Snake Venom Metalloproteinases

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (31 August 2016) | Viewed by 113682

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Special Issue Editors

Department of Microbiology, University of Virginia, Charlottesville, VA, USA
Interests: snake venom metalloproteinases; SVMPs; ADAMs; disintegrins; pathophysiology/histology; hemorrhagic toxins; coagulopathy; disintegrin-like/cysteine-rich domains
Special Issues, Collections and Topics in MDPI journals
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
Interests: venom metalloproteinases and phospholipases A2; snake venom proteomics; mechanisms of tissue damage by snake venoms; preclinical efficacy of antivenoms; public health aspects of snakebites

Special Issue Information

Dear Colleagues,

This special edition of Toxins will cover recent developments in snake venom metalloproteinase structure, function and clinical implications. The special edition will include a historical retrospective of the discovery of SVMPs and early insights into their biochemical mechanisms and how they function in envenomation. The individual articles will review

  • SVMP Structure
  • Pathologies associated with SVMPs activities
  • Mechanism of action; Evolution and orthologs
  • SVMP processing and disintegrins
  • Potential clinical applications of SVMP scaffolds

Prof. Dr. Jay Fox
Prof. Dr. José María Gutiérrez
Guest Editor

Published Papers (13 papers)

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Editorial

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1173 KiB  
Editorial
Understanding the Snake Venom Metalloproteinases: An Interview with Jay Fox and José María Gutiérrez
by Jay W. Fox and José María Gutiérrez
Toxins 2017, 9(1), 33; https://doi.org/10.3390/toxins9010033 - 16 Jan 2017
Cited by 4 | Viewed by 6553
Abstract
Jay W. Fox and José María Gutiérrez recently finished editing a Special Issue on the topic “Snake Venom Metalloproteinases” in Toxins. The Special Issue covers a wide range of topics, including the molecular evolution and structure of snake venom metalloproteinases (SVMPs), the [...] Read more.
Jay W. Fox and José María Gutiérrez recently finished editing a Special Issue on the topic “Snake Venom Metalloproteinases” in Toxins. The Special Issue covers a wide range of topics, including the molecular evolution and structure of snake venom metalloproteinases (SVMPs), the mechanisms involved in the generation of diversity of SVMPs, the mechanism of action of SVMPs, and their role in the pathophysiology of envenomings, with implications for improving the therapy of envenomings. In this interview, we discussed with Jay W. Fox and José María Gutiérrez their research on the SVMPs and their perspectives on the future trends and challenges for studying snake venoms. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Research

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Article
Snake Venom Metalloproteinases and Their Peptide Inhibitors from Myanmar Russell’s Viper Venom
by Khin Than Yee, Morgan Pitts, Pumipat Tongyoo, Ponlapat Rojnuckarin and Mark C. Wilkinson
Toxins 2017, 9(1), 15; https://doi.org/10.3390/toxins9010015 - 30 Dec 2016
Cited by 30 | Viewed by 7601
Abstract
Russell’s viper bites are potentially fatal from severe bleeding, renal failure and capillary leakage. Snake venom metalloproteinases (SVMPs) are attributed to these effects. In addition to specific antivenom therapy, endogenous inhibitors from snakes are of interest in studies of new treatment modalities for [...] Read more.
Russell’s viper bites are potentially fatal from severe bleeding, renal failure and capillary leakage. Snake venom metalloproteinases (SVMPs) are attributed to these effects. In addition to specific antivenom therapy, endogenous inhibitors from snakes are of interest in studies of new treatment modalities for neutralization of the effect of toxins. Two major snake venom metalloproteinases (SVMPs): RVV-X and Daborhagin were purified from Myanmar Russell’s viper venom using a new purification strategy. Using the Next Generation Sequencing (NGS) approach to explore the Myanmar RV venom gland transcriptome, mRNAs of novel tripeptide SVMP inhibitors (SVMPIs) were discovered. Two novel endogenous tripeptides, pERW and pEKW were identified and isolated from the crude venom. Both purified SVMPs showed caseinolytic activity. Additionally, RVV-X displayed specific proteolytic activity towards gelatin and Daborhagin showed potent fibrinogenolytic activity. These activities were inhibited by metal chelators. Notably, the synthetic peptide inhibitors, pERW and pEKW, completely inhibit the gelatinolytic and fibrinogenolytic activities of respective SVMPs at 5 mM concentration. These complete inhibitory effects suggest that these tripeptides deserve further study for development of a therapeutic candidate for Russell’s viper envenomation. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Article
Viperid Envenomation Wound Exudate Contributes to Increased Vascular Permeability via a DAMPs/TLR-4 Mediated Pathway
by Alexandra Rucavado, Carolina A. Nicolau, Teresa Escalante, Junho Kim, Cristina Herrera, José María Gutiérrez and Jay W. Fox
Toxins 2016, 8(12), 349; https://doi.org/10.3390/toxins8120349 - 24 Nov 2016
Cited by 46 | Viewed by 5172
Abstract
Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate [...] Read more.
Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate itself has the ability to induce increase in vascular permeability in the skin of mice. Proteomics analysis of exudate revealed the presence of cytokines and chemokines, together with abundant damage associated molecular pattern molecules (DAMPs) resulting from both proteolysis of extracellular matrix and cellular lysis. Moreover, significant differences in the amounts of cytokines/chemokines and DAMPs were detected between exudates collected 1 h and 24 h after envenomation, thus highlighting a complex temporal dynamic in the composition of exudate. Pretreatment of mice with Eritoran, an antagonist of Toll-like receptor 4 (TLR4), significantly reduced the exudate-induced increase in vascular permeability, thus suggesting that DAMPs might be acting through this receptor. It is hypothesized that an “Envenomation-induced DAMPs cycle of tissue damage” may be operating in viperid snakebite envenomation through which venom-induced tissue damage generates a variety of DAMPs which may further expand tissue alterations. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Article
Novel Catalytically-Inactive PII Metalloproteinases from a Viperid Snake Venom with Substitutions in the Canonical Zinc-Binding Motif
by Erika Camacho, Libia Sanz, Teresa Escalante, Alicia Pérez, Fabián Villalta, Bruno Lomonte, Ana Gisele C. Neves-Ferreira, Andrés Feoli, Juan J. Calvete, José María Gutiérrez and Alexandra Rucavado
Toxins 2016, 8(10), 292; https://doi.org/10.3390/toxins8100292 - 12 Oct 2016
Cited by 10 | Viewed by 5117
Abstract
Snake venom metalloproteinases (SVMPs) play key biological roles in prey immobilization and digestion. The majority of these activities depend on the hydrolysis of relevant protein substrates in the tissues. Hereby, we describe several isoforms and a cDNA clone sequence, corresponding to PII SVMP [...] Read more.
Snake venom metalloproteinases (SVMPs) play key biological roles in prey immobilization and digestion. The majority of these activities depend on the hydrolysis of relevant protein substrates in the tissues. Hereby, we describe several isoforms and a cDNA clone sequence, corresponding to PII SVMP homologues from the venom of the Central American pit viper Bothriechis lateralis, which have modifications in the residues of the canonical sequence of the zinc-binding motif HEXXHXXGXXH. As a consequence, the proteolytic activity of the isolated proteins was undetectable when tested on azocasein and gelatin. These PII isoforms comprise metalloproteinase and disintegrin domains in the mature protein, thus belonging to the subclass PIIb of SVMPs. PII SVMP homologues were devoid of hemorrhagic and in vitro coagulant activities, effects attributed to the enzymatic activity of SVMPs, but induced a mild edema. One of the isoforms presents the characteristic RGD sequence in the disintegrin domain and inhibits ADP- and collagen-induced platelet aggregation. Catalytically-inactive SVMP homologues may have been hitherto missed in the characterization of snake venoms. The presence of such enzymatically-inactive homologues in snake venoms and their possible toxic and adaptive roles deserve further investigation. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Article
Insights into the Evolution of a Snake Venom Multi-Gene Family from the Genomic Organization of Echis ocellatus SVMP Genes
by Libia Sanz and Juan J. Calvete
Toxins 2016, 8(7), 216; https://doi.org/10.3390/toxins8070216 - 12 Jul 2016
Cited by 14 | Viewed by 6316
Abstract
The molecular events underlying the evolution of the Snake Venom Metalloproteinase (SVMP) family from an A Disintegrin And Metalloproteinase (ADAM) ancestor remain poorly understood. Comparative genomics may provide decisive information to reconstruct the evolutionary history of this multi-locus toxin family. Here, we report [...] Read more.
The molecular events underlying the evolution of the Snake Venom Metalloproteinase (SVMP) family from an A Disintegrin And Metalloproteinase (ADAM) ancestor remain poorly understood. Comparative genomics may provide decisive information to reconstruct the evolutionary history of this multi-locus toxin family. Here, we report the genomic organization of Echis ocellatus genes encoding SVMPs from the PII and PI classes. Comparisons between them and between these genes and the genomic structures of Anolis carolinensis ADAM28 and E. ocellatus PIII-SVMP EOC00089 suggest that insertions and deletions of intronic regions played key roles along the evolutionary pathway that shaped the current diversity within the multi-locus SVMP gene family. In particular, our data suggest that emergence of EOC00028-like PI-SVMP from an ancestral PII(e/d)-type SVMP involved splicing site mutations that abolished both the 3′ splice AG acceptor site of intron 12* and the 5′ splice GT donor site of intron 13*, and resulted in the intronization of exon 13* and the consequent destruction of the structural integrity of the PII-SVMP characteristic disintegrin domain. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review

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Review
Snake Genome Sequencing: Results and Future Prospects
by Harald M. I. Kerkkamp, R. Manjunatha Kini, Alexey S. Pospelov, Freek J. Vonk, Christiaan V. Henkel and Michael K. Richardson
Toxins 2016, 8(12), 360; https://doi.org/10.3390/toxins8120360 - 01 Dec 2016
Cited by 26 | Viewed by 7528
Abstract
Snake genome sequencing is in its infancy—very much behind the progress made in sequencing the genomes of humans, model organisms and pathogens relevant to biomedical research, and agricultural species. We provide here an overview of some of the snake genome projects in progress, [...] Read more.
Snake genome sequencing is in its infancy—very much behind the progress made in sequencing the genomes of humans, model organisms and pathogens relevant to biomedical research, and agricultural species. We provide here an overview of some of the snake genome projects in progress, and discuss the biological findings, with special emphasis on toxinology, from the small number of draft snake genomes already published. We discuss the future of snake genomics, pointing out that new sequencing technologies will help overcome the problem of repetitive sequences in assembling snake genomes. Genome sequences are also likely to be valuable in examining the clustering of toxin genes on the chromosomes, in designing recombinant antivenoms and in studying the epigenetic regulation of toxin gene expression. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
A Comprehensive View of the Structural and Functional Alterations of Extracellular Matrix by Snake Venom Metalloproteinases (SVMPs): Novel Perspectives on the Pathophysiology of Envenoming
by José María Gutiérrez, Teresa Escalante, Alexandra Rucavado, Cristina Herrera and Jay W. Fox
Toxins 2016, 8(10), 304; https://doi.org/10.3390/toxins8100304 - 22 Oct 2016
Cited by 69 | Viewed by 8733
Abstract
Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics [...] Read more.
Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics analysis of exudates collected in the vicinity of tissues affected by SVMPs has provided novel and exciting information on SVMP-induced ECM alterations. The presence of fragments of an array of ECM proteins, including those of the basement membrane, has revealed a complex pathological scenario caused by the direct action of SVMPs. In addition, the time-course analysis of these changes has underscored that degradation of some fibrillar collagens is likely to depend on the action of endogenous proteinases, such as matrix metalloproteinases (MMPs), synthesized as a consequence of the inflammatory process. The action of SVMPs on the ECM also results in the release of ECM-derived biologically-active peptides that exert diverse actions in the tissue, some of which might be associated with reparative events or with further tissue damage. The study of the effects of SVMP on the ECM is an open field of research which may bring a renewed understanding of snake venom-induced pathology. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
Metalloproteases Affecting Blood Coagulation, Fibrinolysis and Platelet Aggregation from Snake Venoms: Definition and Nomenclature of Interaction Sites
by R. Manjunatha Kini and Cho Yeow Koh
Toxins 2016, 8(10), 284; https://doi.org/10.3390/toxins8100284 - 29 Sep 2016
Cited by 107 | Viewed by 14405
Abstract
Snake venom metalloproteases, in addition to their contribution to the digestion of the prey, affect various physiological functions by cleaving specific proteins. They exhibit their activities through activation of zymogens of coagulation factors, and precursors of integrins or receptors. Based on their structure–function [...] Read more.
Snake venom metalloproteases, in addition to their contribution to the digestion of the prey, affect various physiological functions by cleaving specific proteins. They exhibit their activities through activation of zymogens of coagulation factors, and precursors of integrins or receptors. Based on their structure–function relationships and mechanism of action, we have defined classification and nomenclature of functional sites of proteases. These metalloproteases are useful as research tools and in diagnosis and treatment of various thrombotic and hemostatic conditions. They also contribute to our understanding of molecular details in the activation of specific factors involved in coagulation, platelet aggregation and matrix biology. This review provides a ready reference for metalloproteases that interfere in blood coagulation, fibrinolysis and platelet aggregation. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges
by Viviane A. Bastos, Francisco Gomes-Neto, Jonas Perales, Ana Gisele C. Neves-Ferreira and Richard H. Valente
Toxins 2016, 8(9), 250; https://doi.org/10.3390/toxins8090250 - 26 Aug 2016
Cited by 25 | Viewed by 8452
Abstract
The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera [...] Read more.
The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using “gold-standard” methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
Processing of Snake Venom Metalloproteinases: Generation of Toxin Diversity and Enzyme Inactivation
by Ana M. Moura-da-Silva, Michelle T. Almeida, José A. Portes-Junior, Carolina A. Nicolau, Francisco Gomes-Neto and Richard H. Valente
Toxins 2016, 8(6), 183; https://doi.org/10.3390/toxins8060183 - 09 Jun 2016
Cited by 38 | Viewed by 7762
Abstract
Snake venom metalloproteinases (SVMPs) are abundant in the venoms of vipers and rattlesnakes, playing important roles for the snake adaptation to different environments, and are related to most of the pathological effects of these venoms in human victims. The effectiveness of SVMPs is [...] Read more.
Snake venom metalloproteinases (SVMPs) are abundant in the venoms of vipers and rattlesnakes, playing important roles for the snake adaptation to different environments, and are related to most of the pathological effects of these venoms in human victims. The effectiveness of SVMPs is greatly due to their functional diversity, targeting important physiological proteins or receptors in different tissues and in the coagulation system. Functional diversity is often related to the genetic diversification of the snake venom. In this review, we discuss some published evidence that posit that processing and post-translational modifications are great contributors for the generation of functional diversity and for maintaining latency or inactivation of enzymes belonging to this relevant family of venom toxins. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview
by Soichi Takeda
Toxins 2016, 8(5), 155; https://doi.org/10.3390/toxins8050155 - 17 May 2016
Cited by 114 | Viewed by 11807
Abstract
A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major [...] Read more.
A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major components in most viper venoms. SVMPs are primarily responsible for hemorrhagic activity and may also interfere with the hemostatic system in envenomed animals. SVMPs are phylogenetically most closely related to ADAMs and, together with ADAMs and related ADAM with thrombospondin motifs (ADAMTS) family proteinases, constitute adamalysins/reprolysins or the M12B clan (MEROPS database) of metalloproteinases. Although the catalytic domain structure is topologically similar to that of other metalloproteinases such as matrix metalloproteinases, the M12B proteinases have a modular structure with multiple non-catalytic ancillary domains that are not found in other proteinases. Notably, crystallographic studies revealed that, in addition to the conserved metalloproteinase domain, M12B members share a hallmark cysteine-rich domain designated as the “ADAM_CR” domain. Despite their name, ADAMTSs lack disintegrin-like structures and instead comprise two ADAM_CR domains. This review highlights the current state of our knowledge on the three-dimensional structures of M12B proteinases, focusing on their unique domains that may collaboratively participate in directing these proteinases to specific substrates. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions
by Nives Giebeler and Paola Zigrino
Toxins 2016, 8(4), 122; https://doi.org/10.3390/toxins8040122 - 23 Apr 2016
Cited by 116 | Viewed by 10726
Abstract
Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and [...] Read more.
Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Review
Hemorrhage Caused by Snake Venom Metalloproteinases: A Journey of Discovery and Understanding
by José María Gutiérrez, Teresa Escalante, Alexandra Rucavado and Cristina Herrera
Toxins 2016, 8(4), 93; https://doi.org/10.3390/toxins8040093 - 26 Mar 2016
Cited by 135 | Viewed by 11022
Abstract
The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main [...] Read more.
The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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