Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells
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{"title"=>"Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells", "type"=>"journal", "authors"=>[{"first_name"=>"Beatriz", "last_name"=>"Suárez-Álvarez", "scopus_author_id"=>"15078333400"}, {"first_name"=>"Ramón M.", "last_name"=>"Rodriguez", "scopus_author_id"=>"24777158100"}, {"first_name"=>"Vincenzo", "last_name"=>"Calvanese", "scopus_author_id"=>"25624346100"}, {"first_name"=>"Miguel A.", "last_name"=>"Blanco-Gelaz", "scopus_author_id"=>"6602924104"}, {"first_name"=>"Steve T.", "last_name"=>"Suhr", "scopus_author_id"=>"6602515892"}, {"first_name"=>"Francisco", "last_name"=>"Ortega", "scopus_author_id"=>"56806356500"}, {"first_name"=>"Jesus", "last_name"=>"Otero", "scopus_author_id"=>"7102841727"}, {"first_name"=>"Jose B.", "last_name"=>"Cibelli", "scopus_author_id"=>"8442949600"}, {"first_name"=>"Harry", "last_name"=>"Moore", "scopus_author_id"=>"7202286939"}, {"first_name"=>"Mario F.", "last_name"=>"Fraga", "scopus_author_id"=>"7005319930"}, {"first_name"=>"Carlos", "last_name"=>"López-Larrea", "scopus_author_id"=>"7004945114"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"77956337898", "doi"=>"10.1371/journal.pone.0010192", "pui"=>"359482289", "pmid"=>"20419139", "scopus"=>"2-s2.0-77956337898", "issn"=>"19326203", "isbn"=>"1932-6203"}, "id"=>"d038297f-1697-36e3-a90c-3947fcabb7f7", "abstract"=>"Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored.</p> </sec><sec> <title>Methodology/Principal Findings</title> <p>We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation.</p> </sec><sec> <title>Conclusions/Significance</title> <p>Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.</p> </sec>", "link"=>"http://www.mendeley.com/research/epigenetic-mechanisms-regulate-mhc-antigen-processing-molecules-human-embryonic-induced-pluripotent", "reader_count"=>14, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Bachelor"=>3, "Professor"=>1, "Student > Doctoral Student"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>5, "Student > Bachelor"=>3, "Professor"=>1, "Student > Doctoral Student"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>8, "Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

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  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424727/Methods_S1.doc", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424760/Figure_S1.tif", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424803/Figure_S2.tif", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424840/Table_S1.xls", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424854/Table_S2.doc", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424898/Table_S3.doc", "https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/424928/Table_S4.doc"], "description"=>"<div><h3>Background</h3><p>Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored.</p><h3>Methodology/Principal Findings</h3><p>We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation.</p><h3>Conclusions/Significance</h3><p>Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.</p></div>", "links"=>[], "tags"=>["epigenetic", "mechanisms", "mhc", "antigen", "molecules", "embryonic", "induced", "pluripotent", "cells"], "article_id"=>143839, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/Epigenetic_Mechanisms_Regulate_MHC_and_Antigen_Processing_Molecules_in_Human_Embryonic_and_Induced_Pluripotent_Stem_Cells/143839", "title"=>"Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-04-16 01:03:59"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/853772/Figure_1.tif"], "description"=>"<p><b>A</b>) The expression of HLA class I and class II was determined by flow cytometry in undifferentiated Shef-1 and NT2 cell lines. The EBV-transformed B cell line Pitout, which expresses class I and class II, was used as positive control. HLA class I and class II were stained with an anti-pan HLA class I (anti-HLA-ABC mAb)-FITC and HLA-DR-PerCP respectively. Viable cells were gated using 7AAD staining. Thin lines show cells treated with isotype control and black histograms represent positive cells. Similar results were obtained from four independent experiments. <b>B</b>) Quantitative-PCR analysis of classical MHC class I molecules (HLA-A,–B and -C), non-classical MHC molecules (HLA-E,-F and –G), antigen processing molecules (TAP-1, TAP-2, TPN, CNX, CLR, ERp57, LMP2, LMP7) and the transcription factors RFX5 and CIITA in undifferentiated Shef-1 and NT2 cells, compared to the control, Pitout cell line. mRNA levels were normalized to GADPH mRNA. <b>C</b>) Quantitative-PCR analysis of the MHC genes and APM components in iPSCs and parental IMR90 fibroblast line. The upper right histogram has shown the expression levels of the pluripotent transcription factors Nanog and Oct-4 in fibroblast and iPSCs. mRNA levels were normalized to GADPH mRNA. The results of quantitative PCR are represented as means ± SD from triplicate experiments. * P<0.05.</p>", "links"=>[], "tags"=>["mhc", "molecules", "apm", "undifferentiated", "shef-1", "nt2"], "article_id"=>524209, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Expression_of_MHC_class_I_and_class_II_and_the_molecules_involved_in_the_APM_in_undifferentiated_Shef_1_and_NT2_cell_lines_/524209", "title"=>"Expression of MHC class I and class II, and the molecules involved in the APM in undifferentiated Shef-1 and NT2 cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-04-16 01:10:09"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/853882/Figure_2.tif"], "description"=>"<p>Expression levels of the MHC genes and APM components were analyzed by quantitative RT-PCR at different times during the differentiation process to EBs and neuronal precursors. Results are represented as fold up-regulation for each gene in differentiated cells compared to their undifferentiated cells. The results of quantitative PCR are represented as means ± SD from triplicate experiments. * P<0.05. Abbreviation; w: week; RA: Retinoic acid.</p>", "links"=>[], "tags"=>["mhc", "genes", "differentiation"], "article_id"=>524330, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Up_regulation_of_MHC_genes_during_the_differentiation_process_/524330", "title"=>"Up-regulation of MHC genes during the differentiation process.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-04-16 01:12:10"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/853969/Figure_3.tif"], "description"=>"<p>(<b>A</b>) The expression of NKG2D ligands was analyzed in undifferentiated Shef-1 and NT2 cells by flow cytometry using monoclonal antibodies against MICA, MICB, ULBP-1, ULBP-2 and ULBP-3 (1 µg of mAb for sample) followed by FITC-conjugated goat anti-mouse as secondary reagent. Dead cells were excluded by staining with 7AAD. Isotype controls were shown by thin lines and black histograms represented expression of each specific antibody. The HEK-293T cell line was used as positive control. All experiments were performed at least two - three times with similar results. Transcript levels of NKG2D ligands were analyzed by quantitative RT-PCR in undifferentiated human stem cells and during the differentiation process. Undifferentiated Shef-1 (<b>B</b>) and NT2 (<b>C</b>) cells were differentiated to EBs and neuronal precursors, respectively and the expression for NKG2D ligands was analyzed. The induced pluripotent stem cell line, MSUH-002 (<b>D</b>) was compared to parental fibroblast line. The HEK-293T cell line, which expresses mRNA of all the NKG2D ligands, was used as positive control. Histograms represented the relative expression of each gene normalized against the housekeeping gene GADPH. Data are represented as mean ± SD of three independent experiments. * P<0.05. Abbreviation; w: week; RA: Retinoic acid.</p>", "links"=>[], "tags"=>["nkg2d", "ligands", "cells", "undifferentiated", "differentiated"], "article_id"=>524413, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Expression_of_NKG2D_ligands_for_natural_killer_cells_in_undifferentiated_and_differentiated_human_stem_cells_/524413", "title"=>"Expression of NKG2D ligands for natural killer cells in undifferentiated and differentiated human stem cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-04-16 01:13:33"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/854080/Figure_4.tif"], "description"=>"<p><b>A</b>) MHC class I and II cell-surface expression in NT2 cells. Cells were treated with IFN-γ (100 U/ml for 24 h), 5aza-C (2 µM for 48 h), TSA (100 nM for 24 h) or a combination of both. After 24 h in culture, cells were stained with specific monoclonal antibodies for MHC class I and II or isotype controls and analyzed by flow cytometry. Isotype controls were shown by thin lines and black histograms represented expression detected by each specific antibody. The proportions of living, dead and apoptotic cells were determined with 7AAD and Annexin V-FITC. Similar results were obtained from three independent experiments. <b>B</b>) Quantitative PCR analysis of mRNA levels of MHC class I, class II and APM components in Shef-1 cells treated with epigenetic agents. Cells were cultured with 5aza-C (10 µM), TSA (100 nM) and IFN-γ (100 U/ml) alone, or in combination for 6 hours, and maintained for additional 24 h before RNA extraction. The histograms represented the fold increase of each gene after treatment compared to the basal level of untreated undifferentiated Shef-1 cells. Results were mean ± SD from three independent cultures. * P<0.05.</p>", "links"=>[], "tags"=>["treatments", "enhanced", "mhc", "ii", "undifferentiated", "embryonic"], "article_id"=>524524, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Epigenetic_treatments_enhanced_MHC_class_I_and_II_expression_in_undifferentiated_embryonic_stem_cells_/524524", "title"=>"Epigenetic treatments enhanced MHC class I and II expression in undifferentiated embryonic stem cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-04-16 01:15:24"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/854208/Figure_5.tif"], "description"=>"<p>The upper panels displayed a schematic map of each promoter region studied. The position of each CpG dinucleotide was depicted with thin vertical lines. Transcriptional start site is indicated by a thick vertical line and the +1 position indicated the translation start site. Arrows indicated the amplified region by RT-PCR for bisulfite sequencing analysis. In HLA-G, the horizontal gray line marked the CpG island. Ten clones were sequenced for each sample and each circle represented the average methylation for each CpG dinucleotide (open circle: 100% unmethylated, black circle: ≥50% CpG methylated, gray circle: <50% CpG methylated). The numbers denoted the position of each CpG site studied. Pitout cell line, which express MHC class I and II was used as control.</p>", "links"=>[], "tags"=>["ciita", "hla-dra", "promoter", "regions", "undifferentiated", "differentiated", "cells", "bisulfite", "sequencing"], "article_id"=>524644, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Methylation_profile_of_HLA_G_CIITA_and_HLA_DRA_promoter_regions_in_undifferentiated_and_differentiated_cells_by_bisulfite_sequencing_analysis_/524644", "title"=>"Methylation profile of HLA-G, CIITA and HLA-DRA promoter regions in undifferentiated and differentiated cells by bisulfite sequencing analysis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-04-16 01:17:24"}
  • {"files"=>["https://s3-eu-west-1.amazonaws.com/pstorage-plos-3567654/854309/Figure_6.tif"], "description"=>"<p>Levels of the trimethylation H3-K4 (active mark, H3K4me3) and H3-K9 (repressive mark, H3K9me3) were determined at selected regions of MHC genes and APM components in: <b>A</b>) undifferentiated Shef-1 cells (white columns), or embryoid bodies (EBs) (black columns) formed after 10–15 d differentiation in culture and <b>B</b>) IMR90 human fibroblast (light gray columns) and MSUH-002 cells (dark gray columns). Cells were subjected to ChIP assay using antibodies against H3K4me3 and H3K9me3, and analyzed by quantitative PCR with specific primers for each gene. Normal rabbit IgG was used as negative control for the specificity of the immunoprecipitation (IP). As a positive control, aliquots of chromatin fragments obtained before IP were also subjected to Q-PCR analysis (Input). Immunoprecipitated DNA associated with a given histone modification was normalized to a 100-fold dilution of input chromatin. Data are expressed as fold enrichment of each modification compared to negative control antibody (normal rabbit IgG), and represented mean ± SD of two representative experiments with similar results (*P<0.05: **P<0.01).</p>", "links"=>[], "tags"=>["histones", "h3-k4", "h3-k9", "regulated", "mhc", "hes", "ips"], "article_id"=>524752, "categories"=>["Immunology", "Cell Biology", "Genetics"], "users"=>["Beatriz Suárez-Álvarez", "Ramón M. Rodriguez", "Vincenzo Calvanese", "Miguel A. Blanco-Gelaz", "Steve T. Suhr", "Francisco Ortega", "Jesus Otero", "Jose B. Cibelli", "Harry Moore", "Mario F. Fraga", "Carlos López-Larrea"], "doi"=>["http://dx.doi.org/10.1371/journal.pone.0010192.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"http://figshare.com/articles/_Methylation_of_histones_H3_K4_and_H3_K9_regulated_MHC_expression_in_hES_and_iPS_cells_/524752", "title"=>"Methylation of histones H3-K4 and H3-K9 regulated MHC expression in hES and iPS cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-04-16 01:19:12"}

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  • {"unique-ip"=>"16", "full-text"=>"12", "pdf"=>"8", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"10"}
  • {"unique-ip"=>"12", "full-text"=>"13", "pdf"=>"8", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
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  • {"unique-ip"=>"13", "full-text"=>"9", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"12"}
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  • {"unique-ip"=>"10", "full-text"=>"9", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2015", "month"=>"11"}
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  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
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  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"9"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
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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"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
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  • {"unique-ip"=>"20", "full-text"=>"27", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"35", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
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  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"11", "full-text"=>"8", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"11", "full-text"=>"8", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"12", "full-text"=>"10", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"27", "full-text"=>"23", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"4", "cited-by"=>"2", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"15", "full-text"=>"15", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"13", "full-text"=>"15", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"15", "full-text"=>"15", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"16", "full-text"=>"14", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"8", "full-text"=>"8", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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Relative Metric

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