An anthrax toxin variant with an improved activity in tumor targeting View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

Alexander N Wein, Diane E Peters, Zaheer Valivullah, Benjamin J Hoover, Aparna Tatineni, Qian Ma, Rasem Fattah, Thomas H Bugge, Stephen H Leppla, Shihui Liu

ABSTRACT

Anthrax lethal toxin (LT) is an A-B type toxin secreted by Bacillus anthracis, consisting of the cellular binding moiety, protective antigen (PA), and the catalytic moiety, lethal factor (LF). To target cells, PA binds to cell-surface receptors and is then proteolytically processed forming a LF-binding competent PA oligomer where each LF binding site is comprised of three subsites on two adjacent PA monomers. We previously generated PA-U2-R200A, a urokinase-activated PA variant with LF-binding subsite II residue Arg200 mutated to Ala, and PA-L1-I210A, a matrix metalloproteinase-activated PA variant with subsite III residue Ile210 mutated to Ala. PA-U2-R200A and PA-L1-I210A displayed reduced cytotoxicity when used singly. However, when combined, they formed LF-binding competent heterogeneous oligomers by intermolecular complementation, and achieved high specificity in tumor targeting. Nevertheless, each of these proteins, in particular PA-L1-I210A, retained residual LF-binding ability. In this work, we screened a library containing all possible amino acid substitutions for LF-binding site to find variants with activity strictly dependent upon intermolecular complementation. PA-I207R was identified as an excellent replacement for the original clockwise-side variant, PA-I210A. Consequently, the new combination of PA-L1-I207R and PA-U2-R200A showed potent anti-tumor activity and low toxicity, exceeding the performance of the original combination, and warranting further investigation. More... »

PAGES

16267

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/srep16267

DOI

http://dx.doi.org/10.1038/srep16267

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1010320728

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26584669


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/0601", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biochemistry and Cell Biology", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/06", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Biological Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Animals", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Antigens, Bacterial", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Bacterial Toxins", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Cell Line", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Cell Line, Tumor", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Cell Survival", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Dose-Response Relationship, Drug", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Female", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Macrophages", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Male", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mice, Inbred C57BL", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mutant Proteins", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mutation, Missense", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Neoplasms, Experimental", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Time Factors", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Tumor Burden", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Wein", 
        "givenName": "Alexander N", 
        "id": "sg:person.01336574177.41", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01336574177.41"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Tufts University", 
          "id": "https://www.grid.ac/institutes/grid.429997.8", 
          "name": [
            "Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.", 
            "Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Peters", 
        "givenName": "Diane E", 
        "id": "sg:person.0747500652.03", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0747500652.03"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Valivullah", 
        "givenName": "Zaheer", 
        "id": "sg:person.0772656663.04", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0772656663.04"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Hoover", 
        "givenName": "Benjamin J", 
        "id": "sg:person.01043070274.85", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01043070274.85"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Tatineni", 
        "givenName": "Aparna", 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Ma", 
        "givenName": "Qian", 
        "id": "sg:person.01155220463.20", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01155220463.20"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Fattah", 
        "givenName": "Rasem", 
        "id": "sg:person.01132255131.02", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01132255131.02"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Dental and Craniofacial Research", 
          "id": "https://www.grid.ac/institutes/grid.419633.a", 
          "name": [
            "Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Bugge", 
        "givenName": "Thomas H", 
        "id": "sg:person.014711620557.63", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014711620557.63"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Leppla", 
        "givenName": "Stephen H", 
        "id": "sg:person.010320513717.65", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010320513717.65"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "National Institute of Allergy and Infectious Diseases", 
          "id": "https://www.grid.ac/institutes/grid.419681.3", 
          "name": [
            "Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA."
          ], 
          "type": "Organization"
        }, 
        "familyName": "Liu", 
        "givenName": "Shihui", 
        "id": "sg:person.01137304423.20", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01137304423.20"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "https://doi.org/10.1172/jci6870", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1000641829"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nature12510", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1001404301", 
          "https://doi.org/10.1038/nature12510"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1146/annurev.cb.09.110193.002545", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003666291"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.062160399", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1003751392"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1371/journal.pone.0020532", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1004513365"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1371/journal.pone.0020532", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1004513365"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1074/jbc.m113.452110", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1009906378"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.0431098100", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011115393"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nbt1091", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011689957", 
          "https://doi.org/10.1038/nbt1091"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nbt1091", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011689957", 
          "https://doi.org/10.1038/nbt1091"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/cddis.2013.540", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1012467483", 
          "https://doi.org/10.1038/cddis.2013.540"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/n35101999", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1013838376", 
          "https://doi.org/10.1038/n35101999"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/n35101999", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1013838376", 
          "https://doi.org/10.1038/n35101999"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.molonc.2012.12.003", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1020709348"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1462-5822.2006.00845.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1021080713"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1074/jbc.m707419200", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1021868614"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.89.21.10277", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1026760846"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/1535-7163.mct-13-0358", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1029360370"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.pep.2011.05.016", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1029910194"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1371/journal.ppat.1000456", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1032958644"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1074/jbc.m011085200", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1033430327"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1158/1078-0432.ccr-11-0493", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1036647968"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nsmb.1923", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1037348056", 
          "https://doi.org/10.1038/nsmb.1923"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/nsmb.1923", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1037348056", 
          "https://doi.org/10.1038/nsmb.1923"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.tim.2014.02.012", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1040680464"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.052160199", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045836758"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1073/pnas.0236849100", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1046291438"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1046/j.1365-2672.1999.00893.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048438382"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1699-0463.1999.tb01534.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048953000"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1111/j.1699-0463.1999.tb01534.x", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048953000"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1016/j.taap.2014.06.010", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1052236846"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1172/jci17991", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1053460996"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/science.280.5364.734", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1062560949"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1126/scitranslmed.3006941", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1062688084"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://doi.org/10.1517/14712598.3.5.843", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1067589325"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1074730784", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1078951597", 
        "type": "CreativeWork"
      }, 
      {
        "id": "https://app.dimensions.ai/details/publication/pub.1082568781", 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2015-12", 
    "datePublishedReg": "2015-12-01", 
    "description": "Anthrax lethal toxin (LT) is an A-B type toxin secreted by Bacillus anthracis, consisting of the cellular binding moiety, protective antigen (PA), and the catalytic moiety, lethal factor (LF). To target cells, PA binds to cell-surface receptors and is then proteolytically processed forming a LF-binding competent PA oligomer where each LF binding site is comprised of three subsites on two adjacent PA monomers. We previously generated PA-U2-R200A, a urokinase-activated PA variant with LF-binding subsite II residue Arg200 mutated to Ala, and PA-L1-I210A, a matrix metalloproteinase-activated PA variant with subsite III residue Ile210 mutated to Ala. PA-U2-R200A and PA-L1-I210A displayed reduced cytotoxicity when used singly. However, when combined, they formed LF-binding competent heterogeneous oligomers by intermolecular complementation, and achieved high specificity in tumor targeting. Nevertheless, each of these proteins, in particular PA-L1-I210A, retained residual LF-binding ability. In this work, we screened a library containing all possible amino acid substitutions for LF-binding site to find variants with activity strictly dependent upon intermolecular complementation. PA-I207R was identified as an excellent replacement for the original clockwise-side variant, PA-I210A. Consequently, the new combination of PA-L1-I207R and PA-U2-R200A showed potent anti-tumor activity and low toxicity, exceeding the performance of the original combination, and warranting further investigation. ", 
    "genre": "research_article", 
    "id": "sg:pub.10.1038/srep16267", 
    "inLanguage": [
      "en"
    ], 
    "isAccessibleForFree": true, 
    "isFundedItemOf": [
      {
        "id": "sg:grant.2723156", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2724655", 
        "type": "MonetaryGrant"
      }, 
      {
        "id": "sg:grant.2683860", 
        "type": "MonetaryGrant"
      }
    ], 
    "isPartOf": [
      {
        "id": "sg:journal.1045337", 
        "issn": [
          "2045-2322"
        ], 
        "name": "Scientific Reports", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "1", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "5"
      }
    ], 
    "name": "An anthrax toxin variant with an improved activity in tumor targeting", 
    "pagination": "16267", 
    "productId": [
      {
        "name": "readcube_id", 
        "type": "PropertyValue", 
        "value": [
          "312b4b5017a7d556cc03b8bc2836e724792ae930175bb199ee89456591988ff7"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "26584669"
        ]
      }, 
      {
        "name": "nlm_unique_id", 
        "type": "PropertyValue", 
        "value": [
          "101563288"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1038/srep16267"
        ]
      }, 
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1010320728"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1038/srep16267", 
      "https://app.dimensions.ai/details/publication/pub.1010320728"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2019-04-10T18:56", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000001_0000000264/records_8678_00000422.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "http://www.nature.com/srep/2015/151120/srep16267/full/srep16267.html"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/srep16267'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/srep16267'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/srep16267'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/srep16267'


 

This table displays all metadata directly associated to this object as RDF triples.

308 TRIPLES      21 PREDICATES      78 URIs      37 LITERALS      25 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1038/srep16267 schema:about N2f1f5aebbdeb47bba508ee84138ddd1a
2 N397faa55a79c4584a4fb0635808ed601
3 N50c2bcc2e45543deba0f414600061305
4 N707bda476b9b465d89d1cf04c7fa9156
5 N7c0bbbd1d87d420c90917be317cb55bc
6 N8044003c7a774d0c851bc9d9fe788b7f
7 N826d55a8576945a1a5e96d1b46c831e3
8 N8620d4f97d7943e0b117521eadfbcda6
9 N889ecc7222234140a74185cf9ede1038
10 N9aa497a8b6c64fd5b4488878458b5dc4
11 Na71510d4252840d3a392fd1b231524d2
12 Na8c3879ef88542c38a718a323bc46d54
13 Nacdbfb393a2947f4bd47a78e6e32ea82
14 Nbff3f59532a7430d8e13962d9aa7afda
15 Ne5cc79222ea14737a9aa7cb4f7ce5c4d
16 Nfcfd185194834d73925d045ec0d6e6ed
17 anzsrc-for:06
18 anzsrc-for:0601
19 schema:author N455a6d313a844db0b291fb0eec1ea107
20 schema:citation sg:pub.10.1038/cddis.2013.540
21 sg:pub.10.1038/n35101999
22 sg:pub.10.1038/nature12510
23 sg:pub.10.1038/nbt1091
24 sg:pub.10.1038/nsmb.1923
25 https://app.dimensions.ai/details/publication/pub.1074730784
26 https://app.dimensions.ai/details/publication/pub.1078951597
27 https://app.dimensions.ai/details/publication/pub.1082568781
28 https://doi.org/10.1016/j.molonc.2012.12.003
29 https://doi.org/10.1016/j.pep.2011.05.016
30 https://doi.org/10.1016/j.taap.2014.06.010
31 https://doi.org/10.1016/j.tim.2014.02.012
32 https://doi.org/10.1046/j.1365-2672.1999.00893.x
33 https://doi.org/10.1073/pnas.0236849100
34 https://doi.org/10.1073/pnas.0431098100
35 https://doi.org/10.1073/pnas.052160199
36 https://doi.org/10.1073/pnas.062160399
37 https://doi.org/10.1073/pnas.89.21.10277
38 https://doi.org/10.1074/jbc.m011085200
39 https://doi.org/10.1074/jbc.m113.452110
40 https://doi.org/10.1074/jbc.m707419200
41 https://doi.org/10.1111/j.1462-5822.2006.00845.x
42 https://doi.org/10.1111/j.1699-0463.1999.tb01534.x
43 https://doi.org/10.1126/science.280.5364.734
44 https://doi.org/10.1126/scitranslmed.3006941
45 https://doi.org/10.1146/annurev.cb.09.110193.002545
46 https://doi.org/10.1158/1078-0432.ccr-11-0493
47 https://doi.org/10.1158/1535-7163.mct-13-0358
48 https://doi.org/10.1172/jci17991
49 https://doi.org/10.1172/jci6870
50 https://doi.org/10.1371/journal.pone.0020532
51 https://doi.org/10.1371/journal.ppat.1000456
52 https://doi.org/10.1517/14712598.3.5.843
53 schema:datePublished 2015-12
54 schema:datePublishedReg 2015-12-01
55 schema:description Anthrax lethal toxin (LT) is an A-B type toxin secreted by Bacillus anthracis, consisting of the cellular binding moiety, protective antigen (PA), and the catalytic moiety, lethal factor (LF). To target cells, PA binds to cell-surface receptors and is then proteolytically processed forming a LF-binding competent PA oligomer where each LF binding site is comprised of three subsites on two adjacent PA monomers. We previously generated PA-U2-R200A, a urokinase-activated PA variant with LF-binding subsite II residue Arg200 mutated to Ala, and PA-L1-I210A, a matrix metalloproteinase-activated PA variant with subsite III residue Ile210 mutated to Ala. PA-U2-R200A and PA-L1-I210A displayed reduced cytotoxicity when used singly. However, when combined, they formed LF-binding competent heterogeneous oligomers by intermolecular complementation, and achieved high specificity in tumor targeting. Nevertheless, each of these proteins, in particular PA-L1-I210A, retained residual LF-binding ability. In this work, we screened a library containing all possible amino acid substitutions for LF-binding site to find variants with activity strictly dependent upon intermolecular complementation. PA-I207R was identified as an excellent replacement for the original clockwise-side variant, PA-I210A. Consequently, the new combination of PA-L1-I207R and PA-U2-R200A showed potent anti-tumor activity and low toxicity, exceeding the performance of the original combination, and warranting further investigation.
56 schema:genre research_article
57 schema:inLanguage en
58 schema:isAccessibleForFree true
59 schema:isPartOf N29923bfc5551414ebd3896e6368e7797
60 N55e28517c6d1415ea6ecfa0155f07863
61 sg:journal.1045337
62 schema:name An anthrax toxin variant with an improved activity in tumor targeting
63 schema:pagination 16267
64 schema:productId N0a3a1356680d46aab1e0a9fb67b101ba
65 N1976bd212a034886a55d99ba1c235370
66 N6099e77ef5574379b6e86d5b4e6ed0cf
67 N6d86b010192a429bb7f33c71ffa50141
68 Na0751ac99dac406789128285d9ba1a00
69 schema:sameAs https://app.dimensions.ai/details/publication/pub.1010320728
70 https://doi.org/10.1038/srep16267
71 schema:sdDatePublished 2019-04-10T18:56
72 schema:sdLicense https://scigraph.springernature.com/explorer/license/
73 schema:sdPublisher Nb2766fc73adc4e068aeee52864c192c1
74 schema:url http://www.nature.com/srep/2015/151120/srep16267/full/srep16267.html
75 sgo:license sg:explorer/license/
76 sgo:sdDataset articles
77 rdf:type schema:ScholarlyArticle
78 N02e9ae44445c4d3ba5559c88d560fff5 rdf:first sg:person.010320513717.65
79 rdf:rest Nc3004dcba3b94e5b9821ed06ef517b4d
80 N0a3a1356680d46aab1e0a9fb67b101ba schema:name readcube_id
81 schema:value 312b4b5017a7d556cc03b8bc2836e724792ae930175bb199ee89456591988ff7
82 rdf:type schema:PropertyValue
83 N1976bd212a034886a55d99ba1c235370 schema:name pubmed_id
84 schema:value 26584669
85 rdf:type schema:PropertyValue
86 N1d6606b5e02e4cd889d56b071ff55e2c rdf:first sg:person.0747500652.03
87 rdf:rest N2c3d1493394649c0985ed1d4250edbeb
88 N29923bfc5551414ebd3896e6368e7797 schema:volumeNumber 5
89 rdf:type schema:PublicationVolume
90 N2c3d1493394649c0985ed1d4250edbeb rdf:first sg:person.0772656663.04
91 rdf:rest N560a7bf48338498480335e25642e9fd2
92 N2f1f5aebbdeb47bba508ee84138ddd1a schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
93 schema:name Macrophages
94 rdf:type schema:DefinedTerm
95 N31bd1a47b5484330801f0a6057c511c4 rdf:first sg:person.01132255131.02
96 rdf:rest Nf0fd3279219c4f78ab3cec6cd24a61cc
97 N3698461252f24fdb90350eac8b06467e rdf:first N708f9cc98ca9475481e9069e3b82adf1
98 rdf:rest Nea6112031cc0409ead12a1575d9baded
99 N397faa55a79c4584a4fb0635808ed601 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
100 schema:name Neoplasms, Experimental
101 rdf:type schema:DefinedTerm
102 N455a6d313a844db0b291fb0eec1ea107 rdf:first sg:person.01336574177.41
103 rdf:rest N1d6606b5e02e4cd889d56b071ff55e2c
104 N50c2bcc2e45543deba0f414600061305 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
105 schema:name Cell Survival
106 rdf:type schema:DefinedTerm
107 N55e28517c6d1415ea6ecfa0155f07863 schema:issueNumber 1
108 rdf:type schema:PublicationIssue
109 N560a7bf48338498480335e25642e9fd2 rdf:first sg:person.01043070274.85
110 rdf:rest N3698461252f24fdb90350eac8b06467e
111 N6099e77ef5574379b6e86d5b4e6ed0cf schema:name nlm_unique_id
112 schema:value 101563288
113 rdf:type schema:PropertyValue
114 N6d86b010192a429bb7f33c71ffa50141 schema:name dimensions_id
115 schema:value pub.1010320728
116 rdf:type schema:PropertyValue
117 N707bda476b9b465d89d1cf04c7fa9156 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
118 schema:name Mutant Proteins
119 rdf:type schema:DefinedTerm
120 N708f9cc98ca9475481e9069e3b82adf1 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
121 schema:familyName Tatineni
122 schema:givenName Aparna
123 rdf:type schema:Person
124 N7c0bbbd1d87d420c90917be317cb55bc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
125 schema:name Cell Line, Tumor
126 rdf:type schema:DefinedTerm
127 N8044003c7a774d0c851bc9d9fe788b7f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
128 schema:name Bacterial Toxins
129 rdf:type schema:DefinedTerm
130 N826d55a8576945a1a5e96d1b46c831e3 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
131 schema:name Male
132 rdf:type schema:DefinedTerm
133 N8620d4f97d7943e0b117521eadfbcda6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
134 schema:name Female
135 rdf:type schema:DefinedTerm
136 N889ecc7222234140a74185cf9ede1038 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
137 schema:name Cell Line
138 rdf:type schema:DefinedTerm
139 N9aa497a8b6c64fd5b4488878458b5dc4 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
140 schema:name Tumor Burden
141 rdf:type schema:DefinedTerm
142 Na0751ac99dac406789128285d9ba1a00 schema:name doi
143 schema:value 10.1038/srep16267
144 rdf:type schema:PropertyValue
145 Na71510d4252840d3a392fd1b231524d2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
146 schema:name Time Factors
147 rdf:type schema:DefinedTerm
148 Na8c3879ef88542c38a718a323bc46d54 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
149 schema:name Animals
150 rdf:type schema:DefinedTerm
151 Nacdbfb393a2947f4bd47a78e6e32ea82 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
152 schema:name Mutation, Missense
153 rdf:type schema:DefinedTerm
154 Nb2766fc73adc4e068aeee52864c192c1 schema:name Springer Nature - SN SciGraph project
155 rdf:type schema:Organization
156 Nbff3f59532a7430d8e13962d9aa7afda schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
157 schema:name Mice, Inbred C57BL
158 rdf:type schema:DefinedTerm
159 Nc3004dcba3b94e5b9821ed06ef517b4d rdf:first sg:person.01137304423.20
160 rdf:rest rdf:nil
161 Ne5cc79222ea14737a9aa7cb4f7ce5c4d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
162 schema:name Dose-Response Relationship, Drug
163 rdf:type schema:DefinedTerm
164 Nea6112031cc0409ead12a1575d9baded rdf:first sg:person.01155220463.20
165 rdf:rest N31bd1a47b5484330801f0a6057c511c4
166 Nf0fd3279219c4f78ab3cec6cd24a61cc rdf:first sg:person.014711620557.63
167 rdf:rest N02e9ae44445c4d3ba5559c88d560fff5
168 Nfcfd185194834d73925d045ec0d6e6ed schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
169 schema:name Antigens, Bacterial
170 rdf:type schema:DefinedTerm
171 anzsrc-for:06 schema:inDefinedTermSet anzsrc-for:
172 schema:name Biological Sciences
173 rdf:type schema:DefinedTerm
174 anzsrc-for:0601 schema:inDefinedTermSet anzsrc-for:
175 schema:name Biochemistry and Cell Biology
176 rdf:type schema:DefinedTerm
177 sg:grant.2683860 http://pending.schema.org/fundedItem sg:pub.10.1038/srep16267
178 rdf:type schema:MonetaryGrant
179 sg:grant.2723156 http://pending.schema.org/fundedItem sg:pub.10.1038/srep16267
180 rdf:type schema:MonetaryGrant
181 sg:grant.2724655 http://pending.schema.org/fundedItem sg:pub.10.1038/srep16267
182 rdf:type schema:MonetaryGrant
183 sg:journal.1045337 schema:issn 2045-2322
184 schema:name Scientific Reports
185 rdf:type schema:Periodical
186 sg:person.010320513717.65 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
187 schema:familyName Leppla
188 schema:givenName Stephen H
189 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.010320513717.65
190 rdf:type schema:Person
191 sg:person.01043070274.85 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
192 schema:familyName Hoover
193 schema:givenName Benjamin J
194 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01043070274.85
195 rdf:type schema:Person
196 sg:person.01132255131.02 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
197 schema:familyName Fattah
198 schema:givenName Rasem
199 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01132255131.02
200 rdf:type schema:Person
201 sg:person.01137304423.20 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
202 schema:familyName Liu
203 schema:givenName Shihui
204 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01137304423.20
205 rdf:type schema:Person
206 sg:person.01155220463.20 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
207 schema:familyName Ma
208 schema:givenName Qian
209 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01155220463.20
210 rdf:type schema:Person
211 sg:person.01336574177.41 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
212 schema:familyName Wein
213 schema:givenName Alexander N
214 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01336574177.41
215 rdf:type schema:Person
216 sg:person.014711620557.63 schema:affiliation https://www.grid.ac/institutes/grid.419633.a
217 schema:familyName Bugge
218 schema:givenName Thomas H
219 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.014711620557.63
220 rdf:type schema:Person
221 sg:person.0747500652.03 schema:affiliation https://www.grid.ac/institutes/grid.429997.8
222 schema:familyName Peters
223 schema:givenName Diane E
224 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0747500652.03
225 rdf:type schema:Person
226 sg:person.0772656663.04 schema:affiliation https://www.grid.ac/institutes/grid.419681.3
227 schema:familyName Valivullah
228 schema:givenName Zaheer
229 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0772656663.04
230 rdf:type schema:Person
231 sg:pub.10.1038/cddis.2013.540 schema:sameAs https://app.dimensions.ai/details/publication/pub.1012467483
232 https://doi.org/10.1038/cddis.2013.540
233 rdf:type schema:CreativeWork
234 sg:pub.10.1038/n35101999 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013838376
235 https://doi.org/10.1038/n35101999
236 rdf:type schema:CreativeWork
237 sg:pub.10.1038/nature12510 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001404301
238 https://doi.org/10.1038/nature12510
239 rdf:type schema:CreativeWork
240 sg:pub.10.1038/nbt1091 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011689957
241 https://doi.org/10.1038/nbt1091
242 rdf:type schema:CreativeWork
243 sg:pub.10.1038/nsmb.1923 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037348056
244 https://doi.org/10.1038/nsmb.1923
245 rdf:type schema:CreativeWork
246 https://app.dimensions.ai/details/publication/pub.1074730784 schema:CreativeWork
247 https://app.dimensions.ai/details/publication/pub.1078951597 schema:CreativeWork
248 https://app.dimensions.ai/details/publication/pub.1082568781 schema:CreativeWork
249 https://doi.org/10.1016/j.molonc.2012.12.003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020709348
250 rdf:type schema:CreativeWork
251 https://doi.org/10.1016/j.pep.2011.05.016 schema:sameAs https://app.dimensions.ai/details/publication/pub.1029910194
252 rdf:type schema:CreativeWork
253 https://doi.org/10.1016/j.taap.2014.06.010 schema:sameAs https://app.dimensions.ai/details/publication/pub.1052236846
254 rdf:type schema:CreativeWork
255 https://doi.org/10.1016/j.tim.2014.02.012 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040680464
256 rdf:type schema:CreativeWork
257 https://doi.org/10.1046/j.1365-2672.1999.00893.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1048438382
258 rdf:type schema:CreativeWork
259 https://doi.org/10.1073/pnas.0236849100 schema:sameAs https://app.dimensions.ai/details/publication/pub.1046291438
260 rdf:type schema:CreativeWork
261 https://doi.org/10.1073/pnas.0431098100 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011115393
262 rdf:type schema:CreativeWork
263 https://doi.org/10.1073/pnas.052160199 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045836758
264 rdf:type schema:CreativeWork
265 https://doi.org/10.1073/pnas.062160399 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003751392
266 rdf:type schema:CreativeWork
267 https://doi.org/10.1073/pnas.89.21.10277 schema:sameAs https://app.dimensions.ai/details/publication/pub.1026760846
268 rdf:type schema:CreativeWork
269 https://doi.org/10.1074/jbc.m011085200 schema:sameAs https://app.dimensions.ai/details/publication/pub.1033430327
270 rdf:type schema:CreativeWork
271 https://doi.org/10.1074/jbc.m113.452110 schema:sameAs https://app.dimensions.ai/details/publication/pub.1009906378
272 rdf:type schema:CreativeWork
273 https://doi.org/10.1074/jbc.m707419200 schema:sameAs https://app.dimensions.ai/details/publication/pub.1021868614
274 rdf:type schema:CreativeWork
275 https://doi.org/10.1111/j.1462-5822.2006.00845.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1021080713
276 rdf:type schema:CreativeWork
277 https://doi.org/10.1111/j.1699-0463.1999.tb01534.x schema:sameAs https://app.dimensions.ai/details/publication/pub.1048953000
278 rdf:type schema:CreativeWork
279 https://doi.org/10.1126/science.280.5364.734 schema:sameAs https://app.dimensions.ai/details/publication/pub.1062560949
280 rdf:type schema:CreativeWork
281 https://doi.org/10.1126/scitranslmed.3006941 schema:sameAs https://app.dimensions.ai/details/publication/pub.1062688084
282 rdf:type schema:CreativeWork
283 https://doi.org/10.1146/annurev.cb.09.110193.002545 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003666291
284 rdf:type schema:CreativeWork
285 https://doi.org/10.1158/1078-0432.ccr-11-0493 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036647968
286 rdf:type schema:CreativeWork
287 https://doi.org/10.1158/1535-7163.mct-13-0358 schema:sameAs https://app.dimensions.ai/details/publication/pub.1029360370
288 rdf:type schema:CreativeWork
289 https://doi.org/10.1172/jci17991 schema:sameAs https://app.dimensions.ai/details/publication/pub.1053460996
290 rdf:type schema:CreativeWork
291 https://doi.org/10.1172/jci6870 schema:sameAs https://app.dimensions.ai/details/publication/pub.1000641829
292 rdf:type schema:CreativeWork
293 https://doi.org/10.1371/journal.pone.0020532 schema:sameAs https://app.dimensions.ai/details/publication/pub.1004513365
294 rdf:type schema:CreativeWork
295 https://doi.org/10.1371/journal.ppat.1000456 schema:sameAs https://app.dimensions.ai/details/publication/pub.1032958644
296 rdf:type schema:CreativeWork
297 https://doi.org/10.1517/14712598.3.5.843 schema:sameAs https://app.dimensions.ai/details/publication/pub.1067589325
298 rdf:type schema:CreativeWork
299 https://www.grid.ac/institutes/grid.419633.a schema:alternateName National Institute of Dental and Craniofacial Research
300 schema:name Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
301 rdf:type schema:Organization
302 https://www.grid.ac/institutes/grid.419681.3 schema:alternateName National Institute of Allergy and Infectious Diseases
303 schema:name Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
304 rdf:type schema:Organization
305 https://www.grid.ac/institutes/grid.429997.8 schema:alternateName Tufts University
306 schema:name Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA.
307 Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
308 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...