Experimental and molecular pathology最新文献

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Corrigendum to "Characteristics of liver fibrosis associated with chronic Opisthorchis felineus infection in Syrian hamsters and humans" [Experimental and Molecular Pathology 110 (2019) 104274]. “叙利亚仓鼠和人类慢性猫腹绦虫感染相关肝纤维化特征”[实验与分子病理学110(2019)104274]的勘误。
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-06-09 DOI: 10.1016/j.yexmp.2025.104975
Anna V Kovner, Maria Y Pakharukova, Galina A Maksimova, Viatcheslav A Mordvinov
{"title":"Corrigendum to \"Characteristics of liver fibrosis associated with chronic Opisthorchis felineus infection in Syrian hamsters and humans\" [Experimental and Molecular Pathology 110 (2019) 104274].","authors":"Anna V Kovner, Maria Y Pakharukova, Galina A Maksimova, Viatcheslav A Mordvinov","doi":"10.1016/j.yexmp.2025.104975","DOIUrl":"https://doi.org/10.1016/j.yexmp.2025.104975","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":" ","pages":"104975"},"PeriodicalIF":2.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to "Upregulation of CDK7 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis" [Experimental and Molecular Pathology 100 (2016) 514-521]. “胃癌细胞CDK7上调促进肿瘤细胞增殖并预测预后不良”[实验与分子病理学100(2016)514-521]更正。
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-06-04 DOI: 10.1016/j.yexmp.2025.104974
Qiuhong Wang, Manhua Li, Xunlei Zhang, Hua Huang, Jianfei Huang, Jing Ke, Haifang Ding, Jinzhang Xiao, Xiaohang Shan, Qingqing Liu, Bojun Bao, Lei Yang
{"title":"Corrigendum to \"Upregulation of CDK7 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis\" [Experimental and Molecular Pathology 100 (2016) 514-521].","authors":"Qiuhong Wang, Manhua Li, Xunlei Zhang, Hua Huang, Jianfei Huang, Jing Ke, Haifang Ding, Jinzhang Xiao, Xiaohang Shan, Qingqing Liu, Bojun Bao, Lei Yang","doi":"10.1016/j.yexmp.2025.104974","DOIUrl":"https://doi.org/10.1016/j.yexmp.2025.104974","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":" ","pages":"104974"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Retraction notice to “Matrine protects neuro-axon from CNS inflammation-induced injury” [Experimental and Molecular Pathology 98 (2015) 124–130] “苦参碱保护神经轴突免受中枢神经系统炎症性损伤”的撤稿通知[实验与分子病理学98(2015)124-130]。
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-06-01 DOI: 10.1016/j.yexmp.2025.104968
Quan-Cheng Kan , Peng Lv , Xiao-Jian Zhang , Yu-Ming Xu , Guang-Xian Zhang , Lin Zhu
{"title":"Retraction notice to “Matrine protects neuro-axon from CNS inflammation-induced injury” [Experimental and Molecular Pathology 98 (2015) 124–130]","authors":"Quan-Cheng Kan , Peng Lv , Xiao-Jian Zhang , Yu-Ming Xu , Guang-Xian Zhang , Lin Zhu","doi":"10.1016/j.yexmp.2025.104968","DOIUrl":"10.1016/j.yexmp.2025.104968","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"142 ","pages":"Article 104968"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expression of concern: "Matrine ameliorates experimental autoimmune encephalomyelitis by modulating chemokines and their receptors" [Experimental and Molecular Pathology 99 (2015) 212-219]. 关注表达:“苦参碱通过调节趋化因子及其受体改善实验性自身免疫性脑脊髓炎”[experimental and Molecular Pathology 99(2015) 212-219]。
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-06-01 Epub Date: 2025-04-03 DOI: 10.1016/j.yexmp.2025.104962
{"title":"Expression of concern: \"Matrine ameliorates experimental autoimmune encephalomyelitis by modulating chemokines and their receptors\" [Experimental and Molecular Pathology 99 (2015) 212-219].","authors":"","doi":"10.1016/j.yexmp.2025.104962","DOIUrl":"10.1016/j.yexmp.2025.104962","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"142 ","pages":"104962"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expression of concern: "Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis" [Experimental and Molecular Pathology 97 (2014) 470-476]. 关注表达:“实验性自身免疫性脑脊髓炎中苦参碱治疗免疫调节分子的上调”[实验与分子病理学97(2014)470-476]。
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-06-01 Epub Date: 2025-04-04 DOI: 10.1016/j.yexmp.2025.104961
{"title":"Expression of concern: \"Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis\" [Experimental and Molecular Pathology 97 (2014) 470-476].","authors":"","doi":"10.1016/j.yexmp.2025.104961","DOIUrl":"10.1016/j.yexmp.2025.104961","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"142 ","pages":"104961"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evaluation of direct-to-PCR (D2P) method for molecular diagnosis of infectious diseases 直接- pcr (D2P)方法在传染病分子诊断中的应用评价
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-05-26 DOI: 10.1016/j.yexmp.2025.104972
Rahul Sharma , Vaibhav K. Tamrakar , Rob E. Carpenter , Aditya Sharma , Kamalpreet Suri , Salima Karki , Katelyn Kyser , Randy Sronce , Sadia Almas
{"title":"Evaluation of direct-to-PCR (D2P) method for molecular diagnosis of infectious diseases","authors":"Rahul Sharma ,&nbsp;Vaibhav K. Tamrakar ,&nbsp;Rob E. Carpenter ,&nbsp;Aditya Sharma ,&nbsp;Kamalpreet Suri ,&nbsp;Salima Karki ,&nbsp;Katelyn Kyser ,&nbsp;Randy Sronce ,&nbsp;Sadia Almas","doi":"10.1016/j.yexmp.2025.104972","DOIUrl":"10.1016/j.yexmp.2025.104972","url":null,"abstract":"<div><div>This study evaluates the performance of the Direct-to-PCR (D2P) method as a streamlined, extraction-independent alternative to conventional nucleic acid extraction techniques for diagnosing urinary tract infections, sexually transmitted infections, and respiratory tract infections. The D2P approach employs proprietary antimicrobial peptide-based lysis buffers tailored for bacterial, fungal, and viral targets, enabling direct amplification from clinical and contrived specimens without column- or bead-based purification. Comparative analyses were conducted against silica column-based (QIAGEN) and magnetic bead-based (KingFisher) extraction methods using both microbial reference isolates and 116 residual clinical samples. Results demonstrate that the D2P method yields comparable sensitivity and specificity to conventional extraction workflows across a diverse panel of pathogens—including Gram-negative and Gram-positive bacteria, <em>Candida</em> species, ssRNA viruses (e.g., CoV-229E, Parainfluenza Virus 1 and 2), and dsDNA viruses (e.g., HSV, HAdV). Notably, D2P outperformed both QIAGEN and KingFisher in extracting nucleic acids from <em>Candida auris</em>, a multidrug-resistant fungal pathogen. Limit of detection and amplification efficiency remained within acceptable ranges across all platforms, with R<sup>2</sup> values between 0.92 and 0.99, and slopes consistent with MIQE standards. The D2P protocol reduced total sample processing time from ∼120 min to ∼45 min, minimized hands-on steps, and demonstrated effective performance in turbid or hemolyzed samples—making it suitable for high-throughput and resource-limited settings. However, limitations were observed in samples with high PCR-inhibitor content or low target yield, and broader validation across additional matrices is recommended. These findings support D2P as a reliable, efficient, and scalable molecular diagnostic alternative with broad clinical utility. Integration of D2P into diagnostic workflows could enhance access to rapid, cost-effective pathogen detection in both centralized laboratories and decentralized or point-of-care environments.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104972"},"PeriodicalIF":2.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Estrogen induces the alternative activation of macrophages through binding to estrogen receptor-alpha 雌激素通过与雌激素受体结合诱导巨噬细胞的选择性活化
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-05-20 DOI: 10.1016/j.yexmp.2025.104971
Amina Belboul , Jason Ashworth , Abdulmannan Fadel , Jessica Mcloughlin , Ayman Mahmoud , Mohamed El Mohtadi
{"title":"Estrogen induces the alternative activation of macrophages through binding to estrogen receptor-alpha","authors":"Amina Belboul ,&nbsp;Jason Ashworth ,&nbsp;Abdulmannan Fadel ,&nbsp;Jessica Mcloughlin ,&nbsp;Ayman Mahmoud ,&nbsp;Mohamed El Mohtadi","doi":"10.1016/j.yexmp.2025.104971","DOIUrl":"10.1016/j.yexmp.2025.104971","url":null,"abstract":"<div><div>Age-related impaired wounds represent a major health burden resulting in considerable morbidity and mortality in the elderly. When injury occurs, monocytes migrate to the damaged site and undergo differentiation into tissue-resident macrophages, which are crucial for wound repair. For proper resolution of the inflammatory response, macrophages differentiate into two distinct phenotypes classified as classically-activatedpro-inflammatory and alternatively-activatedanti-inflammatory macrophages. Pro-inflammatory macrophages are commonly linked with pro-inflammatory events, while anti-inflammatory macrophages are known to be pro-regenerative. The age-related delay in wound repair is often attributed to the age-related decrease in local and systemic estrogen levels in both genders. However, despite its well-documented anti-inflammatory effect in wound healing, the role of estrogen and involvement of Estrogen Receptors (ERs) in macrophage polarization has gained little attention to date. To investigate the impact of estrogen and ERs on the polarization of macrophages, monocyte-derived macrophages were pre-treated with estrogen, ER-alpha agonist/antagonist or ER-beta agonist/antagonist prior to stimulation with LPS/IFN-γ or IL-4/IL-13 to produce pro-inflammatory or anti-inflammatory macrophages. Our findings confirm that estrogen promotes the alternative activation of macrophages <em>via</em> possible ER-α signalling. Selective targeting of ER-α with agents like PPT could potentially lead to the development of novel therapies to treat excessive inflammation in impaired wounds.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104971"},"PeriodicalIF":2.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
From asbestos exposure to carcinogenesis: Transcriptomic signatures in malignant pleural mesothelioma 从石棉暴露到癌变:恶性胸膜间皮瘤的转录组特征
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-05-20 DOI: 10.1016/j.yexmp.2025.104973
Diletta Rosati , Bianca Giulia Maurizi , Viola Bianca Serio , Debora Maffeo , Angela Rina , Francesca Mari , Maria Palmieri , Antonio Giordano , Elisa Frullanti
{"title":"From asbestos exposure to carcinogenesis: Transcriptomic signatures in malignant pleural mesothelioma","authors":"Diletta Rosati ,&nbsp;Bianca Giulia Maurizi ,&nbsp;Viola Bianca Serio ,&nbsp;Debora Maffeo ,&nbsp;Angela Rina ,&nbsp;Francesca Mari ,&nbsp;Maria Palmieri ,&nbsp;Antonio Giordano ,&nbsp;Elisa Frullanti","doi":"10.1016/j.yexmp.2025.104973","DOIUrl":"10.1016/j.yexmp.2025.104973","url":null,"abstract":"<div><h3>Background</h3><div>The incidence of malignant pleural mesothelioma (MPM) has surged due to widespread asbestos exposure, particularly since the mid-20th century. Despite significant advancements in cancer treatment, an effective cure for MPM remains elusive, largely due to a limited understanding of the molecular mechanisms underlying asbestos-related carcinogenesis. This exploratory study aims to uncover gene expression patterns uniquely altered in mesothelioma patients with documented asbestos exposure, providing a solid foundation for future research focused on identifying novel prognostic and predictive biomarkers.</div></div><div><h3>Methods</h3><div>Publicly available RNA sequencing data were analyzed through a bioinformatics pipeline to perform differential gene expression analysis. Additionally, functional enrichment analysis was applied to highlight significantly enriched Gene Ontology (GO) terms related to biological processes, molecular functions, and cellular components, offering insights into the molecular pathways involved in MPM development.</div></div><div><h3>Results</h3><div>The analysis uncovered a set of differentially expressed genes (DEGs) in MPM patients with documented asbestos exposure, as well as key GO terms. These enriched biological terms reflect processes such as ion homeostasis and oxidative stress response, providing crucial information on the cellular alterations driven by asbestos exposure.</div></div><div><h3>Conclusion</h3><div>This study's findings deepen our understanding of the molecular landscape underlying asbestos-induced carcinogenesis in MPM. The identification of specific DEGs and enriched GO terms lays the foundation for future investigations, including the development of biomarkers, with potential implications for the diagnostic and prognostic assessment of MPM.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104973"},"PeriodicalIF":2.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
m6A demethylase FTO/ALKBH5 promotes diabetes-induced endothelial cell dysfunction by negatively regulating lncRNA H19 m6A去甲基化酶FTO/ALKBH5通过负调控lncRNA H19促进糖尿病诱导的内皮细胞功能障碍
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-05-16 DOI: 10.1016/j.yexmp.2025.104970
Yanli Luo , Wanjun Luo , Yanan Cao , Zhanpeng Wang
{"title":"m6A demethylase FTO/ALKBH5 promotes diabetes-induced endothelial cell dysfunction by negatively regulating lncRNA H19","authors":"Yanli Luo ,&nbsp;Wanjun Luo ,&nbsp;Yanan Cao ,&nbsp;Zhanpeng Wang","doi":"10.1016/j.yexmp.2025.104970","DOIUrl":"10.1016/j.yexmp.2025.104970","url":null,"abstract":"<div><div>Endothelial cell dysfunction induced by glucose is the most important cause of diabetic vascular complications, which are the leading causes of blindness, disability, renal failure, heart failure, stroke, and even death in diabetic patients. RNA m6A modification is involved in the pathogenesis of human disease. However, the role and underlying mechanism of RNA m6A modification in high glucose-induced endothelial cell dysfunction is not well understood. Herein, this study first demonstrated that m6A levels were decreased and that the demethylases FTO and ALKBH5 were upregulated in diabetic patients and an STZ-induced diabetic mouse model. This study revealed that high glucose induced decreased m6A levels and increased expression of FTO and ALKBH5, and silencing of FTO and ALKBH5 restored high glucose-induced decreases in m6A levels and dysfunction of HUVECs. Next, this study systematically screened differentially expressed lncRNAs, including H19, in HUVECs under high glucose conditions. This study revealed that FTO-ALKBH5 inhibited H19 expression by decreasing m6A modification in H19 transcripts. In addition, this study demonstrated the role of the FTO/ALKBH5/H19 pathway in high glucose-induced cellular dysfunction of HUVECs. Ultimately, this study uncovered that silencing of H19 promoted the expression of cell cycle-related genes, including PTEN, p21 and p27 via interacting with EZH2 and affecting the H3K27me3 histone modification. Overall, this study is the first to dissect the regulation of lncRNA by m6A modification in hyperglycaemia, identifying a new regulatory pathway in high glucose-induced cellular dysfunction and providing biomarkers with the potential to serve as therapeutic targets for high glucose-induced cellular dysfunction.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104970"},"PeriodicalIF":2.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The multifunctional protein CCN1/CYR61: Bridging physiology and disease 多功能蛋白CCN1/CYR61:连接生理和疾病
IF 2.8 4区 医学
Experimental and molecular pathology Pub Date : 2025-04-25 DOI: 10.1016/j.yexmp.2025.104969
Racha Kerek, Joe Sawma Awad , Mariam Bassam , Carla Hajjar , Fouad Ghantous, Karelle Rizk, Mohamad Rima
{"title":"The multifunctional protein CCN1/CYR61: Bridging physiology and disease","authors":"Racha Kerek,&nbsp;Joe Sawma Awad ,&nbsp;Mariam Bassam ,&nbsp;Carla Hajjar ,&nbsp;Fouad Ghantous,&nbsp;Karelle Rizk,&nbsp;Mohamad Rima","doi":"10.1016/j.yexmp.2025.104969","DOIUrl":"10.1016/j.yexmp.2025.104969","url":null,"abstract":"<div><div>The matricellular protein CYR61/CCN1 is a member of the CCN protein family that plays significant roles in a broad range of physiological processes, including development, tissue repair, and inflammation, among others. CCN1 is also implicated in pathological conditions such as cancer and fibrosis. The diverse functions of CCN1 arise from its ability to bind different receptors located on many cell types, thereby activating diverse signaling pathways. The diverse, yet contradictory, functions mediated by CCN1 makes it a compelling target for investigation, as it offers the prospect of understanding fundamental cellular topics and their possible implications in various diseases. Recently, new cellular functions were attributed to CCN1, including senescence, pro-/anti- fibrosis, and rejuvenation. In this review, we discuss all these new findings along with the basic knowledge about CCN1 to provide an overall understanding of its conflicting roles and their potential corresponding mechanisms of action.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"142 ","pages":"Article 104969"},"PeriodicalIF":2.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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