Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress
Identifieur interne : 000C42 ( Pmc/Checkpoint ); précédent : 000C41; suivant : 000C43Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress
Auteurs : Raymond H. Kim [Canada] ; Patrice D. Smith [Canada] ; Hossein Aleyasin [Canada] ; Shawn Hayley [Canada] ; Matthew P. Mount [Canada] ; Scott Pownall [Canada] ; Andrew Wakeham [Canada] ; Annick J. You-Ten [Canada] ; Suneil K. Kalia [Canada] ; Patrick Horne [Canada] ; David Westaway [Canada] ; Andres M. Lozano [Canada] ; Hymie Anisman [Canada] ; David S. Park [Canada] ; Tak W. Mak [Canada]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2005.
Abstract
Mutations of the
Url:
DOI: 10.1073/pnas.0501282102
PubMed: 15784737
PubMed Central: 555037
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress</title>
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<author><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name>
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<author><name sortKey="Pownall, Scott" sort="Pownall, Scott" uniqKey="Pownall S" first="Scott" last="Pownall">Scott Pownall</name>
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<author><name sortKey="Wakeham, Andrew" sort="Wakeham, Andrew" uniqKey="Wakeham A" first="Andrew" last="Wakeham">Andrew Wakeham</name>
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<author><name sortKey="You Ten, Annick J" sort="You Ten, Annick J" uniqKey="You Ten A" first="Annick J." last="You-Ten">Annick J. You-Ten</name>
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<author><name sortKey="Kalia, Suneil K" sort="Kalia, Suneil K" uniqKey="Kalia S" first="Suneil K." last="Kalia">Suneil K. Kalia</name>
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<author><name sortKey="Horne, Patrick" sort="Horne, Patrick" uniqKey="Horne P" first="Patrick" last="Horne">Patrick Horne</name>
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<author><name sortKey="Westaway, David" sort="Westaway, David" uniqKey="Westaway D" first="David" last="Westaway">David Westaway</name>
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<orgName type="university">Université de Toronto</orgName>
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</placeName>
</affiliation>
</author>
<author><name sortKey="Lozano, Andres M" sort="Lozano, Andres M" uniqKey="Lozano A" first="Andres M." last="Lozano">Andres M. Lozano</name>
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<author><name sortKey="Anisman, Hymie" sort="Anisman, Hymie" uniqKey="Anisman H" first="Hymie" last="Anisman">Hymie Anisman</name>
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<placeName><settlement type="city">Toronto</settlement>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress</title>
<author><name sortKey="Kim, Raymond H" sort="Kim, Raymond H" uniqKey="Kim R" first="Raymond H." last="Kim">Raymond H. Kim</name>
<affiliation wicri:level="4"><nlm:aff id="N0x98a91e0.0x9eb80d0">Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1;</nlm:aff>
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<placeName><settlement type="city">Toronto</settlement>
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</placeName>
</affiliation>
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<author><name sortKey="Smith, Patrice D" sort="Smith, Patrice D" uniqKey="Smith P" first="Patrice D." last="Smith">Patrice D. Smith</name>
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<author><name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name>
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<author><name sortKey="Hayley, Shawn" sort="Hayley, Shawn" uniqKey="Hayley S" first="Shawn" last="Hayley">Shawn Hayley</name>
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<wicri:noRegion>ON</wicri:noRegion>
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<author><name sortKey="Mount, Matthew P" sort="Mount, Matthew P" uniqKey="Mount M" first="Matthew P." last="Mount">Matthew P. Mount</name>
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<author><name sortKey="Pownall, Scott" sort="Pownall, Scott" uniqKey="Pownall S" first="Scott" last="Pownall">Scott Pownall</name>
<affiliation wicri:level="1"><nlm:aff id="N0x98a91e0.0x9eb80d0">enGene Incorporated, Vancouver, BC, Canada V6T 1Z3;</nlm:aff>
<country>Canada</country>
<wicri:regionArea>enGene Incorporated, Vancouver, BC</wicri:regionArea>
<wicri:noRegion>BC</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wakeham, Andrew" sort="Wakeham, Andrew" uniqKey="Wakeham A" first="Andrew" last="Wakeham">Andrew Wakeham</name>
<affiliation wicri:level="4"><nlm:aff id="N0x98a91e0.0x9eb80d0">Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1;</nlm:aff>
<country>Canada</country>
<wicri:regionArea>Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="You Ten, Annick J" sort="You Ten, Annick J" uniqKey="You Ten A" first="Annick J." last="You-Ten">Annick J. You-Ten</name>
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<country>Canada</country>
<wicri:regionArea>Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kalia, Suneil K" sort="Kalia, Suneil K" uniqKey="Kalia S" first="Suneil K." last="Kalia">Suneil K. Kalia</name>
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<country>Canada</country>
<wicri:regionArea>Division of Applied and Interventional Research, Toronto Western Hospital Research Institute, Toronto, ON</wicri:regionArea>
<wicri:noRegion>ON</wicri:noRegion>
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</author>
<author><name sortKey="Horne, Patrick" sort="Horne, Patrick" uniqKey="Horne P" first="Patrick" last="Horne">Patrick Horne</name>
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<wicri:regionArea>Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Westaway, David" sort="Westaway, David" uniqKey="Westaway D" first="David" last="Westaway">David Westaway</name>
<affiliation wicri:level="4"><nlm:aff id="N0x98a91e0.0x9eb80d0">Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2</nlm:aff>
<country>Canada</country>
<wicri:regionArea>Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lozano, Andres M" sort="Lozano, Andres M" uniqKey="Lozano A" first="Andres M." last="Lozano">Andres M. Lozano</name>
<affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="N0x98a91e0.0x9eb80d0">Division of Applied and Interventional Research, Toronto Western Hospital Research Institute, Toronto, ON, Canada M5T 2S8</nlm:aff>
<country>Canada</country>
<wicri:regionArea>Division of Applied and Interventional Research, Toronto Western Hospital Research Institute, Toronto, ON</wicri:regionArea>
<wicri:noRegion>ON</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Anisman, Hymie" sort="Anisman, Hymie" uniqKey="Anisman H" first="Hymie" last="Anisman">Hymie Anisman</name>
<affiliation wicri:level="1"><nlm:aff id="N0x98a91e0.0x9eb80d0">Institute for Neuroscience, Carleton University, Ottawa, ON, Canada K1H 6N5;</nlm:aff>
<country>Canada</country>
<wicri:regionArea>Institute for Neuroscience, Carleton University, Ottawa, ON</wicri:regionArea>
<wicri:noRegion>ON</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name>
<affiliation wicri:level="1"><nlm:aff id="N0x98a91e0.0x9eb80d0">Neuroscience Research Group, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff>
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<wicri:regionArea>Neuroscience Research Group, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON</wicri:regionArea>
<wicri:noRegion>ON</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Mak, Tak W" sort="Mak, Tak W" uniqKey="Mak T" first="Tak W." last="Mak">Tak W. Mak</name>
<affiliation wicri:level="4"><nlm:aff id="N0x98a91e0.0x9eb80d0">Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1;</nlm:aff>
<country>Canada</country>
<wicri:regionArea>Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
<idno type="ISSN">0027-8424</idno>
<idno type="eISSN">1091-6490</idno>
<imprint><date when="2005">2005</date>
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<front><div type="abstract" xml:lang="en"><p>Mutations of the <italic>DJ-1</italic>
(PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the <italic>substantia nigra</italic>
and fiber densities and dopamine levels in the striatum were normal. However, DJ-1–/– mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1–/–embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1–/– mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress <italic>in vitro</italic>
. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id>
<journal-id journal-id-type="publisher-id">pnas</journal-id>
<journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title>
<issn pub-type="ppub">0027-8424</issn>
<issn pub-type="epub">1091-6490</issn>
<publisher><publisher-name>National Academy of Sciences</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">15784737</article-id>
<article-id pub-id-type="pmc">555037</article-id>
<article-id pub-id-type="publisher-id">01025215</article-id>
<article-id pub-id-type="doi">10.1073/pnas.0501282102</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject>
<subj-group><subject>Neuroscience</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Raymond H.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">*</xref>
<xref ref-type="fn" rid="fn1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smith</surname>
<given-names>Patrice D.</given-names>
</name>
<xref ref-type="fn" rid="fn1">†</xref>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Aleyasin</surname>
<given-names>Hossein</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hayley</surname>
<given-names>Shawn</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">§</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mount</surname>
<given-names>Matthew P.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pownall</surname>
<given-names>Scott</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">¶</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wakeham</surname>
<given-names>Andrew</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>You-Ten</surname>
<given-names>Annick J.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kalia</surname>
<given-names>Suneil K.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">∥</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Horne</surname>
<given-names>Patrick</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">**</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Westaway</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">**</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lozano</surname>
<given-names>Andres M.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">∥</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Anisman</surname>
<given-names>Hymie</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">§</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Park</surname>
<given-names>David S.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">‡</xref>
<xref ref-type="fn" rid="fn2">††</xref>
<xref ref-type="corresp" rid="cor1">‡‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mak</surname>
<given-names>Tak W.</given-names>
</name>
<xref ref-type="aff" rid="N0x98a91e0.0x9eb80d0">*</xref>
<xref ref-type="fn" rid="fn2">††</xref>
<xref ref-type="corresp" rid="cor1">‡‡</xref>
</contrib>
</contrib-group>
<aff id="N0x98a91e0.0x9eb80d0"><label>*</label>
Campbell Family Institute for Breast Cancer Research, Advanced Medical Discovery Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1;<label>‡</label>
Neuroscience Research Group, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5;<label>§</label>
Institute for Neuroscience, Carleton University, Ottawa, ON, Canada K1H 6N5;<label>¶</label>
enGene Incorporated, Vancouver, BC, Canada V6T 1Z3;<label>∥</label>
Division of Applied and Interventional Research, Toronto Western Hospital Research Institute, Toronto, ON, Canada M5T 2S8; and<label>**</label>
Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada M5S 3H2</aff>
<author-notes><fn id="cor1"><label>‡‡</label>
<p> To whom correspondence may be addressed. E-mail: <email>dpark@uottawa.ca</email>
or <email>tmak@uhnres.utoronto.ca</email>
. </p>
</fn>
<fn id="fn1"><label>†</label>
<p>R.H.K. and P.D.S. contributed equally to this work.</p>
</fn>
<fn id="fn2"><label>††</label>
<p>D.S.P. and T.W.M. contributed equally to this work.</p>
</fn>
<fn><p>Contributed by Tak W. Mak, February 16, 2005</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>5</day>
<month>4</month>
<year>2005</year>
</pub-date>
<pub-date pub-type="epub"><day>22</day>
<month>3</month>
<year>2005</year>
</pub-date>
<volume>102</volume>
<issue>14</issue>
<fpage>5215</fpage>
<lpage>5220</lpage>
<copyright-statement>Copyright © 2005, The National Academy of Sciences</copyright-statement>
<copyright-year>2005</copyright-year>
<license><p>Freely available online through the PNAS open access option.</p>
</license>
<abstract><p>Mutations of the <italic>DJ-1</italic>
(PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the <italic>substantia nigra</italic>
and fiber densities and dopamine levels in the striatum were normal. However, DJ-1–/– mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1–/–embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1–/– mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress <italic>in vitro</italic>
. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.</p>
</abstract>
</article-meta>
<notes><fn-group><fn><p>Author contributions: R.H.K., P.D.S., H. Aleyasin, S.H., S.P., S.K.K., D.W., A.M.L., D.S.P., and T.W.M. designed research; R.H.K., P.D.S., H. Aleyasin, S.H., M.P.M., A.W., A.J.Y.-T., and H. Anisman performed research; P.H. contributed new reagents/analytic tools; R.H.K. and D.S.P. analyzed data; and R.H.K. and D.S.P. wrote the paper.</p>
</fn>
<fn><p>Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine; MPP+, active metabolite of MPTP; PD, Parkinson's disease; SNc, <italic>substantia nigra pars compacta</italic>
; TH, tyrosine hydroxylase; DAT, dopamine transporter protein.</p>
</fn>
</fn-group>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Canada</li>
</country>
<region><li>Ontario</li>
</region>
<settlement><li>Toronto</li>
</settlement>
<orgName><li>Université de Toronto</li>
</orgName>
</list>
<tree><country name="Canada"><region name="Ontario"><name sortKey="Kim, Raymond H" sort="Kim, Raymond H" uniqKey="Kim R" first="Raymond H." last="Kim">Raymond H. Kim</name>
</region>
<name sortKey="Aleyasin, Hossein" sort="Aleyasin, Hossein" uniqKey="Aleyasin H" first="Hossein" last="Aleyasin">Hossein Aleyasin</name>
<name sortKey="Anisman, Hymie" sort="Anisman, Hymie" uniqKey="Anisman H" first="Hymie" last="Anisman">Hymie Anisman</name>
<name sortKey="Hayley, Shawn" sort="Hayley, Shawn" uniqKey="Hayley S" first="Shawn" last="Hayley">Shawn Hayley</name>
<name sortKey="Horne, Patrick" sort="Horne, Patrick" uniqKey="Horne P" first="Patrick" last="Horne">Patrick Horne</name>
<name sortKey="Kalia, Suneil K" sort="Kalia, Suneil K" uniqKey="Kalia S" first="Suneil K." last="Kalia">Suneil K. Kalia</name>
<name sortKey="Lozano, Andres M" sort="Lozano, Andres M" uniqKey="Lozano A" first="Andres M." last="Lozano">Andres M. Lozano</name>
<name sortKey="Mak, Tak W" sort="Mak, Tak W" uniqKey="Mak T" first="Tak W." last="Mak">Tak W. Mak</name>
<name sortKey="Mount, Matthew P" sort="Mount, Matthew P" uniqKey="Mount M" first="Matthew P." last="Mount">Matthew P. Mount</name>
<name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name>
<name sortKey="Pownall, Scott" sort="Pownall, Scott" uniqKey="Pownall S" first="Scott" last="Pownall">Scott Pownall</name>
<name sortKey="Smith, Patrice D" sort="Smith, Patrice D" uniqKey="Smith P" first="Patrice D." last="Smith">Patrice D. Smith</name>
<name sortKey="Wakeham, Andrew" sort="Wakeham, Andrew" uniqKey="Wakeham A" first="Andrew" last="Wakeham">Andrew Wakeham</name>
<name sortKey="Westaway, David" sort="Westaway, David" uniqKey="Westaway D" first="David" last="Westaway">David Westaway</name>
<name sortKey="You Ten, Annick J" sort="You Ten, Annick J" uniqKey="You Ten A" first="Annick J." last="You-Ten">Annick J. You-Ten</name>
</country>
</tree>
</affiliations>
</record>
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