Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice
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{"title"=>"Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice", "type"=>"journal", "authors"=>[{"first_name"=>"Valentina M.", "last_name"=>"Factor", "scopus_author_id"=>"7003497054"}, {"first_name"=>"Daekwan", "last_name"=>"Seo", "scopus_author_id"=>"36601393800"}, {"first_name"=>"Tsuyoshi", "last_name"=>"Ishikawa", "scopus_author_id"=>"55624477502"}, {"first_name"=>"Pal", "last_name"=>"Kaposi-Novak", "scopus_author_id"=>"6506868710"}, {"first_name"=>"Jens U.", "last_name"=>"Marquardt", "scopus_author_id"=>"36096818000"}, {"first_name"=>"Jesper B.", "last_name"=>"Andersen", "scopus_author_id"=>"26540929900"}, {"first_name"=>"Elizabeth A.", "last_name"=>"Conner", "scopus_author_id"=>"7006581554"}, {"first_name"=>"Snorri S.", "last_name"=>"Thorgeirsson", "scopus_author_id"=>"35434346900"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"359839064", "sgr"=>"77958544269", "issn"=>"19326203", "pmid"=>"20862286", "scopus"=>"2-s2.0-77958544269", "doi"=>"10.1371/journal.pone.0012739", "isbn"=>"1932-6203"}, "id"=>"215c697a-e7a2-3894-84a9-037777752e9e", "abstract"=>"Previous work has established that HGF/c-Met signaling plays a pivotal role in regulating the onset of S phase following partial hepatectomy (PH). In this study, we used Met(fl/fl);Alb-Cre(+/-) conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration.", "link"=>"http://www.mendeley.com/research/loss-cmet-disrupts-gene-expression-program-required-g2m-progression-during-liver-regeneration-mice", "reader_count"=>35, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>6, "Medicine and Dentistry"=>7, "Agricultural and Biological Sciences"=>16, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Japan"=>1, "Poland"=>1, "Spain"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/829926"], "description"=>"<p>(<b>A</b>) Expression profiles of 184 genes encoding G2/M regulators based on the Ingenuity Pathway Analysis. (<b>B</b>) The ten top-ranked Gene Ontology categories reflecting biological changes in Met mutant livers. Only the GO categories that were significantly underrepresented in Met livers are indicated together the number of genes altered in each category (X-axis).</p>", "links"=>[], "tags"=>["genes", "progression"], "article_id"=>500286, "categories"=>["Cell Biology"], "users"=>["Valentina M. Factor", "Daekwan Seo", "Tsuyoshi Ishikawa", "Pal Kaposi-Novak", "Jens U. Marquardt", "Jesper B. Andersen", "Elizabeth A. Conner", "Snorri S. Thorgeirsson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012739.g003", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Downregulation_of_genes_involved_in_G2_M_progression_in_Met_fl_fl_Alb_Cre_8722_mice_/500286", "title"=>"Downregulation of genes involved in G2/M progression in <i>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-09-16 00:04:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/830030"], "description"=>"<p>(<b>A</b> and <b>B</b>) Whole cell lysates were prepared from <i>Met<sup>wt/wt</sup>;Alb-Cre<sup>+/−</sup></i> and <i>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></i> livers at the indicated times and probed by Western blotting using the indicated antibodies. (<b>C</b>) Western blotting of whole cell lysates prepared from <i>Met<sup>fl/fl</sup></i> and <i>Met<sup>fl/fl</sup>;Mx1-Cre<sup>+/−</sup></i> livers. Representative immunoblots are shown. Actin served as a loading control.</p>", "links"=>[], "tags"=>["regulated", "proteins", "c-met-deficient", "regenerating"], "article_id"=>500396, "categories"=>["Cell Biology"], "users"=>["Valentina M. Factor", "Daekwan Seo", "Tsuyoshi Ishikawa", "Pal Kaposi-Novak", "Jens U. Marquardt", "Jesper B. Andersen", "Elizabeth A. Conner", "Snorri S. Thorgeirsson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012739.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Downregulation_of_cell_cycle_regulated_proteins_in_c_Met_deficient_regenerating_livers_/500396", "title"=>"Downregulation of cell cycle regulated proteins in c-Met-deficient regenerating livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-09-16 00:06:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/413169", "https://ndownloader.figshare.com/files/413187", "https://ndownloader.figshare.com/files/413277", "https://ndownloader.figshare.com/files/413368", "https://ndownloader.figshare.com/files/413398", "https://ndownloader.figshare.com/files/413500", "https://ndownloader.figshare.com/files/413551"], "description"=>"<div><h3>Background</h3><p>Previous work has established that HGF/c-Met signaling plays a pivotal role in regulating the onset of S phase following partial hepatectomy (PH). In this study, we used <em>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></em> conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration.</p><h3>Methodology/Principal Finding</h3><p>The priming events appeared to be intact in <em>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></em> livers. Up-regulation of stress response (<em>MAFK</em>, <em>IKBZ</em>, <em>SOCS3</em>) and early growth response (<em>c-Myc</em>, <em>c-Jun</em>, <em>c-Fos</em>, <em>DUSP1</em> and <em>6</em>) genes as assessed by RT-qPCR and/or microarray profiling was unchanged. This was consistent with an early induction of MAPK/Erk and STAT3. However, after a successful completion of the first round of DNA replication, c-Met deficient hepatocytes were blocked in early/mid G2 phase as shown by staining with phosphorylated form of histone H3. Furthermore, loss of c-Met in hepatocytes diminished the subsequent G1/S progression and delayed liver recovery after partial hepatectomy. Upstream signaling pathways involved in the blockage of G2/M transition included lack of persistent Erk1/2 activation and inability to up-regulate the levels of Cdk1, Plk1, Aurora A and B, and Mad2 along with a defective histone 3 phosphorylation and lack of chromatin condensation. Continuous supplementation with EGF <em>in vitro</em> increased proliferation of <em>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></em> primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures.</p><h3>Conclusion/Significance</h3><p>In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration.</p></div>", "links"=>[], "tags"=>["c-met", "disrupts", "progression", "regeneration", "mice"], "article_id"=>141626, "categories"=>["Cell Biology"], "users"=>["Valentina M. Factor", "Daekwan Seo", "Tsuyoshi Ishikawa", "Pal Kaposi-Novak", "Jens U. Marquardt", "Jesper B. Andersen", "Elizabeth A. Conner", "Snorri S. Thorgeirsson"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0012739.s001", "https://dx.doi.org/10.1371/journal.pone.0012739.s002", "https://dx.doi.org/10.1371/journal.pone.0012739.s003", "https://dx.doi.org/10.1371/journal.pone.0012739.s004", "https://dx.doi.org/10.1371/journal.pone.0012739.s005", "https://dx.doi.org/10.1371/journal.pone.0012739.s006", "https://dx.doi.org/10.1371/journal.pone.0012739.s007"], "stats"=>{"downloads"=>26, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Loss_of_c_Met_Disrupts_Gene_Expression_Program_Required_for_G2_M_Progression_during_Liver_Regeneration_in_Mice/141626", "title"=>"Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-09-16 00:27:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/829837"], "description"=>"<p>(<b>A</b>) Heatmap depicts a subset of 20 genes that are commonly regulated in <i>Met<sup>wt/wt</sup>;Alb-Cre<sup>+/−</sup></i> and <i>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></i> mice within the first 2 hr of liver regeneration (1.5-fold, <i>P</i><0.01 in at least 80% of arrays). (<b>B</b>) Representative western blots and quantification of total and phosphorylated Stat3 protein levels relative to β-actin. Results shown are the means ± SE of 3 experiments.</p>", "links"=>[], "tags"=>["genes", "priming", "c-met", "mutant", "livers"], "article_id"=>500199, "categories"=>["Cell Biology"], "users"=>["Valentina M. Factor", "Daekwan Seo", "Tsuyoshi Ishikawa", "Pal Kaposi-Novak", "Jens U. Marquardt", "Jesper B. Andersen", "Elizabeth A. Conner", "Snorri S. Thorgeirsson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012739.g002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_genes_associated_with_priming_phase_in_c_Met_mutant_livers_after_partial_hepatectomy_/500199", "title"=>"Induction of genes associated with priming phase in c-Met mutant livers after partial hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-09-16 00:03:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/829733"], "description"=>"<p>(<b>A</b>) Normal induction of the first but reduced second wave of DNA replication and (<b>B</b>) inhibition of mitosis in <i>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></i> livers. The labeling and mitotic indexes were calculated by randomly counting BrdU-stained nuclei (<b>A</b>) and mitotic figures (<b>B</b>) in a total of 2,000 hepatocytes and expressed as percent. Results shown are the means ± SE (n = 5−7 mice/group/time point). Asterisks indicate statistical significance assessed by Student's <i>t</i>- test (<i>P<0.05</i>). (<b>C</b>) Representative photomicrographs of PCNA (top) and phosphor-histone H3 staining of liver sections. Shown are cells in S phase (arrows), G2 (G2), prophase (P) and metaphase (M). Scale bars, 10 µm. (<b>D</b> and <b>E</b>) Block of G2/M transition in Met-deficient livers shown by staining with phosphor-histone H3. Positive cells were counted in 10–20 randomly selected fields in <i>Met<sup>wt/wt</sup>;Alb-Cre<sup>+/−</sup></i> (<b>D</b>) and <i>Met<sup>f/f</sup>;Alb-Cre<sup>+/−</sup></i> (<b>E</b>) liver sections under confocal microscope and expressed as percent from a total of 600–2000 nuclei. Results shown are the means ± SE (n = 5−7 mice/group/time point).</p>", "links"=>[], "tags"=>["progression", "defects", "c-met-deficient", "regenerating"], "article_id"=>500093, "categories"=>["Cell Biology"], "users"=>["Valentina M. Factor", "Daekwan Seo", "Tsuyoshi Ishikawa", "Pal Kaposi-Novak", "Jens U. Marquardt", "Jesper B. Andersen", "Elizabeth A. Conner", "Snorri S. Thorgeirsson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012739.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_cycle_progression_defects_in_c_Met_deficient_regenerating_livers_/500093", "title"=>"Cell cycle progression defects in c-Met-deficient regenerating livers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-09-16 00:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/830174"], "description"=>"<p>(<b>A</b>) Hepatocytes were isolated from 2-month-old <i>Met<sup>wt/wt</sup>;Alb-Cre<sup>+/−</sup></i> and <i>Met<sup>fl/fl</sup>;Alb-Cre<sup>+/−</sup></i> livers and cultured in the presence of HGF (40 ng/ml), EGF (20 ng/ml) or HGF+EGF for 3 days. DNA replication was analyzed by <sup>3</sup>H-Thymidine incorporation expressed as counts per minute per microgram of protein. Cells were exposed to <sup>3</sup>H-Thymidin for 24 hr before harvesting. Shown are the means ± SE of duplicates from 4 independent experiments. (<b>B</b>) Western blot analysis of whole cell lysates with indicated antibodies. Cells were grown in the absence (NT) or presence of HGF (H), EGF (E), and both (H+E) for 3 days. The experiments were performed twice, and representative immunoblots are shown. α-tubulin served as a loading control.</p>", "links"=>[], "tags"=>["dna", "replication", "diminished", "proteins", "c-met", "deficient"], "article_id"=>500535, "categories"=>["Cell Biology"], "users"=>["Valentina M. Factor", "Daekwan Seo", "Tsuyoshi Ishikawa", "Pal Kaposi-Novak", "Jens U. Marquardt", "Jesper B. Andersen", "Elizabeth A. Conner", "Snorri S. Thorgeirsson"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0012739.g005", "stats"=>{"downloads"=>10, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_DNA_replication_and_diminished_expression_of_cell_cycle_proteins_in_c_Met_deficient_primary_hepatocytes_/500535", "title"=>"Reduced DNA replication and diminished expression of cell cycle proteins in c-Met deficient primary hepatocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-09-16 00:08:55"}

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  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
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  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"1"}
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  • {"unique-ip"=>"13", "full-text"=>"10", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"3"}
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  • {"unique-ip"=>"8", "full-text"=>"9", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"5"}
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  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
  • {"unique-ip"=>"9", "full-text"=>"8", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"4", "full-text"=>"2", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
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  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
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  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"10", "full-text"=>"5", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"9", "full-text"=>"5", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
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  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"9", "full-text"=>"6", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"13", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"20", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"12", "full-text"=>"7", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"10", "full-text"=>"12", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"3", "full-text"=>"1", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"8", "full-text"=>"8", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
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Relative Metric

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