Scott Layzell, Alessandro Barbarulo, Geert van Loo, Rudi Beyaert, Benedict Seddon
{"title":"Correction: NF-κB regulated expression of A20 controls IKK dependent repression of RIPK1 induced cell death in activated T cells.","authors":"Scott Layzell, Alessandro Barbarulo, Geert van Loo, Rudi Beyaert, Benedict Seddon","doi":"10.1038/s41418-024-01424-0","DOIUrl":"10.1038/s41418-024-01424-0","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CTCF enhances pancreatic cancer progression via FLG-AS1-dependent epigenetic regulation and macrophage polarization","authors":"Yihao Liu, Pengyi Liu, Songqi Duan, Jiayu Lin, Wenxin Qi, Zhengwei Yu, Xia Gao, Xiuqiao Sun, Jia Liu, Jiewei Lin, Shuyu Zhai, Kai Qin, Yizhi Cao, Jingwei Li, Yang Liu, Mengmin Chen, Siyi Zou, Chenlei Wen, Jiao Wang, Da Fu, Jiancheng Wang, Haili Bao, Keyan Sun, Yu Jiang, Baiyong Shen","doi":"10.1038/s41418-024-01423-1","DOIUrl":"https://doi.org/10.1038/s41418-024-01423-1","url":null,"abstract":"<p>CCCTC-binding factor (CTCF) regulates chromatin organization and is upregulated in pancreatic ductal adenocarcinoma (PDAC). We found that CTCF interacts with HNRNPU through a FLG-AS1-dependent mechanism, facilitating the recruitment of EP300 and activation of the m6A reader IGF2BP2. This activation promotes histone lactylation at the promoter region of IGF2BP2 stimulating the proliferation of PDAC cells. IGF2BP2 enhanced the mRNA stability of CSF1 and MYC. Moreover, FLG-AS1 directly interacts with HNRNPU to modulate alternative splicing of CSF1, thus promoting the M2 polarization of tumor associated macrophages (TAMs) in PDAC. The results indicated that CTCF-induced oncogenic modification of histone lactylation, m6A and alternative spilcing as multi-regulation modes of TAMs reprogramming in PDAC and identifies CTCF as a potential therapeutic target for PDAC immunotherapy whose inhibition M2 polarization through the IGF2BP2/CSF1/CSF1R axis. Curaxin combined with gemcitabine treatment has shown promising antitumor efficacy against PDAC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hang Yao, Yang Liu, Yueping Wang, You Xue, Siyuan Jiang, Xin Sun, Minjun Ji, Zhipeng Xu, Jianhua Ding, Gang Hu, Ming Lu
{"title":"Dural Tregs driven by astrocytic IL-33 mitigate depression through the EGFR signals in mPFC neurons","authors":"Hang Yao, Yang Liu, Yueping Wang, You Xue, Siyuan Jiang, Xin Sun, Minjun Ji, Zhipeng Xu, Jianhua Ding, Gang Hu, Ming Lu","doi":"10.1038/s41418-024-01421-3","DOIUrl":"https://doi.org/10.1038/s41418-024-01421-3","url":null,"abstract":"<p>The dura sinus-resident immune cells can influence the process of central neural system (CNS) diseases by communicating with central nerve cells. In clinical, Tregs are also frequently impaired in depression. However, the significance of this relationship remains unknown. In the present study, we found a significant increase in dural Treg populations in mouse models of depression, whereas depleting them by neutralizing antibodies injection could exacerbate depressive phenotypes. Through RNA sequencing, we identified that the antidepressant effects of dural Tregs are at least in part through the production of amphiregulin, increasing the expression of its receptor EGFR in medial prefrontal cortex (mPFC) pyramidal neurons. Furthermore, dural Tregs expressed high levels of ST2, and their expansion in depressed mice depended on astrocyte-derived IL33 secretion. Our study shows that dural Treg signaling can be enhanced by treatment with fluoxetine, highlighting that dural Tregs can be utilized as a potential target cell in major depressive disorder (MDD).</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"78 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Yang, Shi-yuan Wan, Qiu-yi Song, Yun-hao Xie, Jun Wan, Yi-hao Zhou, Zi-tong Zhang, Yu-shuo Xiao, Xi Li, Hong Chen, Xin-ran Liu, Li Xu, Hui-juan You, De-sheng Hu, Robert B. Petersen, Yong-hui Zhang, Ling Zheng, Yu Zhang, Kun Huang
{"title":"Angiopoietin-like protein 8 directs DNA damage responses towards apoptosis by stabilizing PARP1-DNA condensates","authors":"Jing Yang, Shi-yuan Wan, Qiu-yi Song, Yun-hao Xie, Jun Wan, Yi-hao Zhou, Zi-tong Zhang, Yu-shuo Xiao, Xi Li, Hong Chen, Xin-ran Liu, Li Xu, Hui-juan You, De-sheng Hu, Robert B. Petersen, Yong-hui Zhang, Ling Zheng, Yu Zhang, Kun Huang","doi":"10.1038/s41418-024-01422-2","DOIUrl":"https://doi.org/10.1038/s41418-024-01422-2","url":null,"abstract":"<p>Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of <i>ANGPTL8</i> is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"68 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C Tringali, B Lupo, F Cirillo, N Papini, L Anastasia, G Lamorte, P Colombi, R Bresciani, E Monti, G Tettamanti, B Venerando
{"title":"Retraction Note: Silencing of membrane-associated sialidase Neu3 diminishes apoptosis resistance and triggers megakaryocytic differentiation of chronic myeloid leukemic cells K562 through the increase of ganglioside GM3.","authors":"C Tringali, B Lupo, F Cirillo, N Papini, L Anastasia, G Lamorte, P Colombi, R Bresciani, E Monti, G Tettamanti, B Venerando","doi":"10.1038/s41418-024-01420-4","DOIUrl":"https://doi.org/10.1038/s41418-024-01420-4","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Le Zhang, Prashanthi Ramesh, Lidia Atencia Taboada, Rebecca Roessler, Dick W. Zijlmans, Michiel Vermeulen, Daisy I. Picavet-Havik, Nicole N. van der Wel, Frédéric M. Vaz, Jan Paul Medema
{"title":"UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer","authors":"Le Zhang, Prashanthi Ramesh, Lidia Atencia Taboada, Rebecca Roessler, Dick W. Zijlmans, Michiel Vermeulen, Daisy I. Picavet-Havik, Nicole N. van der Wel, Frédéric M. Vaz, Jan Paul Medema","doi":"10.1038/s41418-024-01418-y","DOIUrl":"https://doi.org/10.1038/s41418-024-01418-y","url":null,"abstract":"<p>Elevated de novo lipid synthesis is a remarkable adaptation of cancer cells that can be exploited for therapy. However, the role of altered lipid metabolism in the regulation of apoptosis is still poorly understood. Using thermal proteome profiling, we identified Manidipine-2HCl, targeting UGT8, a key enzyme in the synthesis of sulfatides. In agreement, lipidomic analysis indicated that sulfatides are strongly reduced in colorectal cancer cells upon treatment with Manidipine-2HCl. Intriguingly, this reduction led to severe mitochondrial swelling and a strong synergism with BH3 mimetics targeting BCL-XL, leading to the activation of mitochondria-dependent apoptosis. Mechanistically, Manidipine-2HCl enhanced mitochondrial BAX localization in a sulfatide-dependent fashion, facilitating its activation by BH3 mimetics. In conclusion, our data indicates that UGT8 mediated synthesis of sulfatides controls mitochondrial homeostasis and BAX localization, dictating apoptosis sensitivity of colorectal cancer cells.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"9 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Runkun Liu, Yixian Guo, Liang Wang, Guozhi Yin, Hang Tuo, Yifeng Zhu, Wei Yang, Qingguang Liu, Yufeng Wang
{"title":"A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment","authors":"Runkun Liu, Yixian Guo, Liang Wang, Guozhi Yin, Hang Tuo, Yifeng Zhu, Wei Yang, Qingguang Liu, Yufeng Wang","doi":"10.1038/s41418-024-01419-x","DOIUrl":"https://doi.org/10.1038/s41418-024-01419-x","url":null,"abstract":"<p>Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"110 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Annemarie Schwab, Mohammad Aarif Siddiqui, Vignesh Ramesh, Paradesi Naidu Gollavilli, Adriana Martinez Turtos, Sarah Søgaard Møller, Luisa Pinna, Jesper F. Havelund, Anne Mette A. Rømer, Pelin Gülizar Ersan, Beatrice Parma, Sabine Marschall, Katja Dettmer, Mohammed Alhusayan, Pietro Bertoglio, Giulia Querzoli, Dirk Mielenz, Ozgur Sahin, Nils J. Færgeman, Irfan A. Asangani, Paolo Ceppi
{"title":"Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer","authors":"Annemarie Schwab, Mohammad Aarif Siddiqui, Vignesh Ramesh, Paradesi Naidu Gollavilli, Adriana Martinez Turtos, Sarah Søgaard Møller, Luisa Pinna, Jesper F. Havelund, Anne Mette A. Rømer, Pelin Gülizar Ersan, Beatrice Parma, Sabine Marschall, Katja Dettmer, Mohammed Alhusayan, Pietro Bertoglio, Giulia Querzoli, Dirk Mielenz, Ozgur Sahin, Nils J. Færgeman, Irfan A. Asangani, Paolo Ceppi","doi":"10.1038/s41418-024-01415-1","DOIUrl":"https://doi.org/10.1038/s41418-024-01415-1","url":null,"abstract":"<p>Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KBTBD2 controls bone development by regulating IGF-1 signaling during osteoblast differentiation","authors":"Yu Xun, Yiao Jiang, Aysha Khalid, Zeru Tian, Jonathan Rios, Zhao Zhang","doi":"10.1038/s41418-024-01416-0","DOIUrl":"https://doi.org/10.1038/s41418-024-01416-0","url":null,"abstract":"<p>Kelch repeat and BTB (POZ) domain-containing 2 (KBTBD2) is known for its pivotal role in metabolic regulation, particularly in adipocytes. However, its significance in skeletal development has remained elusive. Here, we uncover a previously unrecognized function of KBTBD2 in bone formation. Conditional knockout of <i>Kbtbd2</i> in embryonic osteochondroprogenitor cells or osteoblasts results in impaired osteogenic differentiation, leading to reduced skeletal growth and mineralization. Mechanistically, the loss of KBTBD2 during osteogenesis leads to the accumulation of p85α, a regulatory subunit encoded by <i>phosphoinositide-3-kinase regulatory subunit 1</i> (<i>Pik3r1</i>), which exerts a potent inhibitory effect on insulin-like growth factor 1 (IGF-1)-induced activation of AKT. Moreover, our study extends the understanding of KBTBD2’s relevance beyond bone biology to the context of SHORT syndrome, a rare genetic disorder marked by short stature and various physical abnormalities. We demonstrate that p85α harboring the p.(Arg649Trp) mutation, most frequently found in SHORT syndrome patients, exhibits reduced binding to KBTBD2, leading to impaired IGF-1-mediated activation of AKT. These findings reveal that KBTBD2 is essential in bone formation via regulating the IGF-1 signaling pathway and suggest loss of KBTBD2-mediated regulation of p85α as a potential mechanism for SHORT syndrome.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"46 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ACBP/DBI neutralization for the experimental treatment of fatty liver disease.","authors":"Omar Motiño, Flavia Lambertucci, Adrien Joseph, Sylvère Durand, Gerasimos Anagnostopoulos, Sijing Li, Vincent Carbonnier, Uxía Nogueira-Recalde, Léa Montégut, Hui Chen, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Chiara Maiuri, Federico Pietrocola, Dominique Valla, Cédric Laouénan, Jean-François Gautier, Laurent Castera, Isabelle Martins, Guido Kroemer","doi":"10.1038/s41418-024-01410-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01410-6","url":null,"abstract":"<p><p>Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl<sub>4</sub>, and (iv) a combination of CCl<sub>4</sub> injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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