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A Network Integration Approach to Predict Conserved Regulators Related to Pathogenicity of Influenza and SARS-CoV Respiratory Viruses

Identifieur interne : 000483 ( Pmc/Checkpoint ); précédent : 000482; suivant : 000484

A Network Integration Approach to Predict Conserved Regulators Related to Pathogenicity of Influenza and SARS-CoV Respiratory Viruses

Auteurs : Hugh D. Mitchell [États-Unis] ; Amie J. Eisfeld [États-Unis] ; Amy C. Sims [États-Unis] ; Jason E. Mcdermott [États-Unis] ; Melissa M. Matzke [États-Unis] ; Bobbi-Jo M. Webb-Robertson [États-Unis] ; Susan C. Tilton [États-Unis] ; Nicolas Tchitchek [États-Unis] ; Laurence Josset [États-Unis] ; Chengjun Li [États-Unis] ; Amy L. Ellis [États-Unis] ; Jean H. Chang [États-Unis] ; Robert A. Heegel [États-Unis] ; Maria L. Luna [États-Unis] ; Athena A. Schepmoes [États-Unis] ; Anil K. Shukla [États-Unis] ; Thomas O. Metz [États-Unis] ; Gabriele Neumann [États-Unis] ; Arndt G. Benecke [États-Unis, France] ; Richard D. Smith [États-Unis] ; Ralph S. Baric [États-Unis] ; Yoshihiro Kawaoka [États-Unis, Japon] ; Michael G. Katze [États-Unis] ; Katrina M. Waters [États-Unis]

Source :

RBID : PMC:3723910

Abstract

Respiratory infections stemming from influenza viruses and the Severe Acute Respiratory Syndrome corona virus (SARS-CoV) represent a serious public health threat as emerging pandemics. Despite efforts to identify the critical interactions of these viruses with host machinery, the key regulatory events that lead to disease pathology remain poorly targeted with therapeutics. Here we implement an integrated network interrogation approach, in which proteome and transcriptome datasets from infection of both viruses in human lung epithelial cells are utilized to predict regulatory genes involved in the host response. We take advantage of a novel “crowd-based” approach to identify and combine ranking metrics that isolate genes/proteins likely related to the pathogenicity of SARS-CoV and influenza virus. Subsequently, a multivariate regression model is used to compare predicted lung epithelial regulatory influences with data derived from other respiratory virus infection models. We predicted a small set of regulatory factors with conserved behavior for consideration as important components of viral pathogenesis that might also serve as therapeutic targets for intervention. Our results demonstrate the utility of integrating diverse ‘omic datasets to predict and prioritize regulatory features conserved across multiple pathogen infection models.


Url:
DOI: 10.1371/journal.pone.0069374
PubMed: 23935999
PubMed Central: 3723910


Affiliations:


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PMC:3723910

Le document en format XML

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<name sortKey="Smith, Richard D" sort="Smith, Richard D" uniqKey="Smith R" first="Richard D." last="Smith">Richard D. Smith</name>
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<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
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<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
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<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
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<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
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<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
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<wicri:regionArea>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin</wicri:regionArea>
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<addr-line>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line>
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<addr-line>Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line>
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<wicri:regionArea>Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo</wicri:regionArea>
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<addr-line>ERATO Infection-Induced Host Responses Project, Saitama, Japan</addr-line>
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<name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
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<name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M." last="Waters">Katrina M. Waters</name>
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<title xml:lang="en" level="a" type="main">A Network Integration Approach to Predict Conserved Regulators Related to Pathogenicity of Influenza and SARS-CoV Respiratory Viruses</title>
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<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
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<name sortKey="Eisfeld, Amie J" sort="Eisfeld, Amie J" uniqKey="Eisfeld A" first="Amie J." last="Eisfeld">Amie J. Eisfeld</name>
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<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin</wicri:regionArea>
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<region type="state">Wisconsin</region>
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<name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name>
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</affiliation>
</author>
<author>
<name sortKey="Mcdermott, Jason E" sort="Mcdermott, Jason E" uniqKey="Mcdermott J" first="Jason E." last="Mcdermott">Jason E. Mcdermott</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Matzke, Melissa M" sort="Matzke, Melissa M" uniqKey="Matzke M" first="Melissa M." last="Matzke">Melissa M. Matzke</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Webb Robertson, Bobbi Jo M" sort="Webb Robertson, Bobbi Jo M" uniqKey="Webb Robertson B" first="Bobbi-Jo M." last="Webb-Robertson">Bobbi-Jo M. Webb-Robertson</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Tilton, Susan C" sort="Tilton, Susan C" uniqKey="Tilton S" first="Susan C." last="Tilton">Susan C. Tilton</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Tchitchek, Nicolas" sort="Tchitchek, Nicolas" uniqKey="Tchitchek N" first="Nicolas" last="Tchitchek">Nicolas Tchitchek</name>
<affiliation wicri:level="4">
<nlm:aff id="aff4">
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author>
<name sortKey="Josset, Laurence" sort="Josset, Laurence" uniqKey="Josset L" first="Laurence" last="Josset">Laurence Josset</name>
<affiliation wicri:level="4">
<nlm:aff id="aff4">
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author>
<name sortKey="Li, Chengjun" sort="Li, Chengjun" uniqKey="Li C" first="Chengjun" last="Li">Chengjun Li</name>
<affiliation wicri:level="2">
<nlm:aff id="aff2">
<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin</wicri:regionArea>
<placeName>
<region type="state">Wisconsin</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Ellis, Amy L" sort="Ellis, Amy L" uniqKey="Ellis A" first="Amy L." last="Ellis">Amy L. Ellis</name>
<affiliation wicri:level="2">
<nlm:aff id="aff2">
<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin</wicri:regionArea>
<placeName>
<region type="state">Wisconsin</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Chang, Jean H" sort="Chang, Jean H" uniqKey="Chang J" first="Jean H." last="Chang">Jean H. Chang</name>
<affiliation wicri:level="4">
<nlm:aff id="aff4">
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author>
<name sortKey="Heegel, Robert A" sort="Heegel, Robert A" uniqKey="Heegel R" first="Robert A." last="Heegel">Robert A. Heegel</name>
<affiliation wicri:level="2">
<nlm:aff id="aff6">
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Luna, Maria L" sort="Luna, Maria L" uniqKey="Luna M" first="Maria L." last="Luna">Maria L. Luna</name>
<affiliation wicri:level="2">
<nlm:aff id="aff6">
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Schepmoes, Athena A" sort="Schepmoes, Athena A" uniqKey="Schepmoes A" first="Athena A." last="Schepmoes">Athena A. Schepmoes</name>
<affiliation wicri:level="2">
<nlm:aff id="aff6">
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Shukla, Anil K" sort="Shukla, Anil K" uniqKey="Shukla A" first="Anil K." last="Shukla">Anil K. Shukla</name>
<affiliation wicri:level="2">
<nlm:aff id="aff6">
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Metz, Thomas O" sort="Metz, Thomas O" uniqKey="Metz T" first="Thomas O." last="Metz">Thomas O. Metz</name>
<affiliation wicri:level="2">
<nlm:aff id="aff6">
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Neumann, Gabriele" sort="Neumann, Gabriele" uniqKey="Neumann G" first="Gabriele" last="Neumann">Gabriele Neumann</name>
<affiliation wicri:level="2">
<nlm:aff id="aff2">
<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin</wicri:regionArea>
<placeName>
<region type="state">Wisconsin</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Benecke, Arndt G" sort="Benecke, Arndt G" uniqKey="Benecke A" first="Arndt G." last="Benecke">Arndt G. Benecke</name>
<affiliation wicri:level="4">
<nlm:aff id="aff4">
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff5">
<addr-line>Université Pierre et Marie Curie, Centre National de la Recherche Scientifique UMR7224, Paris, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Université Pierre et Marie Curie, Centre National de la Recherche Scientifique UMR7224, Paris</wicri:regionArea>
<placeName>
<region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Pierre-et-Marie-Curie</orgName>
</affiliation>
</author>
<author>
<name sortKey="Smith, Richard D" sort="Smith, Richard D" uniqKey="Smith R" first="Richard D." last="Smith">Richard D. Smith</name>
<affiliation wicri:level="2">
<nlm:aff id="aff6">
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<affiliation wicri:level="4">
<nlm:aff id="aff3">
<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author>
<name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
<affiliation wicri:level="2">
<nlm:aff id="aff2">
<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin</wicri:regionArea>
<placeName>
<region type="state">Wisconsin</region>
</placeName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff7">
<addr-line>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo</wicri:regionArea>
<placeName>
<settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff8">
<addr-line>Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo</wicri:regionArea>
<placeName>
<settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff9">
<addr-line>ERATO Infection-Induced Host Responses Project, Saitama, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>ERATO Infection-Induced Host Responses Project, Saitama</wicri:regionArea>
<wicri:noRegion>Saitama</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
<affiliation wicri:level="4">
<nlm:aff id="aff4">
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff10">
<addr-line>Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Washington National Primate Research Center, University of Washington, Seattle, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author>
<name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M." last="Waters">Katrina M. Waters</name>
<affiliation wicri:level="2">
<nlm:aff id="aff1">
<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea>
<placeName>
<region type="state">Washington (État)</region>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j">PLoS ONE</title>
<idno type="eISSN">1932-6203</idno>
<imprint>
<date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Respiratory infections stemming from influenza viruses and the Severe Acute Respiratory Syndrome corona virus (SARS-CoV) represent a serious public health threat as emerging pandemics. Despite efforts to identify the critical interactions of these viruses with host machinery, the key regulatory events that lead to disease pathology remain poorly targeted with therapeutics. Here we implement an integrated network interrogation approach, in which proteome and transcriptome datasets from infection of both viruses in human lung epithelial cells are utilized to predict regulatory genes involved in the host response. We take advantage of a novel “crowd-based” approach to identify and combine ranking metrics that isolate genes/proteins likely related to the pathogenicity of SARS-CoV and influenza virus. Subsequently, a multivariate regression model is used to compare predicted lung epithelial regulatory influences with data derived from other respiratory virus infection models. We predicted a small set of regulatory factors with conserved behavior for consideration as important components of viral pathogenesis that might also serve as therapeutic targets for intervention. Our results demonstrate the utility of integrating diverse ‘omic datasets to predict and prioritize regulatory features conserved across multiple pathogen infection models.</p>
</div>
</front>
<back>
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<name sortKey="Jaitly, N" uniqKey="Jaitly N">N Jaitly</name>
</author>
<author>
<name sortKey="Shaw, Jl" uniqKey="Shaw J">JL Shaw</name>
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<name sortKey="Adkins, Jn" uniqKey="Adkins J">JN Adkins</name>
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<name sortKey="Matzke, Mm" uniqKey="Matzke M">MM Matzke</name>
</author>
<author>
<name sortKey="Waters, Km" uniqKey="Waters K">KM Waters</name>
</author>
<author>
<name sortKey="Metz, To" uniqKey="Metz T">TO Metz</name>
</author>
<author>
<name sortKey="Jacobs, Jm" uniqKey="Jacobs J">JM Jacobs</name>
</author>
<author>
<name sortKey="Sims, Ac" uniqKey="Sims A">AC Sims</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Webb Robertson, Bj" uniqKey="Webb Robertson B">BJ Webb-Robertson</name>
</author>
<author>
<name sortKey="Matzke, Mm" uniqKey="Matzke M">MM Matzke</name>
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<author>
<name sortKey="Jacobs, Jm" uniqKey="Jacobs J">JM Jacobs</name>
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<name sortKey="Pounds, Jg" uniqKey="Pounds J">JG Pounds</name>
</author>
<author>
<name sortKey="Waters, Km" uniqKey="Waters K">KM Waters</name>
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</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Polpitiya, Ad" uniqKey="Polpitiya A">AD Polpitiya</name>
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<name sortKey="Qian, Wj" uniqKey="Qian W">WJ Qian</name>
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<name sortKey="Adkins, Jn" uniqKey="Adkins J">JN Adkins</name>
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</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Webb Robertson, Bj" uniqKey="Webb Robertson B">BJ Webb-Robertson</name>
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<author>
<name sortKey="Mccue, La" uniqKey="Mccue L">LA McCue</name>
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<name sortKey="Waters, Km" uniqKey="Waters K">KM Waters</name>
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<name sortKey="Matzke, Mm" uniqKey="Matzke M">MM Matzke</name>
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<author>
<name sortKey="Jacobs, Jm" uniqKey="Jacobs J">JM Jacobs</name>
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</analytic>
</biblStruct>
<biblStruct></biblStruct>
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<analytic>
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<name sortKey="Edgar, R" uniqKey="Edgar R">R Edgar</name>
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<name sortKey="Domrachev, M" uniqKey="Domrachev M">M Domrachev</name>
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<name sortKey="Lash, Ae" uniqKey="Lash A">AE Lash</name>
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<analytic>
<author>
<name sortKey="Zornetzer, Ga" uniqKey="Zornetzer G">GA Zornetzer</name>
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<name sortKey="Rosenzweig, E" uniqKey="Rosenzweig E">E Rosenzweig</name>
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<name sortKey="Korth, Mj" uniqKey="Korth M">MJ Korth</name>
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<name sortKey="Page, C" uniqKey="Page C">C Page</name>
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<name sortKey="Bakthavatsalam, B" uniqKey="Bakthavatsalam B">B Bakthavatsalam</name>
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</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group>
<journal-title>PLoS ONE</journal-title>
</journal-title-group>
<issn pub-type="epub">1932-6203</issn>
<publisher>
<publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">23935999</article-id>
<article-id pub-id-type="pmc">3723910</article-id>
<article-id pub-id-type="publisher-id">PONE-D-13-04628</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0069374</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2">
<subject>Biology</subject>
<subj-group>
<subject>Computational Biology</subject>
<subj-group>
<subject>Genomics</subject>
<subj-group>
<subject>Genome Expression Analysis</subject>
</subj-group>
</subj-group>
<subj-group>
<subject>Microarrays</subject>
<subject>Regulatory Networks</subject>
</subj-group>
</subj-group>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Gene Networks</subject>
</subj-group>
</subj-group>
<subj-group>
<subject>Microbiology</subject>
<subj-group>
<subject>Virology</subject>
<subj-group>
<subject>Animal Models of Infection</subject>
<subject>Emerging Viral Diseases</subject>
<subject>Viral Transmission and Infection</subject>
<subject>Virulence Factors and Mechanisms</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group>
<subject>Proteomics</subject>
<subj-group>
<subject>Proteomic Databases</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2">
<subject>Computer Science</subject>
<subj-group>
<subject>Computer Modeling</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>A Network Integration Approach to Predict Conserved Regulators Related to Pathogenicity of Influenza and SARS-CoV Respiratory Viruses</article-title>
<alt-title alt-title-type="running-head">Prediction of Respiratory Virus Regulators</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Mitchell</surname>
<given-names>Hugh D.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1">
<sup>*</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Eisfeld</surname>
<given-names>Amie J.</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Sims</surname>
<given-names>Amy C.</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>McDermott</surname>
<given-names>Jason E.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Matzke</surname>
<given-names>Melissa M.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Webb-Robertson</surname>
<given-names>Bobbi-Jo M.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tilton</surname>
<given-names>Susan C.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tchitchek</surname>
<given-names>Nicolas</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Josset</surname>
<given-names>Laurence</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Li</surname>
<given-names>Chengjun</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ellis</surname>
<given-names>Amy L.</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chang</surname>
<given-names>Jean H.</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Heegel</surname>
<given-names>Robert A.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Luna</surname>
<given-names>Maria L.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Schepmoes</surname>
<given-names>Athena A.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Shukla</surname>
<given-names>Anil K.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Metz</surname>
<given-names>Thomas O.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Neumann</surname>
<given-names>Gabriele</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Benecke</surname>
<given-names>Arndt G.</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff5">
<sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Smith</surname>
<given-names>Richard D.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kawaoka</surname>
<given-names>Yoshihiro</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff7">
<sup>7</sup>
</xref>
<xref ref-type="aff" rid="aff8">
<sup>8</sup>
</xref>
<xref ref-type="aff" rid="aff9">
<sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Katze</surname>
<given-names>Michael G.</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff10">
<sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Waters</surname>
<given-names>Katrina M.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<label>1</label>
<addr-line>Computational Sciences and Mathematics Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</aff>
<aff id="aff2">
<label>2</label>
<addr-line>Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America</addr-line>
</aff>
<aff id="aff3">
<label>3</label>
<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff4">
<label>4</label>
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</aff>
<aff id="aff5">
<label>5</label>
<addr-line>Université Pierre et Marie Curie, Centre National de la Recherche Scientifique UMR7224, Paris, France</addr-line>
</aff>
<aff id="aff6">
<label>6</label>
<addr-line>Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America</addr-line>
</aff>
<aff id="aff7">
<label>7</label>
<addr-line>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line>
</aff>
<aff id="aff8">
<label>8</label>
<addr-line>Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan</addr-line>
</aff>
<aff id="aff9">
<label>9</label>
<addr-line>ERATO Infection-Induced Host Responses Project, Saitama, Japan</addr-line>
</aff>
<aff id="aff10">
<label>10</label>
<addr-line>Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America</addr-line>
</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Pekosz</surname>
<given-names>Andrew</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">
<addr-line>Johns Hopkins University - Bloomberg School of Public Health, United States of America</addr-line>
</aff>
<author-notes>
<corresp id="cor1">* E-mail:
<email>hugh.mitchell@pnnl.gov</email>
</corresp>
<fn fn-type="COI-statement">
<p>
<bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con">
<p>Conceived and designed the experiments: HDM JEM TOM ACS AJE GN AGB RDS RSB YK MGK KMW. Performed the experiments: CL ALE RAH MLL AAS AKS ACS JHC TOM. Analyzed the data: HDM MMM BMW SCT NT LJ AGB. Wrote the paper: HDM AJE ACS GN AGB KMW.</p>
</fn>
</author-notes>
<pub-date pub-type="collection">
<year>2013</year>
</pub-date>
<pub-date pub-type="epub">
<day>25</day>
<month>7</month>
<year>2013</year>
</pub-date>
<volume>8</volume>
<issue>7</issue>
<elocation-id>e69374</elocation-id>
<history>
<date date-type="received">
<day>22</day>
<month>1</month>
<year>2013</year>
</date>
<date date-type="accepted">
<day>7</day>
<month>6</month>
<year>2013</year>
</date>
</history>
<permissions>
<copyright-year>2013</copyright-year>
<license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/">
<license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p>
</license>
</permissions>
<abstract>
<p>Respiratory infections stemming from influenza viruses and the Severe Acute Respiratory Syndrome corona virus (SARS-CoV) represent a serious public health threat as emerging pandemics. Despite efforts to identify the critical interactions of these viruses with host machinery, the key regulatory events that lead to disease pathology remain poorly targeted with therapeutics. Here we implement an integrated network interrogation approach, in which proteome and transcriptome datasets from infection of both viruses in human lung epithelial cells are utilized to predict regulatory genes involved in the host response. We take advantage of a novel “crowd-based” approach to identify and combine ranking metrics that isolate genes/proteins likely related to the pathogenicity of SARS-CoV and influenza virus. Subsequently, a multivariate regression model is used to compare predicted lung epithelial regulatory influences with data derived from other respiratory virus infection models. We predicted a small set of regulatory factors with conserved behavior for consideration as important components of viral pathogenesis that might also serve as therapeutic targets for intervention. Our results demonstrate the utility of integrating diverse ‘omic datasets to predict and prioritize regulatory features conserved across multiple pathogen infection models.</p>
</abstract>
<funding-group>
<funding-statement>This project has been funded with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Department of Health and Human Services, under Contract No. HHSN272200800060C, and with NIH Grant P41 GM103493. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts>
<page-count count="16"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations>
<list>
<country>
<li>France</li>
<li>Japon</li>
<li>États-Unis</li>
</country>
<region>
<li>Caroline du Nord</li>
<li>Région de Kantō</li>
<li>Washington (État)</li>
<li>Wisconsin</li>
<li>Île-de-France</li>
</region>
<settlement>
<li>Chapel Hill (Caroline du Nord)</li>
<li>Paris</li>
<li>Seattle</li>
<li>Tokyo</li>
</settlement>
<orgName>
<li>Université Pierre-et-Marie-Curie</li>
<li>Université de Caroline du Nord à Chapel Hill</li>
<li>Université de Tokyo</li>
<li>Université de Washington</li>
</orgName>
</list>
<tree>
<country name="États-Unis">
<region name="Washington (État)">
<name sortKey="Mitchell, Hugh D" sort="Mitchell, Hugh D" uniqKey="Mitchell H" first="Hugh D." last="Mitchell">Hugh D. Mitchell</name>
</region>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Benecke, Arndt G" sort="Benecke, Arndt G" uniqKey="Benecke A" first="Arndt G." last="Benecke">Arndt G. Benecke</name>
<name sortKey="Chang, Jean H" sort="Chang, Jean H" uniqKey="Chang J" first="Jean H." last="Chang">Jean H. Chang</name>
<name sortKey="Eisfeld, Amie J" sort="Eisfeld, Amie J" uniqKey="Eisfeld A" first="Amie J." last="Eisfeld">Amie J. Eisfeld</name>
<name sortKey="Ellis, Amy L" sort="Ellis, Amy L" uniqKey="Ellis A" first="Amy L." last="Ellis">Amy L. Ellis</name>
<name sortKey="Heegel, Robert A" sort="Heegel, Robert A" uniqKey="Heegel R" first="Robert A." last="Heegel">Robert A. Heegel</name>
<name sortKey="Josset, Laurence" sort="Josset, Laurence" uniqKey="Josset L" first="Laurence" last="Josset">Laurence Josset</name>
<name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
<name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
<name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
<name sortKey="Li, Chengjun" sort="Li, Chengjun" uniqKey="Li C" first="Chengjun" last="Li">Chengjun Li</name>
<name sortKey="Luna, Maria L" sort="Luna, Maria L" uniqKey="Luna M" first="Maria L." last="Luna">Maria L. Luna</name>
<name sortKey="Matzke, Melissa M" sort="Matzke, Melissa M" uniqKey="Matzke M" first="Melissa M." last="Matzke">Melissa M. Matzke</name>
<name sortKey="Mcdermott, Jason E" sort="Mcdermott, Jason E" uniqKey="Mcdermott J" first="Jason E." last="Mcdermott">Jason E. Mcdermott</name>
<name sortKey="Metz, Thomas O" sort="Metz, Thomas O" uniqKey="Metz T" first="Thomas O." last="Metz">Thomas O. Metz</name>
<name sortKey="Neumann, Gabriele" sort="Neumann, Gabriele" uniqKey="Neumann G" first="Gabriele" last="Neumann">Gabriele Neumann</name>
<name sortKey="Schepmoes, Athena A" sort="Schepmoes, Athena A" uniqKey="Schepmoes A" first="Athena A." last="Schepmoes">Athena A. Schepmoes</name>
<name sortKey="Shukla, Anil K" sort="Shukla, Anil K" uniqKey="Shukla A" first="Anil K." last="Shukla">Anil K. Shukla</name>
<name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name>
<name sortKey="Smith, Richard D" sort="Smith, Richard D" uniqKey="Smith R" first="Richard D." last="Smith">Richard D. Smith</name>
<name sortKey="Tchitchek, Nicolas" sort="Tchitchek, Nicolas" uniqKey="Tchitchek N" first="Nicolas" last="Tchitchek">Nicolas Tchitchek</name>
<name sortKey="Tilton, Susan C" sort="Tilton, Susan C" uniqKey="Tilton S" first="Susan C." last="Tilton">Susan C. Tilton</name>
<name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M." last="Waters">Katrina M. Waters</name>
<name sortKey="Webb Robertson, Bobbi Jo M" sort="Webb Robertson, Bobbi Jo M" uniqKey="Webb Robertson B" first="Bobbi-Jo M." last="Webb-Robertson">Bobbi-Jo M. Webb-Robertson</name>
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<name sortKey="Benecke, Arndt G" sort="Benecke, Arndt G" uniqKey="Benecke A" first="Arndt G." last="Benecke">Arndt G. Benecke</name>
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<name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
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<name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
<name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
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</record>

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