulin-like receptors with two immunoglobulin domains and long cytoplasmic tail 3 (KIR2DL3) on NK cells and initiating dephosphorylation of Vav1 and phosphorylation of Crk, ultimately attenuating NK cell lethality. Our findings elucidate the mechanism by which platelets transfer MHC class I to the T. pallidum surface to evade NK cell immune clearance.

The incompletely eliminated Treponema pallidum (T. pallidum) during primary syphilis chancre infection can result in the progression of secondary, tertiary, or latent syphilis in individuals, suggesting that T. pallidum has successfully evaded the immune response and spread to distant sites. The mechanism underlying the dissemination of T. pallidum is unclear. Here, a syphilitic rabbit model dorsal-injected with recombinant Tp0136 protein or Tp0136 antibody subcutaneously was used to demonstrate the role of Tp0136 protein in promoting the dissemination of T. pallidum to the testis and angiogenesis in vivo; vascular endothelial cell line HMEC-1 was employed to display that Tp0136 protein enhances the angiogenesis. Furthermore, the three-dimensional microfluidic angiogenesis system showed that the angiogenesis would heighten vascular permeability. Then transcriptome sequencing analysis, in conjunction with cell-level validation, elucidated the critical role of the PI3K-AKT signaling pathway in the promotion of angiogenesis by Tp0136 protein, resulting in heightened permeability. These findings elucidate the strategy employed by T. pallidum in evading immune clearance.

Compact and adaptable CRISPR-Cas systems enable genome engineering applications in various contexts via high-efficiency delivery. The adeno-associated virus (AAV) is a widely used delivery system. One of the most compact type II-C Cas9 orthologs—CjCas9, derived from Campylobacter jejuni, is particularly appealing for AAV delivery. However, the editing efficiency of CjCas9 limits its applications. In this study, we used structure-guided protein engineering to improve the editing efficiency of CjCas9. Subsequently, we developed a miniature transcriptional activator (LDE-CjCas9-VPR) and base editors engineered from CjCas9 (LDE-CjABE and LDE-CjCBE). LDE-CjABE effectively induced genome editing in human and mouse cells. Through AAV delivery, LDE-CjABE enhanced the on-target editing efficiency, and off-target editing was not detected in the mouse retina. Therefore, the compact size and high editing efficiency of LDE-CjCas9 broadens the target scope of transcription activation and base editing toolsets for therapeutic applications.

Abstract Human papillomavirus (HPV) 11/16 E6/E7 proteins have been recognized to be pivotal in viral pathogenesis. This study sought to uncover the potential mechanisms of how HPV11/16 E6/E7-transfected keratinocytes inhibit cytokine secretion in peripheral blood mononuclear cells (PBMC). Upon co-culturing HPV11/16 E6/E7-transfected keratinocytes with PBMC in a non-contact manner, we observed a marked decrease in various cytokines secreted by PBMC. To determine if this suppression was mediated by specific common secreted factors, we conducted transcriptomic sequencing on these transfected cells. This analysis identified 53 common differentially secreted genes in all four HPV-transfected cells. Bioinformatics analysis demonstrated these genes were predominantly involved in immune regulation. Results from quantitative PCR (qPCR) and an extensive literature review suggested the downregulation of 12 genes (ACE2, BMP3, BPIFB1, CLU, CST6, CTF1, HMGB2, MMP12, PDGFA, RNASE7, SULF2, TGM2), and upregulation of 7 genes (CCL17, CCL22, FBLN1, PLAU, S100A7, S100A8, S100A9), may be crucial in modulating tumor immunity and combating pathogenic infections, with genes S100A8 and S100A9, and IL-17 signaling pathway being particularly noteworthy. Thus, HPV11/16 E6/E7 proteins may inhibit cytokine secretion of immune cells by altering the expression of host-secreted genes. Further exploration of these genes may yield new insights into the complex dynamics of HPV infection.

Abstract Background Both individuals and society bear a considerable burden from ischemic stroke (IS), not only do patients continue suffering from motor dysfunction after discharge from hospital, but their caregivers also undertake the principal responsibility of assisting them in reintegrating into the family and society. To better improve the IS patients’ limb function and daily life activities, their caregivers should also be involved in the training of the motor function rehabilitation during the period transitioning from hospital back home. This study mainly aims to investigate the effects of a nurse-led training for IS patients and their family caregivers on the improvement of the patients’ physical function and the burden of caregivers. Methods/design A randomized controlled trial with blind assessment will be conducted in hospitals and during the follow-ups at home. Fifty-eight pairs of adults diagnosed with ischemic stroke and their primary caregivers will be included. Participants will be randomly given with (1) a nurse-led, home-based motor rehabilitation training participated by caregivers (intervention group) or (2) routine self-care (control group). Both groups will receive assessment and health guidance on the day of discharge, and the intervention group will receive an additional home-based training program and supervision. These two groups will be followed up every week after discharge. The primary results are drawn from the evaluation of physical function and caregiver-related burden, and the secondary results derived from statistics of the modified Barthel index, stroke-specific quality of life, and National Institutes of Health Stroke Scale. Differences between the two groups will be measured by two-way repeated measures ANOVA, considering the data at baseline and at 1-week and 4-week follow-up after training. Discussion Results may provide novel and valuable information on the effects of this culturally appropriate, caregiver-involved, and home-based rehabilitation training on the physical function of IS patients and caregiver-related burden. Trial registration Chinese Clinical Trial Registry (chictr.org.cn) ChiCTR2300078798. Registered on December 19, 2023.

Abstract This review delves into the detrimental impact of alcohol consumption on internal organs and reproductive health, elucidating the underlying mechanisms involving the Toll‐like receptor 4 (TLR4)/Nuclear factor kappa light chain enhancer of activated B cells (NF‐kB) pathway and the Cytochrome P450 2E1 (CYP2E1)/reactive oxygen species (ROS)/nuclear factor erythroid 2‐related factor 2 (Nrf2) pathways. The TLR4/NF‐kB pathway, crucial for inflammatory and immune responses, triggers the production of pro‐inflammatory agents and type‐1 interferon, disrupting the balance between inflammatory and antioxidant responses when tissues are chronically exposed to alcohol. Alcohol‐induced dysbiosis in gut microbes heightens gut wall permeability to pathogen‐associated molecular patterns (PAMPs), leading to liver cell infection and subsequent inflammation. Concurrently, CYP2E1‐mediated alcohol metabolism generates ROS, causing oxidative stress and damaging cells, lipids, proteins, and deoxyribonucleic acid (DNA). To counteract this inflammatory imbalance, Nrf2 regulates gene expression, inhibiting inflammatory progression and promoting antioxidant responses. Excessive alcohol intake results in elevated liver enzymes (ADH, CYP2E1, and catalase), ROS, NADH, acetaldehyde, and acetate, leading to damage in vital organs such as the heart, brain, and lungs. Moreover, alcohol negatively affects reproductive health by inhibiting the hypothalamic–pituitary‐gonadal axis, causing infertility in both men and women. These findings underscore the profound health concerns associated with alcohol‐induced damage, emphasizing the need for public awareness regarding the intricate interplay between immune responses and the multi‐organ impacts of alcohol consumption.

Abstract Aiming at the problem of "crystallization" on the surface of Yuan blue and white ceramics, which causes reflections and loss of image texture, an image processing method is proposed to repair the image texture information. A multi-scale Retinex pre-processing method is proposed to enhance the contrast between the pattern and the background. A color factor is introduced to prevent color distortion. A weighted average function is constructed to enhance image details and improve texture information. The Yuan blue and white pattern can be effectively segmented from the background using a combination of multi-peak thresholding for segmentation and other techniques. The experimental results demonstrate that, in comparison to other algorithms, the multi-scale Retinex and histogram multi-peak threshold coupled segmentation method proposed in this paper exhibits the highest F1-score of 0.03067 and an accuracy of 92.67% in cross-evaluation with other algorithms. This indicates that the overall performance of the algorithm is the best. The proposed method has the potential to inform the protection of cultural relics.

Abstract In this study, the removal effect of a new MOF-on MOF adsorbent based on Cu–Co bimetallic organic frameworks on tetracycline antibiotics (TCs) in water system was studied. The adsorbent (Cu-MOF@Co-MOF) were synthesized by solvothermal and self-assembly method at different concentrations of Co2+/Cu2+. The characterization results of SEM, XRD, XPS, FTIR and BET indicated that the MOF-on MOF structure of Cu-MOF@Co-MOF exhibited the best recombination and physicochemical properties when the molar ratio of Co2+: Cu2+ is 5:1. In addition, the Cu-MOF@Co-MOF have a high specific surface area and bimetallic clusters, which can achieve multi-target synergistic adsorption of TCs. Based on above advantages, Cu-MOF@Co-MOF provided a strong affinity and could efficiently adsorb more than 80% of pollutants in just 5 to 15 min using only 10 mg of the adsorbent. The adsorption capacity of tetracycline and doxycycline was 434.78 and 476.19 mg/g, respectively, showing satisfactory adsorption performance. The fitting results of the experimental data were more consistent with the Langmuir isotherm model and pseudo-second-order kinetic model, indicating that the adsorption process of TC and DOX occurred at the homogeneous adsorption site and was mainly controlled by chemisorption. Thermodynamic experiments showed that Cu-MOF@Co-MOF was thermodynamically advantageous for the removal of TCs, and the whole process was spontaneous. The excellent adsorption capacity and rapid adsorption kinetics indicate the prepared MOF-on MOF adsorbent can adsorb TCs economically and quickly, and have satisfactory application prospects for removing TCs in practical environments. The results of the study pave a new way for preparing novel MOFs-based water treatment materials with great potential for efficient removal.

Abstract Introduction Juvenile dermatomyositis (JDM) is characterized by persistent non-purulent inflammation in the muscle and skin. The underlying mechanisms still remain uncertain. This study aims to elucidate the mechanism of interleukin-6 (IL-6) activation of Janus kinase/signal transducer and activator of transcription 3 pathway (JAK/STAT3), contributing to the pathogenesis of JDM. Methods Serum IL-6 levels were compared between 72 newly diagnosed patients with JDM and the same patient cohort in treatment remission. Single-cell RNA sequencing (scRNA-seq) was employed to identify differential signaling pathway expression in muscle biopsy samples from two patients with JDM and healthy controls. Immunohistochemistry was used to examine differences in STAT3 phosphorylation between JDM and control muscle tissues. In vitro, skeletal muscle cell lines were stimulated with IL-6, and the transcription levels of genes related to mitochondrial calcium channels were quantified via reverse transcription-polymerase chain reaction (RT-PCR). Reactive oxygen species (ROS) production was measured in both IL-6 treated and untreated groups. ROS levels were then compared between IL-6 receptor antagonist pre-treated skeletal muscle cells and untreated cells. Results IL-6 levels in newly onset patients with JDM were significantly higher compared to the same patient cohort in remission states (p

We de novo assembled and analysed the chloroplast genomes of Capsella bursa-pastoris, Descurainia sophia, and Lepidium apetalum of the plant family Brassicaceae. These chloroplast genomes exhibited a quadripartite structure characterised by inverted repeat regions (26,268–26,460 bp) separating large single copy (83,771–83,870 bp) and small single copy (17,570–18,014 bp) regions. Genetic analysis revealed 112 unique genes, comprising 78 protein-coding genes, 30 transfer RNA (tRNA) genes, and 4 ribosomal RNA (rRNA) genes. Notably, phylogenetic analysis of 21 species revealed close relationships between C. bursa-pastoris and C. orientalis, D. sophia and D. erodiifolia, and L. apetalum and L. cordatum, with 100% bootstrap support. In conclusion, the analysis of these genomes will contribute to the growing knowledge of chloroplast genomes in the Brassicaceae family and of the specific genera Capsella, Descurainia, and Lepidium.

Abstract Backgrounds Microfibril-associated protein 2 (MFAP2) is a protein presenting in the extracellular matrix that governs the activity of microfibrils through its interaction with fibrillin. While the involvement of MFAP2 in metabolic disorders has been documented, its expression and prognostic significance in triple-negative breast cancer (TNBC) remain unexplored. Methods We acquired datasets pertaining to breast cancer (BC) from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Next, a Venn diagram was used to identify the differentially expressed genes (DEGs). The DEGs were used to perform Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI), immune and survival analysis. The expressions of MFAP2, PD-1 and PD-L1 were examined by immunohistochemistry and western blot and their relationship with clinical pathological parameters were analyzed by clinical specimen samples from patients with TNBC. Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/ ) was adopted to calculate the immune infiltration level of TNBC. The link between gene expression and tumor mutational burden (TMB) was described using Spearman’s correlation analysis. Results We identified 66 differentially expressed genes (DEGs) that were up-regulated. Among these DEGs, MFAP2 was found to be overexpressed in TNBC and was associated with a lower probability of survival. This finding was confirmed through the use of immunohistochemistry and western blot techniques. Additionally, MFAP2 was found to be related to various pathological parameters in TNBC patients. Mechanistically, gene set enrichment analysis (GSEA) revealed that MFAP2 primarily influenced cellular biological behavior in terms of epithelial mesenchymal transition, glycolysis, and apical junction. Notably, MFAP2 expression was positively correlated with the abundance of macrophages, while a negative correlation was observed with the abundance of B cells, CD4 + T cells, CD8 + T cells, neutrophils and dendritic cells through immune analysis. Furthermore, it was observed that MFAP2 displayed a negative correlation not only with tumor mutational burden (TMB), a recognized biomarker for PD-1/PD-L1 immunotherapy, but also with PD-L1 in samples of TNBC. Conclusion MFAP2 may be an important prognostic biomarker for TNBC, as well as a viable target for immunotherapy in this disease.

Abstract Background Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self‐renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non‐small cell lung cancer (NSCLC) remains unclear. Methods The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit β‐catenin while pcDNA3‐β‐catenin (S33Y) plasmid enhanced the expression of β‐catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real‐time PCR. Results We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, β‐catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by β‐catenin inhibitor or siRNA knockdown, whereas increased after β‐catenin overexpression. Furthermore, hypoxia treatment suppressed E‐cadherin expression in H520 cells and enhanced N‐cadherin and β‐catenin expression, while this effect was completely opposite in A549 cells. Conclusion The hypoxia‐EMT‐β‐catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

Abstract Background Tall wheatgrass is a perennial salt‐tolerant bunchgrass, which is a promising candidate for establishing a “Coastal Grass Belt” in China, particularly in the coastal saline–alkaline soils surrounding the Bohai Sea. Methods Seven harvesting treatments were performed to explore the optimal harvesting time and frequency for tall wheatgrass in coastal area. The dry matter yield (DMY) and forage nutritional values were investigated for each cut. The correlation between harvesting time and frequency thereof among the investigated traits was also determined. Results The results showed that the two‐cut on June 18 and October 29 produced the highest DMY. Another two‐cut on May 26 and October 29 produced a relatively high crude protein (CP) yield. The DMY, contents of neutral detergent fiber (NDF), acid detergent fiber (ADF), and crude cellulose (CC) as well as CP yield were positively correlated to plant height, while the CP content and the relative feed value (RFV) were negatively correlated to plant height. The accumulating growing degree days, accumulated precipitation, and sunshine duration were positively correlated with plant height, DMY, contents of NDF, ADF, and CC as well as CP yield, but negatively correlated with CP content and RFV for the first cut. Conclusions The two‐cut treatment at the end of May and October may be suitable for tall wheatgrass in the “Coastal Grass Belt” targeted area.

IntroductionMetabolic dysfunction-associated steatotic liver disease (MASLD) frequently confers an increased risk of vascular thrombosis; however, the marketed antiplatelet drugs are investigated for the prevention and treatment of MASLD in patients with these coexisting diseases.MethodsTo determine whether clopidogrel could ameliorate high-fat diet (HFD)-induced hepatic steatosis in mice and how it works, mice were fed on normal diet or HFD alone or in combination with or without clopidogrel for 14 weeks, and primary mouse hepatocytes were treated with palmitate/oleate alone or in combination with the compounds examined for 24 h. Body weight, liver weight, insulin resistance, triglyceride and total cholesterol content in serum and liver, histological morphology, transcriptomic analysis of mouse liver, and multiple key MASLD-associated genes and proteins were measured, respectively.Results and discussionClopidogrel mitigated HFD-induced hepatic steatosis (as measured with oil red O staining and triglyceride kit assay) and reduced elevations in serum aminotransferases, liver weight, and the ratio of liver to body weight. Clopidogrel downregulated the expression of multiple critical lipogenic (Acaca/Acacb, Fasn, Scd1, Elovl6, Mogat1, Pparg, Cd36, and Fabp4), profibrotic (Col1a1, Col1a2, Col3a1, Col4a1, Acta2, and Mmp2), and proinflammatory (Ccl2, Cxcl2, Cxcl10, Il1a, Tlr4, and Nlrp3) genes, and enhanced phosphorylation of AMPK and ACC. However, compound C (an AMPK inhibitor) reversed enhanced phosphorylation of AMPK and ACC in clopidogrel-treated primary mouse hepatocytes and alleviated accumulation of intracellular lipids. We concluded that clopidogrel may prevent and/or reverse HFD-induced hepatic steatosis in mice, suggesting that clopidogrel could be repurposed to fight fatty liver in patients.

Aiming at the large aspect ratio characteristics of large wind turbines, it is easy to cause irreversible damage due to flutter during operation. A two-degree-of-freedom (plunge and pitch) flutter test bench was built using the time domain and frequency domain analysis methods of dynamic signals. The influence of different centroid positions on the flutter boundary was studied. The test shows that the closer the centroid position is to the leading edge of the wing segment, the better the aeroelastic stability of the wing segment is. Under the linear condition, the forward movement of the centroid position has a more significant influence on the flutter. In addition, the main reason for the wing flutter is related to the decrease of net damping and the coupling of the aeroelastic natural frequency of the pitching and plunging motions. The pitch motion is dominant in the two-degree-of-freedom motion. The farther the centre of mass is from the torsion axis, the greater the pitch and plunge motion displacement. The pitch motion has a more significant impact on the system than the plunge motion. Therefore, the study of flutter suppression should focus on pitch motion.

Abstract Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon‐γ (IFN‐γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine‐2,3‐dioxygenase (IDO)‐ kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan‐to‐phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV‐positive GC continuously secreted IFN‐γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV‐positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV‐positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti‐tumor immunotherapy.