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3. The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity

Author

Santavanond, Jascinta P., Chiu, Yu-Hsin, Tixeira, Rochelle, Liu, Zonghan, Yap, Jeremy K. Y., Chen, Kaiwen W., Li, Chen-Lu, Lu, Yi-Ru, Roncero-Carol, Joan, Hoijman, Esteban, Rutter, Stephanie F., Shi, Bo, Ryan, Gemma F., Hodge, Amy L., Caruso, Sarah, Baxter, Amy A., Ozkocak, Dilara C., Johnson, Chad, Day, Zoe I., Mayfosh, Alyce J., Hulett, Mark D., Phan, Thanh K., Atkin-Smith, Georgia K., and Poon, Ivan K. H.

Published
2024
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8. Gasdermins as evolutionarily conserved executors of inflammation and cell death

Author

Chen, Kaiwen W. and Broz, Petr

Abstract

The gasdermins are a family of pore-forming proteins that have recently emerged as executors of pyroptosis, a lytic form of cell death that is induced by the innate immune system to eradicate infected or malignant cells. Mammalian gasdermins comprise a cytotoxic N-terminal domain, a flexible linker and a C-terminal repressor domain. Proteolytic cleavage in the linker releases the cytotoxic domain, thereby allowing it to form β-barrel membrane pores. Formation of gasdermin pores in the plasma membrane eventually leads to a loss of the electrochemical gradient, cell death and membrane rupture. Here we review recent work that has expanded our understanding of gasdermin biology and function in mammals by revealing their activation mechanism, their regulation and their roles in autoimmunity, host defence and cancer. We further highlight fungal and bacterial gasdermin pore formation pointing to a conserved mechanism of cell death induction.

Published
2024
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9. XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation

Author

Lawlor, Kate E., Feltham, Rebecca, Yabal, Monica, Conos, Stephanie A., Chen, Kaiwen W., Ziehe, Stephanie, Graß, Carina, Zhan, Yifan, Nguyen, Tan A., Hall, Cathrine, Vince, Angelina J., Chatfield, Simon M., D’Silva, Damian B., Pang, Kenneth C., Schroder, Kate, Silke, John, Vaux, David L., Jost, Philipp J., and Vince, James E.

Published
2017
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15. Extracorporeal Membrane Oxygenation–Dependent Fulminant Melioidosis From Caspase 4 Mutation Reversed by Interferon Gamma Therapy.

Author

Amali, Aseervatham Anusha, Ravikumar, Sharada, Chew, Wei Leong, Tan, Zhaohong, Sam, Qi Hui, Chen, Kaiwen W, Boucher, Dave, MacLaren, Graeme, and Chai, Louis Yi Ann

Subjects
GLYCOSYLATED hemoglobin, PNEUMONIA, BURKHOLDERIA infections, MELIOIDOSIS, GENETIC mutation, GENETICS, BURKHOLDERIA, INFLAMMATION, EXTRACORPOREAL membrane oxygenation, APOPTOSIS, INTERFERONS, BIOTHERAPY, TREATMENT effectiveness, CASPASES, IMMUNOTHERAPY
Abstract

We describe bedside-to-bench immunological and genetic elucidation of defective pyroptosis attributable to novel caspase 4 defect mediating pathogen-triggered inflammatory programmed cell death, in the setting of severe pneumonia and abscess-forming melioidosis in an overtly healthy host failing to clear Burkholderia pseudomallei infection, and how targeted adjunctive biological therapy led to a successful outcome. [ABSTRACT FROM AUTHOR]

Published
2024
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19. ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

Author

Robinson, Kim S., primary, Toh, Gee Ann, additional, Rozario, Pritisha, additional, Chua, Rae, additional, Bauernfried, Stefan, additional, Sun, Zijin, additional, Firdaus, Muhammad Jasrie, additional, Bayat, Shima, additional, Nadkarni, Rhea, additional, Poh, Zhi Sheng, additional, Tham, Khek Chian, additional, Harapas, Cassandra R., additional, Lim, Chrissie K., additional, Chu, Werncui, additional, Tay, Celest W. S., additional, Tan, Kiat Yi, additional, Zhao, Tianyun, additional, Bonnard, Carine, additional, Sobota, Radoslaw, additional, Connolly, John E., additional, Common, John, additional, Masters, Seth L., additional, Chen, Kaiwen W., additional, Ho, Lena, additional, Wu, Bin, additional, Hornung, Veit, additional, and Zhong, Franklin L., additional

Published
2022
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22. Human NLRP1 is activated by ZAKɑ-driven ribotoxic stress response

Author

ROBINSON, Kim S, primary, TOH, Gee Ann, additional, ROZARIO, Pritisha, additional, BAYAT, Shima, additional, SUN, Zijin, additional, BAUERNFRIED, Stefan, additional, NADKARNI, Rhea, additional, HARAPAS, Cassandra R, additional, LIM, Chrissie K, additional, CHU, Werncui, additional, TAN, Kiat Yi, additional, BONNARD, Carine, additional, SOBOTA, Radoslaw, additional, CONNOLLY, John E, additional, MASTERS, Seth L, additional, CHEN, Kaiwen W, additional, HO, Lena, additional, HORNUNG, Veit, additional, and Zhong, Franklin L, additional

Published
2022
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24. Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection

Author

Bjanes, Elisabet, primary, Sillas, Reyna Garcia, additional, Matsuda, Rina, additional, Demarco, Benjamin, additional, Fettrelet, Timothée, additional, DeLaney, Alexandra A., additional, Kornfeld, Opher S., additional, Lee, Bettina L., additional, Rodríguez López, Eric M., additional, Grubaugh, Daniel, additional, Wynosky-Dolfi, Meghan A., additional, Philip, Naomi H., additional, Krespan, Elise, additional, Tovar, Dorothy, additional, Joannas, Leonel, additional, Beiting, Daniel P., additional, Henao-Mejia, Jorge, additional, Schaefer, Brian C., additional, Chen, Kaiwen W., additional, Broz, Petr, additional, and Brodsky, Igor E., additional

Published
2021
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25. Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD

Author

Heilig, Rosalie, Dilucca, Marisa, Boucher, Dave, Chen, Kaiwen W, Hancz, Dora, Demarco, Benjamin, Shkarina, Kateryna, and Broz, Petr

Subjects
Inflammasomes, Animals, Apoptosis/genetics, Apoptosis Regulatory Proteins/metabolism, BH3 Interacting Domain Death Agonist Protein/deficiency, BH3 Interacting Domain Death Agonist Protein/genetics, Caspase 1/deficiency, Caspase 1/genetics, Cells, Cultured, Gene Editing, Gene Knockout Techniques, Inflammasomes/metabolism, Intracellular Signaling Peptides and Proteins/deficiency, Intracellular Signaling Peptides and Proteins/genetics, Macrophages/metabolism, Macrophages/pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria/metabolism, Mitochondrial Membranes/metabolism, Mitochondrial Proteins/metabolism, Necrosis/genetics, Necrosis/metabolism, Phosphate-Binding Proteins/deficiency, Phosphate-Binding Proteins/genetics, Pyroptosis/genetics, Signal Transduction/genetics, Transfection, Apoptosis, Mitochondrial Proteins, Necrosis, Pyroptosis, Research Articles, Macrophages, Caspase 1, Intracellular Signaling Peptides and Proteins, Phosphate-Binding Proteins, Mitochondria, Mitochondrial Membranes, biological phenomena, cell phenomena, and immunity, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, Signal Transduction, Research Article
Abstract

Caspase-1 activation in GSDMD-deficient cells induces a rapid form of caspase-3–dependent secondary necrosis that is licenced by caspase-1–induced Bid cleavage and the release of mitochondrial SMAC., Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1–driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1–driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1–dependent inflammatory disease.

Published
2020

27. RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signalling

Author

Chen, Kaiwen W., primary, Demarco, Benjamin, additional, Heilig, Rosalie, additional, Ramos, Saray P, additional, Grayczyk, James P, additional, Assenmacher, Charles-Antoine, additional, Radaelli, Enrico, additional, Joannas, Leonel D., additional, Henao-Mejia, Jorge, additional, Brodsky, Igor E, additional, and Broz, Petr, additional

Published
2021
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28. Caspase-8–dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality

Author

Demarco, Benjamin, primary, Grayczyk, James P., additional, Bjanes, Elisabet, additional, Le Roy, Didier, additional, Tonnus, Wulf, additional, Assenmacher, Charles-Antoine, additional, Radaelli, Enrico, additional, Fettrelet, Timothée, additional, Mack, Vanessa, additional, Linkermann, Andreas, additional, Roger, Thierry, additional, Brodsky, Igor E., additional, Chen, Kaiwen W., additional, and Broz, Petr, additional

Published
2020
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35. Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria

Author

Carlos Santos, José, Boucher, Dave, Schneider, Larisa Kapinos, Demarco, Benjamin, Dilucca, Marisa, Shkarina, Kateryna, Heilig, Rosalie, Chen, Kaiwen W., Lim, Roderick Y. H., and Broz, Petr

Abstract

The human non-canonical inflammasome controls caspase-4 activation and gasdermin-Ddependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds and oligomerizes caspase-4, the pathway is thought to proceed without dedicated LPS sensors or an activation platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for non-canonical inflammasome activation by cytosolic Salmonella or upon cytosolic delivery of LPS. GBP1 associates with the surface of cytosolic Salmonella seconds after bacterial escape from their vacuole, initiating the recruitment of GBP2-4 to assemble a GBP coat. The GBP coat then promotes the recruitment of caspase-4 to the bacterial surface and caspase activation, in absence of bacteriolysis. Mechanistically, GBP1 binds LPS with high affinity through electrostatic interactions. Our findings indicate that in human epithelial cells GBP1 acts as a cytosolic LPS sensor and assembles a platform for caspase-4 recruitment and activation at LPS-containing membranes as the first step of noncanonical inflammasome signaling. [ABSTRACT FROM AUTHOR]

Published
2020
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39. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity

Author

Boucher, Dave, primary, Monteleone, Mercedes, additional, Coll, Rebecca C., additional, Chen, Kaiwen W., additional, Ross, Connie M., additional, Teo, Jessica L., additional, Gomez, Guillermo A., additional, Holley, Caroline L., additional, Bierschenk, Damien, additional, Stacey, Katryn J., additional, Yap, Alpha S., additional, Bezbradica, Jelena S., additional, and Schroder, Kate, additional

Published
2018
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40. Pannexin‐1 promotes NLRP3 activation during apoptosis but is dispensable for canonical or noncanonical inflammasome activation.

Author

Chen, Kaiwen W., Demarco, Benjamin, and Broz, Petr

Subjects
PERFORINS, NLRP3 protein, INFLAMMASOMES, CELL death, MEMBRANE permeability (Biology), APOPTOSIS
Abstract

Inflammasomes are multimeric protein complex that assemble in the cytosol upon microbial infection or cellular stress. Upon activation, inflammasomes drive the maturation of proinflammatory cytokines, IL‐1β and IL‐18, and also activate the pore‐forming protein, gasdermin D to initiate a form of lytic cell death known as "pyroptosis". Pannexin‐1 is channel‐forming glycoprotein that promotes membrane permeability and ATP release during apoptosis; and was implicated in canonical NLRP3 or noncanonical inflammasome activation. Here, by utilizing three different pannexin‐1 channel inhibitors and two lines of Panx1–/– macrophages, we provide genetic and pharmacological evidence that pannexin‐1 is dispensable for canonical or noncanonical inflammasome activation. In contrast, we demonstrate that pannexin‐1 cleavage and resulting channel activity during apoptosis promotes NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

Published
2020
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43. A Novel Flow Cytometric Method To Assess Inflammasome Formation

Author

Sester, David P., primary, Thygesen, Sara J., additional, Sagulenko, Vitaliya, additional, Vajjhala, Parimala R., additional, Cridland, Jasmyn A., additional, Vitak, Nazarii, additional, Chen, Kaiwen W., additional, Osborne, Geoffrey W., additional, Schroder, Kate, additional, and Stacey, Katryn J., additional

Published
2015
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44. Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling

Author

Luo, Lin, primary, Wall, Adam A., additional, Yeo, Jeremy C., additional, Condon, Nicholas D., additional, Norwood, Suzanne J., additional, Schoenwaelder, Simone, additional, Chen, Kaiwen W., additional, Jackson, Shaun, additional, Jenkins, Brendan J., additional, Hartland, Elizabeth L., additional, Schroder, Kate, additional, Collins, Brett M., additional, Sweet, Matthew J., additional, and Stow, Jennifer L., additional

Published
2014
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46. XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation

Author

Philipp J. Jost, Angelina J. Vince, Stephanie A. Conos, Yifan Zhan, Kate Schroder, David L. Vaux, Simon M Chatfield, Monica Yabal, Carina Graß, Stephanie Ziehe, John Silke, Kaiwen W. Chen, Kate E. Lawlor, Ken C Pang, Tan A. Nguyen, James E Vince, Damian B D'Silva, Rebecca Feltham, Cathrine Hall, Lawlor, Kate E, Feltham, Rebecca, Yabal, Monica, Conos, Stephanie A, Chen, Kaiwen W, Ziehe, Stephanie, Graß, Carina, Zhan, Yifan, Nguyen, Tan A, Hall, Cathrine, Vince, Angelina J, Chatfield, Simon M, D'Silva, Damian B, Pang, Kenneth C, Schroder, Kate, Silke, John, Vaux, David L, Jost, Philipp J, and Vince, James E

Subjects
0301 basic medicine, Programmed cell death, TRAF2, proteasomal degradation, Necroptosis, Interleukin-1beta, necroptosis, Inhibitor of apoptosis, Caspase 8, RIPK3, General Biochemistry, Genetics and Molecular Biology, caspase-8, Inhibitor of Apoptosis Proteins, 03 medical and health sciences, Mice, XIAP, NLRP3, autoinflammatory disease, autoinflammatory conditions, Toll-like receptor, medicine, XIAP deficiency, Animals, XIAP Deficiency, lcsh:QH301-705.5, Mice, Knockout, Cell Death, Chemistry, Toll-Like Receptors, apoptosis, Inflammasome, interferon, TNF Receptor-Associated Factor 2, 3. Good health, cIAP1, TNFR2, 030104 developmental biology, cell death, interleukin (IL)-18, lcsh:Biology (General), Receptor-Interacting Protein Serine-Threonine Kinases, Myeloid Differentiation Factor 88, Proteolysis, Cancer research, medicine.drug
Abstract

X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. Refereed/Peer-reviewed

Published
2017

47. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity

Author

Dave Boucher, Rebecca C. Coll, Alpha S. Yap, Damien Bierschenk, Jelena S. Bezbradica, Kaiwen W. Chen, Guillermo A. Gomez, Mercedes Monteleone, Kate Schroder, Katryn J. Stacey, Connie M. Ross, Jessica L. Teo, Caroline L. Holley, Boucher, Dave, Monteleone, Mercedes, Coll, Rebecca C, Chen, Kaiwen W, Ross, Connie M, Teo, Jessica L, Gomez, Guillermo A, Holley, Caroline L, Bierschenk, Damien, Stacey, Katryn J, Yap, Alpha S, Bezbradica, Jelena S, and Schroder, Kate

Subjects
0301 basic medicine, Cell type, Inflammasomes, medicine.medical_treatment, animal diseases, viruses, Immunology, Kinetics, Cell, Interleukin-1beta, Caspase 1, caspase-1, inflammasome-dependent inflammatory responses, Article, law.invention, 03 medical and health sciences, Tetramer, law, medicine, otorhinolaryngologic diseases, Immunology and Allergy, inflammasomes, Research Articles, Protease, Chemistry, Macrophages, Inflammasome, Cell biology, 030104 developmental biology, medicine.anatomical_structure, nervous system, Recombinant DNA, sense organs, medicine.drug
Abstract

The inflammasome generates caspase-1 p20/p10, presumed to be the active protease. Boucher et al. demonstrate that the inflammasome contains an active caspase-1 species, p33/p10, and functions as a holoenzyme. Further caspase-1 self-processing generates and releases p20/p10 to terminate protease activity., Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses., Graphical Abstract

Published
2018

48. Analyzing Caspase-8-Dependent GSDMD Cleavage in Response to Yersinia Infection.

Author

Chan FHM and Chen KW

Subjects
Mice, Animals, Caspase 8 metabolism, Apoptosis Regulatory Proteins metabolism, Macrophages metabolism, Caspase 1 metabolism, Inflammasomes metabolism, Apoptosis physiology, Yersinia Infections metabolism
Abstract

Caspase-8 is best known to drive an immunologically silent form of cell death known as apoptosis. However, emerging studies revealed that upon pathogen inhibition of innate immune signalling, such as during Yersinia infection in myeloid cells, caspase-8 associates with RIPK1 and FADD to trigger a proinflammatory death-inducing complex. Under such conditions, caspase-8 cleaves the pore-forming protein gasdermin D (GSDMD) to trigger a lytic form of cell death, known as pyroptosis. Here, we describe our protocol to activate caspase-8-dependent GSDMD cleavage following Yersinia pseudotuberculosis infection in murine bone marrow-derived macrophages (BMDMs). Specifically, we describe protocols on harvesting and plating of BMDM, preparation of type 3 secretion system-inducing Yersinia, macrophage infection, lactate dehydrogenase (LDH) release assay, and Western blot analysis., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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49. Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD.

Author

Heilig R, Dilucca M, Boucher D, Chen KW, Hancz D, Demarco B, Shkarina K, and Broz P

Subjects
Animals, Apoptosis genetics, BH3 Interacting Domain Death Agonist Protein genetics, Caspase 1 genetics, Cells, Cultured, Gene Editing, Gene Knockout Techniques, Inflammasomes metabolism, Intracellular Signaling Peptides and Proteins genetics, Macrophages metabolism, Macrophages pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Membranes metabolism, Necrosis genetics, Necrosis metabolism, Phosphate-Binding Proteins genetics, Pyroptosis genetics, Transfection, Apoptosis Regulatory Proteins metabolism, BH3 Interacting Domain Death Agonist Protein deficiency, Caspase 1 deficiency, Intracellular Signaling Peptides and Proteins deficiency, Mitochondria metabolism, Mitochondrial Proteins metabolism, Phosphate-Binding Proteins deficiency, Signal Transduction genetics
Abstract

Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1-driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd -deficient cells is caused by a synergistic effect of rapid caspase-1-driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1-dependent inflammatory disease., (© 2020 Heilig et al.)

Published
2020
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