Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold
{"title":"Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma","authors":"Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold","doi":"10.1126/sciimmunol.adp6667","DOIUrl":"https://doi.org/10.1126/sciimmunol.adp6667","url":null,"abstract":"The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"63 10 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258318","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}
Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals
{"title":"IL-4 induces CD22 expression to restrain the effector program of virtual memory T cells","authors":"Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals","doi":"","DOIUrl":"","url":null,"abstract":"<div >Parasitic helminths induce the production of interleukin-4 (IL-4), which causes the expansion of virtual memory CD8<sup>+</sup> T cells (T<sub>VM</sub> cells), a cell subset that contributes to the control of coinfection with intracellular pathogens. However, the mechanisms regulating IL-4–dependent T<sub>VM</sub> cell activation and expansion remain ill defined. Here, we used single-cell RNA sequencing of CD8<sup>+</sup> T cells to identify pathways that control IL-4–dependent T<sub>VM</sub> cell responses. Gene signature analysis of CD8<sup>+</sup> T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a selective surface marker of IL-4–induced T<sub>VM</sub> cells. CD22<sup>+</sup> T<sub>VM</sub> cells were enriched for interferon-γ and granzyme A and retained a diverse TCR repertoire while enriched in self-reactive CDR3 sequences. CD22 intrinsically regulated the IL-4–induced CD8<sup>+</sup> T cell effector program, resulting in reduced responsiveness of CD22<sup>+</sup> T<sub>VM</sub> cells and regulatory functions to infection and inflammation. Thus, helminth-induced IL-4 drives the expansion and activation of T<sub>VM</sub> cells that is counterinhibited by CD22.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363129","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}
Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska
{"title":"Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors","authors":"Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska","doi":"","DOIUrl":"","url":null,"abstract":"<div >Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP)<sub>418–426</sub> epitopes (B*35:01-NP<sub>418</sub>) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP<sub>418</sub> variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP<sub>418</sub><sup>+</sup>CD8<sup>+</sup> T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP<sub>418</sub><sup>+</sup>CD8<sup>+</sup> T cell responses. Six TCR–HLA-B*35:01/NP<sub>418</sub> crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP<sub>418</sub> epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP<sub>418</sub> epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn3805","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363115","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":"Afraid of needles? Try lotion: Engineering skin commensals for vaccination.","authors":"Daniel A Shapiro, Christopher A Hunter","doi":"10.1126/sciimmunol.adw3641","DOIUrl":"https://doi.org/10.1126/sciimmunol.adw3641","url":null,"abstract":"<p><p>Commensals induce germinal center-like structures in the skin that can be used for vaccination.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eadw3641"},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371033","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}
Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska
{"title":"Molecular determinants of cross-strain influenza A virus recognition by αβ T cell receptors","authors":"Sergio M. Quiñones-Parra, Stephanie Gras, Thi H. O. Nguyen, Carine Farenc, Christopher Szeto, Louise C. Rowntree, Priyanka Chaurasia, Sneha Sant, Adrianus C. M. Boon, Dhilshan Jayasinghe, Guus F. Rimmelzwaan, Jan Petersen, Peter C. Doherty, Adam P. Uldrich, Dene R. Littler, Jamie Rossjohn, Katherine Kedzierska","doi":"10.1126/sciimmunol.adn3805","DOIUrl":"https://doi.org/10.1126/sciimmunol.adn3805","url":null,"abstract":"Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP) <jats:sub>418–426</jats:sub> epitopes (B*35:01-NP <jats:sub>418</jats:sub> ) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 viruses, we identified functional broadly cross-reactive T cells universally recognizing NP <jats:sub>418</jats:sub> variants. Binding studies demonstrated that TCR cross-reactivity was concomitant with diminished antigen sensitivity. Primary human B*35:01/NP <jats:sub>418</jats:sub> <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cell lines displayed reduced cross-reactivity in the absence of CD8 coreceptor binding, validating the low avidity of cross-reactive B*35:01-NP <jats:sub>418</jats:sub> <jats:sup>+</jats:sup> CD8 <jats:sup>+</jats:sup> T cell responses. Six TCR–HLA-B*35:01/NP <jats:sub>418</jats:sub> crystal structures showed how cross-reactive TCRs recognized multiple B*35:01/NP <jats:sub>418</jats:sub> epitope variants. Specific TCR interactions were formed with invariant and conserved peptide-HLA features, thus remaining distal from highly varied positions of the NP <jats:sub>418</jats:sub> epitope. Our study defines molecular mechanisms associated with extensive TCR cross-reactivity toward naturally occurring viral variants highly relevant to universal protective immunity against influenza.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258317","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":"Afraid of needles? Try lotion: Engineering skin commensals for vaccination","authors":"Daniel A. Shapiro, Christopher A. Hunter","doi":"","DOIUrl":"","url":null,"abstract":"<div >Commensals induce germinal center–like structures in the skin that can be used for vaccination.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363137","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":"Is one lymphocyte's brake another lymphocyte's gas?","authors":"Thomas T Xu, Shiv Pillai","doi":"10.1126/sciimmunol.adw3656","DOIUrl":"https://doi.org/10.1126/sciimmunol.adw3656","url":null,"abstract":"<p><p>PD-1 contributes to memory B cell development and robust antibody responses through B cell extrinsic and intrinsic mechanisms.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eadw3656"},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371035","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":"Is one lymphocyte’s brake another lymphocyte’s gas?","authors":"Thomas T. Xu, Shiv Pillai","doi":"","DOIUrl":"","url":null,"abstract":"<div >PD-1 contributes to memory B cell development and robust antibody responses through B cell extrinsic and intrinsic mechanisms.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363117","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}
Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals
{"title":"IL-4 induces CD22 expression to restrain the effector program of virtual memory T cells","authors":"Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals","doi":"10.1126/sciimmunol.adk4841","DOIUrl":"https://doi.org/10.1126/sciimmunol.adk4841","url":null,"abstract":"Parasitic helminths induce the production of interleukin-4 (IL-4), which causes the expansion of virtual memory CD8 <jats:sup>+</jats:sup> T cells (T <jats:sub>VM</jats:sub> cells), a cell subset that contributes to the control of coinfection with intracellular pathogens. However, the mechanisms regulating IL-4–dependent T <jats:sub>VM</jats:sub> cell activation and expansion remain ill defined. Here, we used single-cell RNA sequencing of CD8 <jats:sup>+</jats:sup> T cells to identify pathways that control IL-4–dependent T <jats:sub>VM</jats:sub> cell responses. Gene signature analysis of CD8 <jats:sup>+</jats:sup> T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a selective surface marker of IL-4–induced T <jats:sub>VM</jats:sub> cells. CD22 <jats:sup>+</jats:sup> T <jats:sub>VM</jats:sub> cells were enriched for interferon-γ and granzyme A and retained a diverse TCR repertoire while enriched in self-reactive CDR3 sequences. CD22 intrinsically regulated the IL-4–induced CD8 <jats:sup>+</jats:sup> T cell effector program, resulting in reduced responsiveness of CD22 <jats:sup>+</jats:sup> T <jats:sub>VM</jats:sub> cells and regulatory functions to infection and inflammation. Thus, helminth-induced IL-4 drives the expansion and activation of T <jats:sub>VM</jats:sub> cells that is counterinhibited by CD22.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"23 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258319","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}
Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold
{"title":"Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma","authors":"Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold","doi":"","DOIUrl":"","url":null,"abstract":"<div >The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp6667","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363144","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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