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  1. Article ; Online: Soluble Collectin 11 (CL-11) Acts as an Immunosuppressive Molecule Potentially Used by Stem Cell-Derived Retinal Epithelial Cells to Modulate T Cell Response.

    Fanelli, Giorgia / Romano, Marco / Lombardi, Giovanna / Sacks, Steven H

    Cells

    2023  Volume 12, Issue 13

    Abstract: Retinal pigment epithelium (RPE) cell allotransplantation is seen as a possible solution to retinal diseases. However, the RPE-complement system triggered by the binding of collectin-11 (CL-11) is a potential barrier for RPE transplantation as the ... ...

    Abstract Retinal pigment epithelium (RPE) cell allotransplantation is seen as a possible solution to retinal diseases. However, the RPE-complement system triggered by the binding of collectin-11 (CL-11) is a potential barrier for RPE transplantation as the complement-mediated inflammatory response may promote T cell recognition. To address this, we investigated the role of CL-11 on T cell immuno-response. We confirmed that RPE cells up-regulated MHC class I and expressed MHC class II molecules in an inflammatory setting. Co-cultures of RPE cells with T cells led to the inhibition of T cell proliferation. We found that CL-11 was partially responsible for this effect as T cell binding of CL-11 inhibited T cell proliferation in association with the downregulation of CD28. We also found that the suppressive action of CL-11 was abrogated in the presence of the RGD peptide given to block the T cell binding of CL-11 by its collagen-like domain. Because RPE cells can bind and secrete CL-11 under stress conditions, we postulate that soluble CL-11 contributes to the immunosuppressive properties of RPE cells. The investigation of this dual biological activity of CL-11, namely as a trigger of the complement cascade and a modulator of T cell responses, may provide additional clues about the mechanisms that orchestrate the immunogenic properties of RPE cells.
    MeSH term(s) T-Lymphocytes/metabolism ; Retinal Pigment Epithelium/metabolism ; Cells, Cultured ; Stem Cells/metabolism ; Collectins/metabolism ; Epithelial Cells/metabolism
    Chemical Substances Collectins
    Language English
    Publishing date 2023-07-07
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12131805
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity.

    Romano, Marco / Fanelli, Giorgia / Albany, Caraugh Jane / Giganti, Giulio / Lombardi, Giovanna

    Frontiers in immunology

    2019  Volume 10, Page(s) 43

    Abstract: Regulatory T cells (Tregs) are important for the induction and maintenance of peripheral tolerance therefore, they are key in preventing excessive immune responses and autoimmunity. In the last decades, several reports have been focussed on understanding ...

    Abstract Regulatory T cells (Tregs) are important for the induction and maintenance of peripheral tolerance therefore, they are key in preventing excessive immune responses and autoimmunity. In the last decades, several reports have been focussed on understanding the biology of Tregs and their mechanisms of action. Preclinical studies have demonstrated the ability of Tregs to delay/prevent graft rejection and to control autoimmune responses following adoptive transfer
    MeSH term(s) Animals ; Autoimmunity ; Clinical Trials as Topic ; Humans ; Immune Tolerance ; Immunomodulation ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; Immunotherapy, Adoptive/trends ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Transplantation Tolerance/immunology ; Treatment Outcome
    Language English
    Publishing date 2019-01-31
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2019.00043
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Rationale for targeting complement in COVID-19.

    Polycarpou, Anastasia / Howard, Mark / Farrar, Conrad A / Greenlaw, Roseanna / Fanelli, Giorgia / Wallis, Russell / Klavinskis, Linda S / Sacks, Steven

    EMBO molecular medicine

    2020  Volume 12, Issue 8, Page(s) e12642

    Abstract: A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life- ... ...

    Abstract A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life-threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro-inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID-19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS-CoV-2 immunopathogenesis and the preceding literature on SARS-CoV-1 and MERS-CoV infection linking severe COVID-19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti-inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.
    MeSH term(s) Adult ; Alveolar Epithelial Cells/immunology ; Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/virology ; Angiotensin-Converting Enzyme 2 ; Animals ; Betacoronavirus/physiology ; COVID-19 ; Child ; Complement Activation/drug effects ; Complement C3b/antagonists & inhibitors ; Complement C3b/physiology ; Complement Inactivating Agents/pharmacology ; Complement Inactivating Agents/therapeutic use ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Cytokine Release Syndrome/drug therapy ; Cytokine Release Syndrome/etiology ; Cytokine Release Syndrome/immunology ; Glycosylation ; Humans ; Immunity, Innate ; Ligands ; Mice ; Models, Animal ; Models, Molecular ; Pandemics ; Pattern Recognition, Automated ; Peptidyl-Dipeptidase A/metabolism ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Protein Conformation ; Protein Processing, Post-Translational ; Receptors, Virus/metabolism ; Respiratory Distress Syndrome/etiology ; Respiratory Distress Syndrome/immunology ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; COVID-19 Drug Treatment
    Chemical Substances Complement Inactivating Agents ; Ligands ; Receptors, Virus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Complement C3b (80295-43-8) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Keywords covid19
    Language English
    Publishing date 2020-07-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.202012642
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Collectin-11 (CL-11) Is a Major Sentinel at Epithelial Surfaces and Key Pattern Recognition Molecule in Complement-Mediated Ischaemic Injury.

    Nauser, Christopher L / Howard, Mark C / Fanelli, Giorgia / Farrar, Conrad A / Sacks, Steven

    Frontiers in immunology

    2018  Volume 9, Page(s) 2023

    Abstract: The complement system is a dynamic subset of the innate immune system, playing roles in host defense, clearance of immune complexes and cell debris, and priming the adaptive immune response. Over the last 40 years our understanding of the complement ... ...

    Abstract The complement system is a dynamic subset of the innate immune system, playing roles in host defense, clearance of immune complexes and cell debris, and priming the adaptive immune response. Over the last 40 years our understanding of the complement system has evolved from identifying its presence and recognizing its role in the blood to now focusing on understanding the role of local complement synthesis in health and disease. In particular, the local synthesis of complement was found to have an involvement in mediating ischaemic injury, including following transplantation. Recent work on elucidating the triggers of local complement synthesis and activation in renal tissue have led to the finding that Collectin-11 (CL-11) engages with L-fucose at the site of ischaemic stress, namely at the surface of the proximal tubular epithelial cells. What remains unknown is the precise structure of the damage-associated ligand that participates in CL-11 binding and subsequent complement activation. In this article, we will discuss our hypothesis regarding the role of CL-11 as an integral tissue-based pattern recognition molecule which we postulate has a significant contributory role in complement-mediated ischaemic injury.
    MeSH term(s) Animals ; Collectins/metabolism ; Complement Activation ; Complement System Proteins/metabolism ; Epithelial Cells/physiology ; Humans ; Ischemia/immunology ; Kidney/metabolism ; Kidney/pathology ; Kidney Transplantation ; Receptors, Pattern Recognition/metabolism
    Chemical Substances Colec11 protein, human ; Collectins ; Receptors, Pattern Recognition ; Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2018-09-06
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.02023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation

    Romano, Marco / Elgueta, Raul / McCluskey, Daniel / Ortega-Prieto, Ana Maria / Stolarczyk, Emilie / Dazzi, Francesco / Lucendo-Villarin, Baltasar / Meseguer-Ripolles, Jose / Williams, James / Fanelli, Giorgia / Hay, David C / Watt, Fiona M / Lombardi, Giovanna

    Cells

    2021  Volume 11, Issue 1

    Abstract: Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, ... ...

    Abstract Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success. The aim of this study was to investigate
    MeSH term(s) Allogeneic Cells/cytology ; Cell Proliferation ; Hepatocytes/cytology ; Humans ; Immunologic Factors/metabolism ; Immunophenotyping ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Induced Pluripotent Stem Cells/cytology ; Lymphocyte Activation/immunology ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Tryptophan/deficiency
    Chemical Substances IDO1 protein, human ; Immunologic Factors ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Receptors, Antigen, T-Cell ; Tryptophan (8DUH1N11BX)
    Language English
    Publishing date 2021-12-22
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11010024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Mesenchymal stem cells inhibit T-cell function through conserved induction of cellular stress.

    Laing, Adam G / Fanelli, Giorgia / Ramirez-Valdez, Andrei / Lechler, Robert I / Lombardi, Giovanna / Sharpe, Paul T

    PloS one

    2019  Volume 14, Issue 3, Page(s) e0213170

    Abstract: The physiological role of mesenchymal stem cells (MSCs) is to provide a source of cells to replace mesenchymal-derivatives in stromal tissues with high cell turnover or following stromal tissue damage to elicit repair. Human MSCs have been shown to ... ...

    Abstract The physiological role of mesenchymal stem cells (MSCs) is to provide a source of cells to replace mesenchymal-derivatives in stromal tissues with high cell turnover or following stromal tissue damage to elicit repair. Human MSCs have been shown to suppress in vitro T-cell responses via a number of mechanisms including indoleamine 2,3-dioxygenase (IDO). This immunomodulatory capacity is likely to be related to their in vivo function in tissue repair where local, transient suppression of immune responses would benefit differentiation. Further understanding of the impact of locally modulated immune responses by MSCs is hampered by evidence that IDO is not produced or utilized by mouse MSCs. In this study, we demonstrate that IDO-mediated tryptophan starvation triggered by human MSCs inhibits T-cell activation and proliferation through induction of cellular stress. Significantly, we show that despite utilizing different means, immunomodulation of murine T-cells also involves cellular stress and thus is a common strategy of immunoregulation conserved between mouse and humans.
    MeSH term(s) Animals ; Bone Marrow Cells/cytology ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Culture Media, Conditioned/pharmacology ; Dental Pulp/cytology ; Endoplasmic Reticulum Stress ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/metabolism ; Lymphocyte Activation ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mice ; Nitric Oxide/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Tryptophan/deficiency ; Tryptophan/metabolism
    Chemical Substances Culture Media, Conditioned ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Nitric Oxide (31C4KY9ESH) ; Tryptophan (8DUH1N11BX) ; EIF2AK4 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-03-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0213170
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Rationale for targeting complement in COVID-19

    Polycarpou, Anastasia / Howard, Mark / Farrar, Conrad A / Greenlaw, Roseanna / Fanelli, Giorgia / Wallis, Russell / Klavinskis, Linda S / Sacks, Steven

    EMBO Mol Med

    Abstract: A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life- ... ...

    Abstract A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life-threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro-inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID-19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS-CoV-2 immunopathogenesis and the preceding literature on SARS-CoV-1 and MERS-CoV infection linking severe COVID-19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti-inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #607958
    Database COVID19

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  8. Article: Expanded Regulatory T Cells Induce Alternatively Activated Monocytes With a Reduced Capacity to Expand T Helper-17 Cells.

    Romano, Marco / Fanelli, Giorgia / Tan, Nicole / Nova-Lamperti, Estefania / McGregor, Reuben / Lechler, Robert I / Lombardi, Giovanna / Scottà, Cristiano

    Frontiers in immunology

    2018  Volume 9, Page(s) 1625

    Abstract: Regulatory T cells (Tregs) are essential in maintaining peripheral immunological tolerance by modulating several subsets of the immune system including monocytes. Under inflammatory conditions, monocytes migrate into the tissues, where they differentiate ...

    Abstract Regulatory T cells (Tregs) are essential in maintaining peripheral immunological tolerance by modulating several subsets of the immune system including monocytes. Under inflammatory conditions, monocytes migrate into the tissues, where they differentiate into dendritic cells or tissue-resident macrophages. As a result of their context-dependent plasticity, monocytes have been implicated in the development/progression of graft-vs-host disease (GvHD), autoimmune diseases and allograft rejection. In the last decade, Tregs have been exploited for their use in cell therapy with the aim to induce tolerance after solid organ transplantation and for the treatment of autoimmune diseases and GvHD. To date, safety and feasibility of Treg infusion has been demonstrated; however, many questions of how these cells induce tolerance have been raised and need to be answered. As monocytes constitute the major cellular component in inflamed tissues, we have developed an
    Language English
    Publishing date 2018-07-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.01625
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage.

    Tung, Sim Lai / Fanelli, Giorgia / Matthews, Robert Ian / Bazoer, Jordan / Letizia, Marilena / Vizcay-Barrena, Gema / Faruqu, Farid N / Philippeos, Christina / Hannen, Rosalind / Al-Jamal, Khuloud T / Lombardi, Giovanna / Smyth, Lesley Ann

    Frontiers in cell and developmental biology

    2020  Volume 8, Page(s) 317

    Abstract: Regulatory T cells (Tregs) are a subpopulation of ... ...

    Abstract Regulatory T cells (Tregs) are a subpopulation of CD4
    Language English
    Publishing date 2020-05-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2020.00317
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype.

    Fanelli, Giorgia / Romano, Marco / Nova-Lamperti, Estefania / Werner Sunderland, Mariana / Nerviani, Alessandra / Scottà, Cristiano / Bombardieri, Michele / Quezada, Sergio A / Sacks, Steven H / Noelle, Randolph J / Pitzalis, Costantino / Lechler, Robert I / Lombardi, Giovanna / Becker, Pablo D

    PLoS biology

    2021  Volume 19, Issue 4, Page(s) e3001199

    Abstract: Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory ... ...

    Abstract Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA-CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity.
    MeSH term(s) B7-H1 Antigen/metabolism ; B7-H1 Antigen/physiology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/physiology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/physiology ; Cell Transdifferentiation/genetics ; Cell Transdifferentiation/immunology ; Cohort Studies ; Humans ; Immune Tolerance/genetics ; Immune Tolerance/immunology ; Immunologic Memory/physiology ; Leukocyte Common Antigens/metabolism ; Phenotype ; Programmed Cell Death 1 Receptor/metabolism ; Programmed Cell Death 1 Receptor/physiology ; Signal Transduction/physiology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/physiology
    Chemical Substances B7-H1 Antigen ; CD274 protein, human ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Leukocyte Common Antigens (EC 3.1.3.48)
    Language English
    Publishing date 2021-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126776-5
    ISSN 1545-7885 ; 1544-9173
    ISSN (online) 1545-7885
    ISSN 1544-9173
    DOI 10.1371/journal.pbio.3001199
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