{"title":"Gasdermin D unlocks metabolic pathways to enhance tissue regeneration.","authors":"Quazi T H Shubhra","doi":"10.1038/s41423-024-01239-6","DOIUrl":"https://doi.org/10.1038/s41423-024-01239-6","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec
{"title":"Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation.","authors":"Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec","doi":"10.1038/s41423-024-01233-y","DOIUrl":"10.1038/s41423-024-01233-y","url":null,"abstract":"<p><p>Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway","authors":"Yunzhu Chen, Baiwen Chen, Jingyu Li, Haixin Li, Gaoyang Wang, Xuemin Cai, Qianqian Zhang, Xiaoxu Liu, Chen Kan, Lei Wang, Zhengting Wang, Hua-Bing Li","doi":"10.1038/s41423-024-01237-8","DOIUrl":"10.1038/s41423-024-01237-8","url":null,"abstract":"Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) of mRNAs in regulating innate immunity remains unclear. In this study, we focused on 3’UTR-APA and demonstrated that Nudt21, a crucial RNA-binding component of the 3’UTR-APA machinery, is significantly upregulated in various inflammatory conditions. By utilizing myeloid-specific Nudt21-deficient mice, we revealed a protective effect of Nudt21 depletion against colitis and severe hyperinflammation, primarily through diminished production of proinflammatory cytokines. Notably, Nudt21 regulates the mRNA stability of key autophagy-related genes, Map1lc3b and Ulk2, by mediating selective 3’UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display increased autophagic activity, which leads to reduced cytokine secretion. Our findings highlight an unexplored role of Nudt21-mediated 3’UTR-APA in modulating macrophage autophagy and offer new insights into the modulation of inflammation and disease progression.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1522-1534"},"PeriodicalIF":21.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01237-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Critical and differential roles of eIF4A1 and eIF4A2 in B-cell development and function.","authors":"Ying Du, Jun Xie, Dewang Liu, Jiayi Zhao, Pengda Chen, Xiaoyu He, Peicheng Hong, Yubing Fu, Yazhen Hong, Wen-Hsien Liu, Changchun Xiao","doi":"10.1038/s41423-024-01234-x","DOIUrl":"https://doi.org/10.1038/s41423-024-01234-x","url":null,"abstract":"<p><p>Eukaryotic initiation factor 4 A (eIF4A) plays critical roles during translation initiation of cellular mRNAs by forming the cap-binding eIF4F complex, recruiting the 40S small ribosome subunit, and scanning the 5' untranslated region (5' UTR) for the start codon. eIF4A1 and eIF4A2, two isoforms of eIF4A, are highly conserved and exchange freely within eIF4F complexes. The understanding of their biological and molecular functions remains incomplete if not fragmentary. In this study, we showed that eIF4A1 and eIF4A2 exhibit different expression patterns during B-cell development and activation. Mouse genetic analyses showed that they play critical but differential roles during B-cell development and humoral immune responses. While eIF4A1 controls global protein synthesis, eIF4A2 regulates the biogenesis of 18S ribosomal RNA and the 40S ribosome subunit. This study demonstrates the distinct cellular and molecular functions of eIF4A1 and eIF4A2 and reveals a new role of eIF4A2 in controlling 40S ribosome biogenesis.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting of TAMs: can we be more clever than cancer cells?","authors":"Julia Kzhyshkowska, Jiaxin Shen, Irina Larionova","doi":"10.1038/s41423-024-01232-z","DOIUrl":"10.1038/s41423-024-01232-z","url":null,"abstract":"With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1376-1409"},"PeriodicalIF":21.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01232-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai
{"title":"Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma","authors":"Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai","doi":"10.1038/s41423-024-01231-0","DOIUrl":"10.1038/s41423-024-01231-0","url":null,"abstract":"Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1505-1521"},"PeriodicalIF":21.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors","authors":"Rui Zheng, Kuo Shen, Sixin Liang, Yanhong Lyu, Siyan Zhang, Hao Dong, Yuanfeng Li, Yujie Han, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Shukun Bai, Jianxun Yang, Guofang Lu, Jia Li, Angang Yang, Rui Zhang, Bo Yan","doi":"10.1038/s41423-024-01228-9","DOIUrl":"10.1038/s41423-024-01228-9","url":null,"abstract":"Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich solid tumors.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1491-1504"},"PeriodicalIF":21.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01228-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amit Sharma, Garima Sharma, Zhen Gao, Ke Li, Mutong Li, Menglin Wu, Chan Johng Kim, Yingjia Chen, Anupam Gautam, Hong Bae Choi, Jin Kim, Jung-Myun Kwak, Sin Man Lam, Guanghou Shui, Sandip Paul, Yongqiang Feng, Keunsoo Kang, Sin-Hyeog Im, Dipayan Rudra
{"title":"Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells","authors":"Amit Sharma, Garima Sharma, Zhen Gao, Ke Li, Mutong Li, Menglin Wu, Chan Johng Kim, Yingjia Chen, Anupam Gautam, Hong Bae Choi, Jin Kim, Jung-Myun Kwak, Sin Man Lam, Guanghou Shui, Sandip Paul, Yongqiang Feng, Keunsoo Kang, Sin-Hyeog Im, Dipayan Rudra","doi":"10.1038/s41423-024-01229-8","DOIUrl":"10.1038/s41423-024-01229-8","url":null,"abstract":"Regulatory T cells (Tregs) establish dominant immune tolerance but obstruct tumor immune surveillance, warranting context-specific mechanistic insights into the functions of tumor-infiltrating Tregs (TIL-Tregs). We show that enhanced posttranslational O-linked N-acetylglucosamine modification (O-GlcNAcylation) of cellular factors is a molecular feature that promotes a tumor-specific gene expression signature and distinguishes TIL-Tregs from their systemic counterparts. We found that altered glucose utilization through the glucose transporter Glut3 is a major facilitator of this process. Treg-specific deletion of Glut3 abrogates tumor immune tolerance, while steady-state immune homeostasis remains largely unaffected in mice. Furthermore, by employing mouse tumor models and human clinical data, we identified the NF-κB subunit c-Rel as one such factor that, through Glut3-dependent O-GlcNAcylation, functionally orchestrates gene expression in Tregs at tumor sites. Together, these results not only identify immunometabolic alterations and molecular events contributing to fundamental aspects of Treg biology, specifically at tumor sites but also reveal tumor-specific cellular properties that can aid in the development of Treg-targeted cancer immunotherapies.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1474-1490"},"PeriodicalIF":21.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna Nogalska, Jiya Eerdeng, Samir Akre, Mary Vergel-Rodriguez, Yeachan Lee, Charles Bramlett, Adnan Y. Chowdhury, Bowen Wang, Colin G. Cess, Stacey D. Finley, Rong Lu
{"title":"Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells","authors":"Anna Nogalska, Jiya Eerdeng, Samir Akre, Mary Vergel-Rodriguez, Yeachan Lee, Charles Bramlett, Adnan Y. Chowdhury, Bowen Wang, Colin G. Cess, Stacey D. Finley, Rong Lu","doi":"10.1038/s41423-024-01225-y","DOIUrl":"10.1038/s41423-024-01225-y","url":null,"abstract":"The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells, which originate from the aging of the stem cells that sustain their regeneration. Aging variation across individuals is well recognized, but its mechanism remains unclear. Here, we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes. We found that some hematopoietic stem cells (HSCs) in early aging mice upregulated genes related to aging, myeloid differentiation, and stem cell proliferation. Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals. These molecular changes align with shifts in HSC function. We found that the lineage biases of 30% to 40% of the HSC clones shifted with age. Moreover, their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype. In early aging mice, the HSC lineage bias shifted toward the myeloid lineage, driving the aging phenotype. In delayed aging mice, HSC lineage bias shifted toward the lymphoid lineage, effectively counteracting aging progression. Furthermore, the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production. Additionally, we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype. Taken together, our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs. Therefore, interventions to delay aging may be possible by targeting a subset of stem cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1459-1473"},"PeriodicalIF":21.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01225-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Young Jae Kim, Sung-Gwon Lee, So Young Park, Sang Min Jeon, Soo In Kim, Kyung Tae Kim, Taylor Roh, Sang-Hee Lee, Min Joung Lee, Jinyoung Lee, Hyeon Ji Kim, So Eui Lee, Jin Kyung Kim, Jun Young Heo, In Soo Kim, Chungoo Park, Seungwha Paik, Eun-Kyeong Jo
{"title":"Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages","authors":"Young Jae Kim, Sung-Gwon Lee, So Young Park, Sang Min Jeon, Soo In Kim, Kyung Tae Kim, Taylor Roh, Sang-Hee Lee, Min Joung Lee, Jinyoung Lee, Hyeon Ji Kim, So Eui Lee, Jin Kyung Kim, Jun Young Heo, In Soo Kim, Chungoo Park, Seungwha Paik, Eun-Kyeong Jo","doi":"10.1038/s41423-024-01222-1","DOIUrl":"10.1038/s41423-024-01222-1","url":null,"abstract":"Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1441-1458"},"PeriodicalIF":21.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01222-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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