{"title":"Hormonal basis of brain fog in cancer treatment.","authors":"Yuan Pan, Jian Hu","doi":"10.1084/jem.20231942","DOIUrl":"https://doi.org/10.1084/jem.20231942","url":null,"abstract":"<p><p>The cognitive side effects of cancer treatment are common, but no targeted therapy exists yet to treat or prevent such neurological sequelae. We explore the role of hormones as mediators between cancer therapy and cognitive impairment, discussing potential future directions.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11009970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140866477","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":"Neutrophil IL-26 fuels autoinflammation.","authors":"Krisztina Futosi, Attila Mócsai","doi":"10.1084/jem.20240229","DOIUrl":"10.1084/jem.20240229","url":null,"abstract":"<p><p>Pustular psoriasis is an inflammatory skin disease with features of neutrophil-mediated sterile autoinflammation. In this issue of JEM, Baldo et al. (https://doi.org/10.1084/jem.20231464) show that this autoinflammation is driven by a vicious cycle through neutrophil-derived IL-26.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335850","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}
David Brenner, Kirsten Sieverding, Jahnavi Srinidhi, Susanne Zellner, Christopher Secker, Rüstem Yilmaz, Julia Dyckow, Shady Amr, Anna Ponomarenko, Esra Tunaboylu, Yasmin Douahem, Joana S Schlag, Lucía Rodríguez Martínez, Georg Kislinger, Cornelia Niemann, Karsten Nalbach, Wolfgang P Ruf, Jonathan Uhl, Johanna Hollenbeck, Lucas Schirmer, Alberto Catanese, Christian S Lobsiger, Karin M Danzer, Deniz Yilmazer-Hanke, Christian Münch, Philipp Koch, Axel Freischmidt, Martina Fetting, Christian Behrends, Rosanna Parlato, Jochen H Weishaupt
{"title":"A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.","authors":"David Brenner, Kirsten Sieverding, Jahnavi Srinidhi, Susanne Zellner, Christopher Secker, Rüstem Yilmaz, Julia Dyckow, Shady Amr, Anna Ponomarenko, Esra Tunaboylu, Yasmin Douahem, Joana S Schlag, Lucía Rodríguez Martínez, Georg Kislinger, Cornelia Niemann, Karsten Nalbach, Wolfgang P Ruf, Jonathan Uhl, Johanna Hollenbeck, Lucas Schirmer, Alberto Catanese, Christian S Lobsiger, Karin M Danzer, Deniz Yilmazer-Hanke, Christian Münch, Philipp Koch, Axel Freischmidt, Martina Fetting, Christian Behrends, Rosanna Parlato, Jochen H Weishaupt","doi":"10.1084/jem.20221190","DOIUrl":"10.1084/jem.20221190","url":null,"abstract":"<p><p>Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10959724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184613","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}
Lixia Wang, Gang Jin, Qiuping Zhou, Yanyan Liu, Xiaocui Zhao, Zhuoyang Li, Na Yin, Min Peng
{"title":"Induction of immortal-like and functional CAR T cells by defined factors.","authors":"Lixia Wang, Gang Jin, Qiuping Zhou, Yanyan Liu, Xiaocui Zhao, Zhuoyang Li, Na Yin, Min Peng","doi":"10.1084/jem.20232368","DOIUrl":"10.1084/jem.20232368","url":null,"abstract":"<p><p>Long-term antitumor efficacy of chimeric antigen receptor (CAR) T cells depends on their functional persistence in vivo. T cells with stem-like properties show better persistence, but factors conferring bona fide stemness to T cells remain to be determined. Here, we demonstrate the induction of CAR T cells into an immortal-like and functional state, termed TIF. The induction of CARTIF cells depends on the repression of two factors, BCOR and ZC3H12A, and requires antigen or CAR tonic signaling. Reprogrammed CARTIF cells possess almost infinite stemness, similar to induced pluripotent stem cells while retaining the functionality of mature T cells, resulting in superior antitumor effects. Following the elimination of target cells, CARTIF cells enter a metabolically dormant state, persisting in vivo with a saturable niche and providing memory protection. TIF represents a novel state of T cells with unprecedented stemness, which confers long-term functional persistence of CAR T cells in vivo and holds broad potential in T cell therapies.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10965394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287567","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}
Antoine Guérin, Marcela Moncada-Vélez, Katherine Jackson, Masato Ogishi, Jérémie Rosain, Mathieu Mancini, David Langlais, Andrea Nunez, Samantha Webster, Jesse Goyette, Taushif Khan, Nico Marr, Danielle T Avery, Geetha Rao, Tim Waterboer, Birgitta Michels, Esmeralda Neves, Cátia Iracema Morais, Jonathan London, Stéphanie Mestrallet, Pierre Quartier Dit Maire, Bénédicte Neven, Franck Rapaport, Yoann Seeleuthner, Atar Lev, Amos J Simon, Jorge Montoya, Ortal Barel, Julio Gómez-Rodríguez, Julio C Orrego, Anne-Sophie L'Honneur, Camille Soudée, Jessica Rojas, Alejandra C Velez, Irini Sereti, Benjamin Terrier, Nancy Marin, Luis F García, Laurent Abel, Stéphanie Boisson-Dupuis, Joel Reis, Antonio Marinho, Andrea Lisco, Emilia Faria, Christopher C Goodnow, Julia Vasconcelos, Vivien Béziat, Cindy S Ma, Raz Somech, Jean-Laurent Casanova, Jacinta Bustamante, Jose Luis Franco, Stuart G Tangye
{"title":"Helper T cell immunity in humans with inherited CD4 deficiency.","authors":"Antoine Guérin, Marcela Moncada-Vélez, Katherine Jackson, Masato Ogishi, Jérémie Rosain, Mathieu Mancini, David Langlais, Andrea Nunez, Samantha Webster, Jesse Goyette, Taushif Khan, Nico Marr, Danielle T Avery, Geetha Rao, Tim Waterboer, Birgitta Michels, Esmeralda Neves, Cátia Iracema Morais, Jonathan London, Stéphanie Mestrallet, Pierre Quartier Dit Maire, Bénédicte Neven, Franck Rapaport, Yoann Seeleuthner, Atar Lev, Amos J Simon, Jorge Montoya, Ortal Barel, Julio Gómez-Rodríguez, Julio C Orrego, Anne-Sophie L'Honneur, Camille Soudée, Jessica Rojas, Alejandra C Velez, Irini Sereti, Benjamin Terrier, Nancy Marin, Luis F García, Laurent Abel, Stéphanie Boisson-Dupuis, Joel Reis, Antonio Marinho, Andrea Lisco, Emilia Faria, Christopher C Goodnow, Julia Vasconcelos, Vivien Béziat, Cindy S Ma, Raz Somech, Jean-Laurent Casanova, Jacinta Bustamante, Jose Luis Franco, Stuart G Tangye","doi":"10.1084/jem.20231044","DOIUrl":"10.1084/jem.20231044","url":null,"abstract":"<p><p>CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αβ T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335849","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":"CD19-directed T cell-engaging antibodies for the treatment of autoimmune disease.","authors":"Jennifer S Michaelson, Patrick A Baeuerle","doi":"10.1084/jem.20240499","DOIUrl":"https://doi.org/10.1084/jem.20240499","url":null,"abstract":"<p><p>Jennifer S. Michaelson, Chief Scientific Officer at Cullinan Oncology, and Patrick A. Baeuerle, scientific advisor to Cullinan Oncology and honorary professor in immunology at Ludwig Maximilians University Munich, discuss the use of CD19-specific T cell-engaging antibody therapies (TCEs) as therapeutics for autoimmune diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11001598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861449","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}
Benjamin P Hurrell, Stephen Shen, Xin Li, Yoshihiro Sakano, Mohammad Hossein Kazemi, Christine Quach, Pedram Shafiei-Jahani, Kei Sakano, Homayon Ghiasi, Omid Akbari
{"title":"Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity.","authors":"Benjamin P Hurrell, Stephen Shen, Xin Li, Yoshihiro Sakano, Mohammad Hossein Kazemi, Christine Quach, Pedram Shafiei-Jahani, Kei Sakano, Homayon Ghiasi, Omid Akbari","doi":"10.1084/jem.20231835","DOIUrl":"10.1084/jem.20231835","url":null,"abstract":"<p><p>Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here, we report that Piezo1 channels repress group 2 innate lymphoid cell (ILC2)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we found that Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human-circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. Our studies define Piezo1 as a critical regulator of ILC2s, and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10965393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288287","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}
Janneke A Eken, Marvyn T Koning, Kristyna Kupcova, Julieta H Sepúlveda Yáñez, Ruben A L de Groen, Edwin Quinten, Jurriaan Janssen, Cornelis A M van Bergen, Joost S P Vermaat, Arjen Cleven, Marcelo A Navarrete, Bauke Ylstra, Daphne de Jong, Ondrej Havranek, Hassan Jumaa, Hendrik Veelken
{"title":"Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL.","authors":"Janneke A Eken, Marvyn T Koning, Kristyna Kupcova, Julieta H Sepúlveda Yáñez, Ruben A L de Groen, Edwin Quinten, Jurriaan Janssen, Cornelis A M van Bergen, Joost S P Vermaat, Arjen Cleven, Marcelo A Navarrete, Bauke Ylstra, Daphne de Jong, Ondrej Havranek, Hassan Jumaa, Hendrik Veelken","doi":"10.1084/jem.20230941","DOIUrl":"10.1084/jem.20230941","url":null,"abstract":"<p><p>Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10959178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174994","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}
Mohammad Arifuzzaman, Tae Hyung Won, Hiroshi Yano, Jazib Uddin, Elizabeth R Emanuel, Elin Hu, Wen Zhang, Ting-Ting Li, Wen-Bing Jin, Alex Grier, Sanchita Kashyap, Chun-Jun Guo, Frank C Schroeder, David Artis
{"title":"Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation.","authors":"Mohammad Arifuzzaman, Tae Hyung Won, Hiroshi Yano, Jazib Uddin, Elizabeth R Emanuel, Elin Hu, Wen Zhang, Ting-Ting Li, Wen-Bing Jin, Alex Grier, Sanchita Kashyap, Chun-Jun Guo, Frank C Schroeder, David Artis","doi":"10.1084/jem.20232148","DOIUrl":"10.1084/jem.20232148","url":null,"abstract":"<p><p>Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, the inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared with controls, implicating this diet-microbiota-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10955042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174995","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":"Immune drivers of physiological and pathological pain.","authors":"Aakanksha Jain, Sara Hakim, Clifford J Woolf","doi":"10.1084/jem.20221687","DOIUrl":"10.1084/jem.20221687","url":null,"abstract":"<p><p>Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon. Here, we discuss recent findings on how immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. We also discuss how both innate and adaptive immune cells, by releasing various ligands and mediators, contribute to the initiation, modulation, persistence, or resolution of various modalities of pain. Finally, we propose that the neuroimmune axis is an attractive target for pain treatment, but the challenges in objectively quantifying pain preclinically, variable sex differences in pain presentation, as well as adverse outcomes associated with immune system modulation, all need to be considered in the development of immunotherapies against pain.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11010323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853158","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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