The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts.
Identifieur interne : 000450 ( Main/Exploration ); précédent : 000449; suivant : 000451The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts.
Auteurs : Vedad Delic [États-Unis] ; Kenyaria Noble [États-Unis] ; Sandra Zivkovic [États-Unis] ; Tam-Anh Phan [États-Unis] ; Christian Reynes [États-Unis] ; Yumeng Zhang [États-Unis] ; Oluwakemi Phillips [États-Unis] ; Charles Claybaker [États-Unis] ; Yen Ta [États-Unis] ; Vinh B. Dinh [États-Unis] ; Josean Cruz [États-Unis] ; Tomas A. Prolla [États-Unis] ; Patrick C. Bradshaw [États-Unis]Source :
- Biology open [ 2046-6390 ] ; 2018.
Abstract
Mitochondrial DNA mutations accumulate with age and may play a role in stem cell aging as suggested by the premature aging phenotype of mitochondrial DNA polymerase gamma (POLG) exonuclease-deficient mice. Therefore, E1A immortalized murine embryonic fibroblasts (MEFs) from POLG exonuclease-deficient and wild-type (WT) mice were constructed. Surprisingly, when some E1A immortalized MEF lines were cultured in pyruvate-containing media they slowly became addicted to the pyruvate. The POLG exonuclease-deficient MEFs were more sensitive to several mitochondrial inhibitors and showed increased reactive oxygen species (ROS) production under standard conditions. When cultured in pyruvate-containing media, POLG exonuclease-deficient MEFs showed decreased oxygen consumption compared to controls. Increased AMP-activated protein kinase (AMPK) signaling and decreased mammalian target of rapamycin (mTOR) signaling delayed aging and influenced mitochondrial function. Therefore, the effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, or rapamycin, an mTOR inhibitor, on measures of mitochondrial function were determined. Rapamycin treatment transiently increased respiration only in WT MEFs and, under most conditions, increased ATP levels. Short term AICAR treatment transiently increased ROS production and, under most conditions, decreased ATP levels. Chronic AICAR treatment decreased respiration and ROS production in WT MEFs. These results demonstrate the context-dependent effects of AICAR and rapamycin on mitochondrial function.
DOI: 10.1242/bio.033852
PubMed: 30177551
PubMed Central: PMC6262855
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Phillips</name><affiliation wicri:level="2"><nlm:affiliation>University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612</wicri:regionArea><placeName><region type="state">Floride</region></placeName></affiliation></author><author><name sortKey="Claybaker, Charles" sort="Claybaker, Charles" uniqKey="Claybaker C" first="Charles" last="Claybaker">Charles Claybaker</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 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Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:30177551</idno><idno type="pmid">30177551</idno><idno type="doi">10.1242/bio.033852</idno><idno type="pmc">PMC6262855</idno><idno type="wicri:Area/Main/Corpus">000464</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000464</idno><idno type="wicri:Area/Main/Curation">000464</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000464</idno><idno type="wicri:Area/Main/Exploration">000464</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts.</title><author><name sortKey="Delic, Vedad" sort="Delic, Vedad" uniqKey="Delic V" first="Vedad" last="Delic">Vedad Delic</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama Birmingham School of Medicine, Birmingham, AL 35233, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama Birmingham School of Medicine, Birmingham, AL 35233</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Noble, Kenyaria" sort="Noble, Kenyaria" uniqKey="Noble K" first="Kenyaria" last="Noble">Kenyaria Noble</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Zivkovic, Sandra" sort="Zivkovic, Sandra" uniqKey="Zivkovic S" first="Sandra" last="Zivkovic">Sandra Zivkovic</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Phan, Tam Anh" sort="Phan, Tam Anh" uniqKey="Phan T" first="Tam-Anh" last="Phan">Tam-Anh Phan</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Reynes, Christian" sort="Reynes, Christian" uniqKey="Reynes C" first="Christian" last="Reynes">Christian Reynes</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Zhang, Yumeng" sort="Zhang, Yumeng" uniqKey="Zhang Y" first="Yumeng" last="Zhang">Yumeng Zhang</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation><affiliation wicri:level="4"><nlm:affiliation>Department of Internal Medicine, University of South Florida, Tampa, FL 33606, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Internal Medicine, University of South Florida, Tampa, FL 33606</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Phillips, Oluwakemi" sort="Phillips, Oluwakemi" uniqKey="Phillips O" first="Oluwakemi" last="Phillips">Oluwakemi Phillips</name><affiliation wicri:level="2"><nlm:affiliation>University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612</wicri:regionArea><placeName><region type="state">Floride</region></placeName></affiliation></author><author><name sortKey="Claybaker, Charles" sort="Claybaker, Charles" uniqKey="Claybaker C" first="Charles" last="Claybaker">Charles Claybaker</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Ta, Yen" sort="Ta, Yen" uniqKey="Ta Y" first="Yen" last="Ta">Yen Ta</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Dinh, Vinh B" sort="Dinh, Vinh B" uniqKey="Dinh V" first="Vinh B" last="Dinh">Vinh B. Dinh</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Cruz, Josean" sort="Cruz, Josean" uniqKey="Cruz J" first="Josean" last="Cruz">Josean Cruz</name><affiliation wicri:level="4"><nlm:affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620</wicri:regionArea><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Prolla, Tomas A" sort="Prolla, Tomas A" uniqKey="Prolla T" first="Tomas A" last="Prolla">Tomas A. Prolla</name><affiliation wicri:level="2"><nlm:affiliation>Department of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706</wicri:regionArea><placeName><region type="state">Wisconsin</region></placeName></affiliation></author><author><name sortKey="Bradshaw, Patrick C" sort="Bradshaw, Patrick C" uniqKey="Bradshaw P" first="Patrick C" last="Bradshaw">Patrick C. Bradshaw</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA bradshawp@etsu.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></analytic><series><title level="j">Biology open</title><idno type="ISSN">2046-6390</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mitochondrial DNA mutations accumulate with age and may play a role in stem cell aging as suggested by the premature aging phenotype of mitochondrial DNA polymerase gamma (POLG) exonuclease-deficient mice. Therefore, E1A immortalized murine embryonic fibroblasts (MEFs) from POLG exonuclease-deficient and wild-type (WT) mice were constructed. Surprisingly, when some E1A immortalized MEF lines were cultured in pyruvate-containing media they slowly became addicted to the pyruvate. The POLG exonuclease-deficient MEFs were more sensitive to several mitochondrial inhibitors and showed increased reactive oxygen species (ROS) production under standard conditions. When cultured in pyruvate-containing media, POLG exonuclease-deficient MEFs showed decreased oxygen consumption compared to controls. Increased AMP-activated protein kinase (AMPK) signaling and decreased mammalian target of rapamycin (mTOR) signaling delayed aging and influenced mitochondrial function. Therefore, the effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, or rapamycin, an mTOR inhibitor, on measures of mitochondrial function were determined. Rapamycin treatment transiently increased respiration only in WT MEFs and, under most conditions, increased ATP levels. Short term AICAR treatment transiently increased ROS production and, under most conditions, decreased ATP levels. Chronic AICAR treatment decreased respiration and ROS production in WT MEFs. These results demonstrate the context-dependent effects of AICAR and rapamycin on mitochondrial function.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">30177551</PMID><DateRevised><Year>2019</Year><Month>11</Month><Day>20</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Print">2046-6390</ISSN><JournalIssue CitedMedium="Print"><Volume>7</Volume><Issue>11</Issue><PubDate><Year>2018</Year><Month>Nov</Month><Day>16</Day></PubDate></JournalIssue><Title>Biology open</Title><ISOAbbreviation>Biol Open</ISOAbbreviation></Journal><ArticleTitle>The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">bio033852</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1242/bio.033852</ELocationID><Abstract><AbstractText>Mitochondrial DNA mutations accumulate with age and may play a role in stem cell aging as suggested by the premature aging phenotype of mitochondrial DNA polymerase gamma (POLG) exonuclease-deficient mice. Therefore, E1A immortalized murine embryonic fibroblasts (MEFs) from POLG exonuclease-deficient and wild-type (WT) mice were constructed. Surprisingly, when some E1A immortalized MEF lines were cultured in pyruvate-containing media they slowly became addicted to the pyruvate. The POLG exonuclease-deficient MEFs were more sensitive to several mitochondrial inhibitors and showed increased reactive oxygen species (ROS) production under standard conditions. When cultured in pyruvate-containing media, POLG exonuclease-deficient MEFs showed decreased oxygen consumption compared to controls. Increased AMP-activated protein kinase (AMPK) signaling and decreased mammalian target of rapamycin (mTOR) signaling delayed aging and influenced mitochondrial function. Therefore, the effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, or rapamycin, an mTOR inhibitor, on measures of mitochondrial function were determined. Rapamycin treatment transiently increased respiration only in WT MEFs and, under most conditions, increased ATP levels. Short term AICAR treatment transiently increased ROS production and, under most conditions, decreased ATP levels. Chronic AICAR treatment decreased respiration and ROS production in WT MEFs. These results demonstrate the context-dependent effects of AICAR and rapamycin on mitochondrial function.</AbstractText><CopyrightInformation>© 2018. Published by The Company of Biologists Ltd.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Delic</LastName><ForeName>Vedad</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama Birmingham School of Medicine, Birmingham, AL 35233, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Noble</LastName><ForeName>Kenyaria</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zivkovic</LastName><ForeName>Sandra</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Phan</LastName><ForeName>Tam-Anh</ForeName><Initials>TA</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reynes</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Yumeng</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Internal Medicine, University of South Florida, Tampa, FL 33606, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Phillips</LastName><ForeName>Oluwakemi</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Claybaker</LastName><ForeName>Charles</ForeName><Initials>C</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-5445-6394</Identifier><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ta</LastName><ForeName>Yen</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dinh</LastName><ForeName>Vinh B</ForeName><Initials>VB</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cruz</LastName><ForeName>Josean</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Prolla</LastName><ForeName>Tomas A</ForeName><Initials>TA</Initials><AffiliationInfo><Affiliation>Department of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bradshaw</LastName><ForeName>Patrick C</ForeName><Initials>PC</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4591-6798</Identifier><AffiliationInfo><Affiliation>Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA bradshawp@etsu.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>11</Month><Day>16</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Biol Open</MedlineTA><NlmUniqueID>101578018</NlmUniqueID><ISSNLinking>2046-6390</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">AMP kinase</Keyword><Keyword MajorTopicYN="N">Aging</Keyword><Keyword MajorTopicYN="N">Mitochondria</Keyword><Keyword MajorTopicYN="N">Pyruvate addiction</Keyword><Keyword MajorTopicYN="N">Rapamycin</Keyword><Keyword MajorTopicYN="N">mTOR</Keyword></KeywordList><CoiStatement>Competing interestsThe authors declare no competing or financial 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Prolla</name><name sortKey="Reynes, Christian" sort="Reynes, Christian" uniqKey="Reynes C" first="Christian" last="Reynes">Christian Reynes</name><name sortKey="Ta, Yen" sort="Ta, Yen" uniqKey="Ta Y" first="Yen" last="Ta">Yen Ta</name><name sortKey="Zhang, Yumeng" sort="Zhang, Yumeng" uniqKey="Zhang Y" first="Yumeng" last="Zhang">Yumeng Zhang</name><name sortKey="Zhang, Yumeng" sort="Zhang, Yumeng" uniqKey="Zhang Y" first="Yumeng" last="Zhang">Yumeng Zhang</name><name sortKey="Zivkovic, Sandra" sort="Zivkovic, Sandra" uniqKey="Zivkovic S" first="Sandra" last="Zivkovic">Sandra Zivkovic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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