Polμ Deficiency Increases Resistance to Oxidative Damage and Delays Liver Aging
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{"title"=>"Polμ deficiency increases resistance to oxidative damage and delays liver aging", "type"=>"journal", "authors"=>[{"first_name"=>"Beatriz", "last_name"=>"Escudero", "scopus_author_id"=>"6603545862"}, {"first_name"=>"Daniel", "last_name"=>"Lucas", "scopus_author_id"=>"7202026071"}, {"first_name"=>"Carmen", "last_name"=>"Albo", "scopus_author_id"=>"7004298140"}, {"first_name"=>"Suveera", "last_name"=>"Dhup", "scopus_author_id"=>"24448151700"}, {"first_name"=>"Jeff W.", "last_name"=>"Bacher", "scopus_author_id"=>"9845284000"}, {"first_name"=>"Aránzazu", "last_name"=>"Sánchez-Muñoz", "scopus_author_id"=>"56119703600"}, {"first_name"=>"Margarita", "last_name"=>"Fernández", "scopus_author_id"=>"35117682000"}, {"first_name"=>"José", "last_name"=>"Rivera-Torres", "scopus_author_id"=>"55772165000"}, {"first_name"=>"Rosa M.", "last_name"=>"Carmona", "scopus_author_id"=>"56120117600"}, {"first_name"=>"Encarnación", "last_name"=>"Fuster", "scopus_author_id"=>"56120169600"}, {"first_name"=>"Candelas", "last_name"=>"Carreiro", "scopus_author_id"=>"6507928230"}, {"first_name"=>"Raquel", "last_name"=>"Bernad", "scopus_author_id"=>"56119676100"}, {"first_name"=>"Manuel A.", "last_name"=>"González", "scopus_author_id"=>"35496783800"}, {"first_name"=>"Vicente", "last_name"=>"Andrés", "scopus_author_id"=>"7004622206"}, {"first_name"=>"Luis", "last_name"=>"Blanco", "scopus_author_id"=>"7103149544"}, {"first_name"=>"Enrique", "last_name"=>"Roche", "scopus_author_id"=>"7005472886"}, {"first_name"=>"Isabel", "last_name"=>"Fabregat", "scopus_author_id"=>"7003817931"}, {"first_name"=>"Enrique", "last_name"=>"Samper", "scopus_author_id"=>"57093804800"}, {"first_name"=>"Antonio", "last_name"=>"Bernad", "scopus_author_id"=>"7003851628"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "sgr"=>"84898854640", "scopus"=>"2-s2.0-84898854640", "pui"=>"372870011", "doi"=>"10.1371/journal.pone.0093074", "pmid"=>"24691161"}, "id"=>"d7dc9e8a-c131-3b2f-9b9f-35ea931af7b0", "abstract"=>"Polμ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polμ (Polμ(-/-)) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polμ(-/-) mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polμ(-/-) deficiency on liver aging. We found that old Polμ(-/-) mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polμ(-/-) liver showed reduced genomic instability and increased apoptosis resistance. However, Polμ(-/-) mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polμ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.", "link"=>"http://www.mendeley.com/research/pol%CE%BC-deficiency-increases-resistance-oxidative-damage-delays-liver-aging", "reader_count"=>7, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>1, "Student > Master"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>5}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Portugal"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1441611", "https://ndownloader.figshare.com/files/1441612", "https://ndownloader.figshare.com/files/1441613", "https://ndownloader.figshare.com/files/1441614", "https://ndownloader.figshare.com/files/1441615", "https://ndownloader.figshare.com/files/1441616", "https://ndownloader.figshare.com/files/1441617", "https://ndownloader.figshare.com/files/1441618"], "description"=>"<div><p>Polμ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polμ (Polμ<sup>−/−</sup>) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polμ<sup>−/−</sup> mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polμ<sup>−/−</sup> deficiency on liver aging. We found that old Polμ<sup>−/−</sup> mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polμ<sup>−/−</sup> liver showed reduced genomic instability and increased apoptosis resistance. However, Polμ<sup>−/−</sup> mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polμ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.</p></div>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models", "deficiency", "oxidative", "delays"], "article_id"=>979591, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0093074.s001", "https://dx.doi.org/10.1371/journal.pone.0093074.s002", "https://dx.doi.org/10.1371/journal.pone.0093074.s003", "https://dx.doi.org/10.1371/journal.pone.0093074.s004", "https://dx.doi.org/10.1371/journal.pone.0093074.s005", "https://dx.doi.org/10.1371/journal.pone.0093074.s006", "https://dx.doi.org/10.1371/journal.pone.0093074.s007", "https://dx.doi.org/10.1371/journal.pone.0093074.s008"], "stats"=>{"downloads"=>9, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pol_956_Deficiency_Increases_Resistance_to_Oxidative_Damage_and_Delays_Liver_Aging_/979591", "title"=>"Polμ Deficiency Increases Resistance to Oxidative Damage and Delays Liver Aging", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-04-01 02:46:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1441606"], "description"=>"<p>(<b>A</b>) Polyploidy (determined by PI staining) in hepatocytes from old (14 m) wt (black) and Polμ<sup>−/−</sup> mice (gray). Data are presented as the relative amounts (arbitrary units) of 8n and ≥8n cells (means ± SEM, 4 samples per genotype. (<b>B</b>) Survival (min) of adult (8–12 w) mice after i.v. injection with paraquat (70 mg/kg). Individual data and means are shown for wt (black) and Polμ<sup>−/−</sup> (gray) mice (n = 13). Data are means ± SEM. (<b>C, D</b>) Comparative mutation frequency (MF) in a panel of selected microsatellites (MS) in Polμ<sup>−/−</sup> mice vs wt animals. The table (<b>D</b>) compares individual absolute MF values in the different MS sequences analyzed in Polμ<sup>−/−</sup> mice relative to wt animals (100%); (*) indicates animals treated with paraquat.</p>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models"], "article_id"=>979586, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093074.g004", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_stability_in_Pol_8722_8722_mice_/979586", "title"=>"Genetic stability in Polμ<sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 02:46:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1441601"], "description"=>"<p>(<b>A</b>) Analysis of 53P1-positive cells in liver of old (>20 months) wt (n = 6; black bars) and Polμ<sup>−/−</sup> mice (n = 6; gray bars). (<b>B</b>) Cell cycle analysis of freshly prepared liver suspensions from wt (black bars) and Polμ<sup>−/−</sup> mice (gray bars), after staining with PI. (<b>C</b>) TUNEL assay in cryopreserved liver tissue from adult (14 m) mice. Percentages of positive (apoptotic) cells per field are shown. Three livers per genotype were analyzed (4771 wt cells and 8289 Polμ<sup>−/−</sup> cells) and individual values (relative to wt) and means ± SEM are shown. (<b>D</b>) Percentage of proliferating (PH3-positive) cells in livers of old (18–23 m) wt (black) and Polμ<sup>−/−</sup> mice (gray) after partial hepatectomy (PH). Percentages of PH3-positive cells are presented as the mean ± SEM of two-three animals per condition; n = 11. Polμ<sup>−/−</sup> animals survived surgery better than wt animals (82%; 9/11 vs 64%; 7/11). (<b>E, F</b>) Representative images of immunostaining for PH3 (E) and CK19 (F) in sections of old (18–23 m) Polμ<sup>−/−</sup> and wt liver at the indicated times after PH. Control indicates negative controls without the primary antibody.</p>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models"], "article_id"=>979581, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093074.g001", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Improved_liver_function_in_old_Pol_8722_8722_mice_/979581", "title"=>"Improved liver function in old Polμ<sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 02:46:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1441609"], "description"=>"<p>Numbers indicates the ratio KO/WT for each parameter. Footnotes.</p>(a)<p>Corresponding specifically to G2/M cells;</p>(b)<p>Evaluation of senescence <i>ex vivo</i>, at atmospheric concentration of O<sub>2</sub>;</p>(c)<p>Ploidy (≥4n) evaluation after PI staining;</p>(d)<p>Aneuploidy and translocation frequency evaluation;</p>(e)<p>Evaluated on CFU-GM progenitors;</p>(f)<p>Evaluated in cell lines;</p>(g)<p>ALT/GPT; AST/GOT; Billirubin and Albumin;</p>(h)<p>P-Hepatect. Recovery: partial hepatectomy recovery;</p>(i)<p>Protein carbonyls;</p>(j)<p>peroxided lipids;</p>(k)<p>Values obtained at atmospheric oxygen;</p>(l)<p>Paraquat Resistance, (70 mg/kg; ip);</p>(m)<p>Analysis of CHO-DN cell line, at atmospheric oxygen;</p>(n)<p>HR express. qRT-PCR analysis of selected functions involved in HR;</p>(o)<p>Tumor susceptibility. Evaluation of spontaneous tumor incidence and susceptibility to thymic lymphomas by low dose of radiation;</p>(p)<p>Evaluations in 129/BALBc and B6 backgrounds, respectively; Abbreviations: Thy, thymus; Sp, spleen; Br, brain, Sk, skin; Ov, ovary; Panc, Pancreas; PB, peripheral blood. Symbols; (<b>++</b>), (<b>+</b>), (<b>+/−</b>) and (−) indicates that values for KO animals were clearly higher, superior, similar and reduced, respectivelly, in comparison with control (wt) animals.</p>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models", "physiological"], "article_id"=>979589, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093074.t001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_different_physiological_parameters_analyzed_in_old_Pol_8722_8722_mice_/979589", "title"=>"Summary of different physiological parameters analyzed in old Polμ<sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-01 02:46:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1441608"], "description"=>"<p>(<b>A</b>) Illustrative example of sister chromatid exchange (SCE) between green chromatids (labeled by BrdU incorporation) and blue chromatids (DAPI stained). The enlarged image to the left shows a chromosome with 3 crossovers (indicated by arrows) in which green and blue are combined in the same chromatid. (<b>B–D</b>) Sister chromatid exchange (SCE) in three models of Polμ deficiency: (<b>B</b>) MEFs, (<b>C</b>) B lymphocytes and (<b>D</b>) CHO-KS4 cells expressing DN-Polμ (ΔN); EV = empty vector.</p>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models", "sce", "cellular"], "article_id"=>979588, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093074.g005", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Evaluation_of_SCE_in_different_cellular_models_of_Pol_956_deficiency_/979588", "title"=>"Evaluation of SCE in different cellular models of Polμ deficiency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 02:46:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1441605"], "description"=>"<p>(<b>A</b>) Involvement of autophagy activity in the Polμ<sup>−/−</sup> lifespan extension phenotype. Heart samples from old (18–25 m; o) and young (8–12 w; y) Polμ<sup>−/−</sup> (gray bars) and wt mice (black bars) were analyzed by qRT-PCR for the expression of a panel of genes essential for autophagy (Atg2l, Atg5l, Atg7l and Map11c3b). Results, expressed as 2∧–(DCT), show mean values ± SD (n = 5). (<b>B</b>) Protein carbonyls (Carb) and peroxided lipids (PeroxL; thiobarbituric acid reactive substances, TBARS), as macromolecular oxidative damage, were determined (nmol/mg prot), as described in the supporting information, in perfused liver of old (>20 months) Polμ<sup>−/−</sup> (black bars) and wt gray bars) mice Results are mean values ± SD (n = 3). (<b>C</b>) Heat map of microarray expression data for livers from adult (14 m) wt and Polμ<sup>−/−</sup> mice. The relative gene expression scale is shown, with normalized scores ranging from 0 to 20. Gene cluster and case cluster dendrograms are plotted to the top and left. (<b>D</b>) Microarray data validation. mRNA levels were determined by TaqMan RT-PCR in livers from adult wt (black) and Polμ<sup>−/−</sup> mice (gray). Each determination was performed in triplicate and normalized to β-actin expression. Data are the means ± SEM of 4 samples per genotype, represented relative to expression in age-matched wt liver. (<b>E</b>) Scheme of the interaction network among apoptosis-related or p53-inducible genes downregulated in old Polμ<sup>−/−</sup> liver.</p>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models", "mice", "shows", "aging-related", "age-matched", "wt"], "article_id"=>979585, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093074.g003", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Liver_from_old_Pol_8722_8722_mice_shows_fewer_aging_related_features_than_liver_from_age_matched_wt_controls_/979585", "title"=>"Liver from old Polμ<sup>−/−</sup> mice shows fewer aging-related features than liver from age-matched wt controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 02:46:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/1441603"], "description"=>"<p>(<b>A–C</b>) Cardiovascular parameters in old Polμ<sup>−/−</sup> (gray) and wt (black) mice (16–18 m). (<b>A</b>) Electrocardiographic parameters; QRS complex and PR segment intervals are shown in miliseconds (msec). (<b>B</b>) Heart rate (beats per minute; bpm). Data are means ±SD of weekly readings collected over a 4-week period. (<b>C</b>) Systolic and diastolic blood pressure (mm Hg) in wt (black) and Polμ<sup>−/−</sup> mice (white) over a 4-week period. Results are means ± SD (n = 3 mice). (<b>D</b>) After DNA array expression analysis of hearts from old (20–24 m) and young (3–4 m) wt mice, six genes showing an aging-related profile were selected and confirmed by qRT-PCR. Data from old mice (black) are presented relative the expression level of each gene in young mice (gray). (<b>E</b>) Comparative gene expression analysis in young (y; 8–12 weeks) and old (o; 20–24 m) heart tissue from wt (black) and Polμ<sup>−/−</sup> mice (gray). Data were normalized to the expression level of each gene in young wt mice. Results, expressed as 2∧–(DCT), are mean values ± SD (n = 3).</p>", "links"=>[], "tags"=>["Biochemistry", "dna", "DNA recombination", "DNA repair", "Nucleic acids", "cell biology", "Cell processes", "Cellular stress responses", "Molecular cell biology", "developmental biology", "Organism development", "aging", "physiology", "Physiological processes", "Model organisms", "Animal models", "Mouse models", "molecular", "cardiovascular", "phenotype"], "article_id"=>979583, "categories"=>["Biological Sciences"], "users"=>["Beatriz Escudero", "Daniel Lucas", "Carmen Albo", "Suveera Dhup", "Jeff W. Bacher", "Aránzazu Sánchez-Muñoz", "Margarita Fernández", "José Rivera-Torres", "Rosa M. Carmona", "Encarnación Fuster", "Candelas Carreiro", "Raquel Bernad", "Manuel A. Gonzalez", "Vicente Andrés", "Luis Blanco", "Enrique Roche", "Isabel Fabregat", "Enrique Samper", "Antonio Bernad"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0093074.g002", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heart_molecular_signature_and_cardiovascular_phenotype_of_Pol_8722_8722_mice_/979583", "title"=>"Heart molecular signature and cardiovascular phenotype of Polμ<sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-01 02:46:17"}

PMC Usage Stats | Further Information

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Relative Metric

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