Multiparameter RNA and Codon Optimization: A Standardized Tool to Assess and Enhance Autologous Mammalian Gene Expression
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{"title"=>"Multiparameter RNA and codon optimization: A standardized tool to assess and enhance autologous mammalian gene expression", "type"=>"journal", "authors"=>[{"first_name"=>"Stephan", "last_name"=>"Fath", "scopus_author_id"=>"35953584100"}, {"first_name"=>"Asli Petra", "last_name"=>"Bauer", "scopus_author_id"=>"36342231500"}, {"first_name"=>"Michael", "last_name"=>"Liss", "scopus_author_id"=>"57130361000"}, {"first_name"=>"Anne", "last_name"=>"Spriestersbach", "scopus_author_id"=>"35209013000"}, {"first_name"=>"Barbara", "last_name"=>"Maertens", "scopus_author_id"=>"35080804700"}, {"first_name"=>"Peter", "last_name"=>"Hahn", "scopus_author_id"=>"25421562300"}, {"first_name"=>"Christine", "last_name"=>"Ludwig", "scopus_author_id"=>"14063731600"}, {"first_name"=>"Frank", "last_name"=>"Schäfer", "scopus_author_id"=>"8509756000"}, {"first_name"=>"Marcus", "last_name"=>"Graf", "scopus_author_id"=>"7203048437"}, {"first_name"=>"Ralf", "last_name"=>"Wagner", "scopus_author_id"=>"7404299375"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"21408612", "doi"=>"10.1371/journal.pone.0017596", "sgr"=>"79952289327", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "scopus"=>"2-s2.0-79952289327", "issn"=>"19326203", "pui"=>"361382330"}, "id"=>"2c7a2689-a952-365a-9ac1-b2369c2a09db", "abstract"=>"Autologous expression of recombinant human proteins in human cells for biomedical research and product development is often hampered by low expression yields limiting subsequent structural and functional analyses. Following RNA and codon optimization, 50 candidate genes representing five classes of human proteins--transcription factors, ribosomal and polymerase subunits, protein kinases, membrane proteins and immunomodulators--all showed reliable, and 86% even elevated expression. Analysis of three representative examples showed no detrimental effect on protein solubility while unaltered functionality was demonstrated for JNK1, JNK3 and CDC2 using optimized constructs. Molecular analysis of a sequence-optimized transgene revealed positive effects at transcriptional, translational, and mRNA stability levels. Since improved expression was consistent in HEK293T, CHO and insect cells, it was not restricted to distinct mammalian cell systems. Additionally, optimized genes represent powerful tools in functional genomics, as demonstrated by the successful rescue of an siRNA-mediated knockdown using a sequence-optimized counterpart. This is the first large-scale study addressing the influence of multiparameter optimization on autologous human protein expression.", "link"=>"http://www.mendeley.com/research/multiparameter-rna-codon-optimization-standardized-tool-assess-enhance-autologous-mammalian-gene-exp", "reader_count"=>226, "reader_count_by_academic_status"=>{"Unspecified"=>6, "Professor > Associate Professor"=>2, "Researcher"=>86, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>64, "Student > Postgraduate"=>9, "Student > Master"=>19, "Other"=>20, "Student > Bachelor"=>8, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>6, "Professor > Associate Professor"=>2, "Researcher"=>86, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>64, "Student > Postgraduate"=>9, "Student > Master"=>19, "Other"=>20, "Student > Bachelor"=>8, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Engineering"=>5, "Biochemistry, Genetics and Molecular Biology"=>39, "Agricultural and Biological Sciences"=>152, "Medicine and Dentistry"=>10, "Neuroscience"=>1, "Business, Management and Accounting"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemical Engineering"=>1, "Chemistry"=>1, "Computer Science"=>6, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>5}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>152}, "Computer Science"=>{"Computer Science"=>6}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>39}, "Unspecified"=>{"Unspecified"=>8}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Chemical Engineering"=>{"Chemical Engineering"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "Austria"=>1, "Belgium"=>1, "United States"=>6, "Ireland"=>1, "Denmark"=>1, "United Kingdom"=>3, "Australia"=>2, "Germany"=>1, "Spain"=>2}, "group_count"=>7}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/397159"], "description"=>"<div><p>Autologous expression of recombinant human proteins in human cells for biomedical research and product development is often hampered by low expression yields limiting subsequent structural and functional analyses. Following RNA and codon optimization, 50 candidate genes representing five classes of human proteins – transcription factors, ribosomal and polymerase subunits, protein kinases, membrane proteins and immunomodulators – all showed reliable, and 86% even elevated expression. Analysis of three representative examples showed no detrimental effect on protein solubility while unaltered functionality was demonstrated for JNK1, JNK3 and CDC2 using optimized constructs. Molecular analysis of a sequence-optimized transgene revealed positive effects at transcriptional, translational, and mRNA stability levels. Since improved expression was consistent in HEK293T, CHO and insect cells, it was not restricted to distinct mammalian cell systems. Additionally, optimized genes represent powerful tools in functional genomics, as demonstrated by the successful rescue of an siRNA-mediated knockdown using a sequence-optimized counterpart. This is the first large-scale study addressing the influence of multiparameter optimization on autologous human protein expression.</p> </div>", "links"=>[], "tags"=>["multiparameter", "rna", "codon", "standardized", "autologous", "mammalian"], "article_id"=>138439, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Multiparameter_RNA_and_Codon_Optimization_A_Standardized_Tool_to_Assess_and_Enhance_Autologous_Mammalian_Gene_Expression/138439", "title"=>"Multiparameter RNA and Codon Optimization: A Standardized Tool to Assess and Enhance Autologous Mammalian Gene Expression", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-03 02:20:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/794070"], "description"=>"<p>(A) Each protein was expressed in triplicate (PP, plasmid preparation) in HEK293T cells. Either cell supernatants (immunomodulators, IM) or cell lysates (all other protein classes) were harvested and analyzed by Western blots using the α-Penta-His antibody. One example from each protein class is shown. A cross-reactive 60 kD band used to standardize protein amounts is visible, including in the empty vector negative controls (mock). Left: molecular weight markers, right: arrows indicating specific protein bands. (B) After quantifying Western blot signals, relative expression levels were derived from comparing mean expression (three independent transfections) of wildtype or optimized constructs, with wildtype set to 1 (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017596#pone-0017596-t001\" target=\"_blank\">Table 1</a>). The x-fold expression increase following gene optimization is indicated for each protein (only opt  =  no detectable wildtype expression). (C) Summary of relative expression levels of all proteins analyzed in each protein class. Average variations ≥10% were considered improved expression. (D) Statistical analysis of gene expression of (n) constructs in each protein class. Expression lists the number (n) and percent (%) of wildtype and optimized gene constructs expressed (successful) or not expressed (unsuccessful). Median opt/wt values of relative expression were calculated from total expression ratios derived as described above: opt/wt>1 indicates higher expression of optimized sequences. Where only the optimized construct was expressed, the opt/wt ratio was set to 2 for median calculation. Cases of opt>wt show the percentage of optimized constructs with elevated protein expression.</p>", "links"=>[], "tags"=>["wildtype", "optimized", "genes"], "article_id"=>464430, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparative_expression_analysis_of_wildtype_versus_optimized_genes_representing_different_protein_classes_/464430", "title"=>"Comparative expression analysis of wildtype <i>versus</i> optimized genes representing different protein classes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:13:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/794165"], "description"=>"<p>(A) Expression statistics for five representative proteins from each protein class. Mammalian HEK293T and CHO-K1 cells were transiently transfected in triplicate, whereas insect-Sf9 cells were transfected in duplicate. Relative protein expression of wildtype <i>versus</i> optimized genes (ratio wt:opt) was calculated from the mean expression values as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017596#pone-0017596-g001\" target=\"_blank\">Figure 1:</a> (+) better expression of optimized gene; ( = ) comparable expression of both genes; (−) better expression of wildtype gene. (B) Western blot analyses of three representative proteins (panels left to right) transfected using three independent plasmid preparations (PP) into HEK293T and CHO-K1 cells, or two independent plasmid preparations into Sf9 cells (panels top to bottom). Signals from HEK293T and CHO-K1 cells were standardized against the ∼60 kD cross-reactive band serving as loading control (visible also in the mock negative control lane). Left: molecular weight markers, right: the x-fold increase (+), decrease (−) or equivalence ( = ) in expression of the optimized genes.</p>", "links"=>[], "tags"=>["wildtype", "sequence-optimized", "constructs", "cho-k1", "insect-sf9"], "article_id"=>464523, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparative_expression_of_human_wildtype_and_human_sequence_optimized_gene_constructs_in_HEK293T_CHO_K1_and_insect_Sf9_cells_/464523", "title"=>"Comparative expression of human wildtype and human sequence-optimized gene constructs in HEK293T, CHO-K1 and insect-Sf9 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:15:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/794256"], "description"=>"<p>(A) Relative protein expression levels of wildtype or optimized <i>mip1α</i> genes stably expressed in CHO-K1 cells were calculated from the mean values* measured by ELISA. (B) <i>De novo</i> transcription of RNA was measured by nuclear run-on assays. Cell nuclei were incubated with biotin-16-labeled dUTPs, separated via streptavidin-labeled magnetic beads, reverse-transcribed, and the resulting cDNAs were quantified by real-time PCR. <i>De novo</i> synthesized <i>mip-1α</i> transcripts* were normalized to <i>hph</i> cDNA levels, and the wildtype value* was set to 100%. (C) To determine mRNA stability both cell lines were incubated with 2.4 µM Actinomycin D for 0, 1.5, 3, 6, 12 and 24 hours. Total RNA was extracted at the respective time points and <i>mip-1α</i> mRNA levels quantified by real-time PCR were standardized against <i>hph-</i>specific mRNA amounts to obtain relative <i>mip-1α</i> mRNA half-lives of wildtype and optimized genes*. (D) Nuclear or cytoplasmic <i>mip-1α</i> mRNAs (2 µg) were subjected to Northern blot analysis using a DIG-labeled probe hybridizing to the BGH-polyA signal. Beta-actin served as an internal loading control. (E) Total RNA was separated from nuclear and cytoplasmic fractions, reverse-transcribed, and subjected to quantitative SYBR-Green real-time PCR using specific primers for both gene variants and the <i>hph</i> gene internal control. The resulting <i>mip-1α</i> cDNAs were verified by sequencing and amounts were standardized to <i>hph</i> cDNA levels to obtain mean mRNA steady-state values*. (F) To determine translation rates, HEK293T cells were infected with MVA-T7 prior to transient transfection with <i>mip-1α</i> variants under the control of a T7-promoter (+MVA). Transfected but uninfected cells served as negative controls (-MVA). Protein levels in cell supernatants were determined 24 hours post-transfection by ELISA. Expression levels obtained from wildtype transfections of infected cells were set to 100% and values from optimized genes were calculated accordingly. *Mean values derived from 2 independent experiments. <b>+</b> indicates relative improvements due to gene optimization.</p>", "links"=>[], "tags"=>["optimization", "expression-related", "mechanisms", "acting", "stably"], "article_id"=>464616, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Influence_of_sequence_optimization_on_expression_related_mechanisms_acting_on_stably_integrated_mip1_945_genes_/464616", "title"=>"Influence of sequence optimization on expression-related mechanisms acting on stably integrated <i>mip1α</i> genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:16:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/794340"], "description"=>"<p>(A) HEK293T cells were transiently transfected with three different plasmid preparations (PP) of wildtype or optimized <i>jnk1, jnk3 and p38a-kinase</i> genes. Cells were lysed under mild conditions followed by subsequent centrifugation for 30 min at 16000 g and protein expression was analyzed by Western blots using the α-Penta-His antibody. Protein expression levels were standardized against the cross-reactive 60 kD protein band displayed on the blots. Relative expression was determined by relating the mean value obtained from optimized genes to the mean value of wildtype genes, with wildtype set at 1. (B) JNK1-kinase assay. Recombinant kinase proteins were purified from cell lysates and saturating amounts were pulled down with GST-c-Jun beads. Equal amounts of the protein complexes were subjected to Western blot analysis using the α-Penta-His antibody, JNK1 protein amounts in each sample were standardized against the cross-reactive 60 kD band. Kinase activity was quantified by <i>in vitro</i> phosphorylation of the bead-bound c-Jun substrate in the presence of ATP and subsequent detection of phosphorylated c-Jun proteins in Western blots using the antibody α-P-Ser63. (C) JNK3-kinase assay was carried out as described in (B).</p>", "links"=>[], "tags"=>["jnk1-", "jnk3", "kinase"], "article_id"=>464697, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Solubility_testing_and_in_vitro_analysis_of_JNK1_and_JNK3_specific_kinase_activity_/464697", "title"=>"Solubility testing and <i>in vitro</i> analysis of JNK1- and JNK3 specific kinase activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:18:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/794424"], "description"=>"<p>(A) Cells were transiently transfected with three different plasmid preparations (PP) of wildtype and optimized <i>cdc2</i> genes and expression levels were analyzed by Western blotting using the α-Penta-His antibody. Relative expression was determined as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017596#pone-0017596-g001\" target=\"_blank\">Figure 1</a>. (B) Untreated MCF-7 cells, or cells transfected with CDC2 siRNA only (knock-down), CDC2 siRNA plus the optimized <i>cdc2</i> gene (rescue), or a non-silencing siRNA plus the optimized <i>cdc2</i> construct were stained with propidium iodide after 72 hours and subjected to FACS analysis to determine cell-cycle distribution. The percentage of negative control cells compared to knockdown phenotype cells shifted from 16.2%/14.9% to 36.3%, i.e. around 20%. Negative control cells compared to rescued cells shifted from 16.2%/14.9% to 23.4%, i.e. around 8%, indicating that the optimized <i>cdc2</i> construct rescued around 60% of cells from knock-down. Endogenous CDC2 knockdown was confirmed by real-time RT-PCR with primers exclusively detecting endogenous <i>cdc2</i>, whereas expression of exogenous CDC2 from the sequence-optimized construct was confirmed by real-time RT-PCR with primers exclusively detecting exogenous <i>cdc2</i> (data not shown). (C) Schematic representation of the expression cassette in plasmid pQE-Tri-System6 containing the optimized <i>cdc2</i> gene sequence and the siRNA target site in the 3′ untranslated region. (D) The specificity of siRNA-mediated knockdown was tested by co-transfecting three sequence-optimized genes from different protein classes with site-specific or non-silencing siRNAs, followed by analyzing protein expression by Western blots.</p>", "links"=>[], "tags"=>["sirna-mediated", "knock-down", "endogenous", "optimized"], "article_id"=>464784, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rescue_of_siRNA_mediated_knock_down_of_an_endogenous_gene_with_an_optimized_gene_variant_/464784", "title"=>"Rescue of siRNA-mediated knock-down of an endogenous gene with an optimized gene variant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-03 01:19:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/794496"], "description"=>"<p>Columns left to right: Ref_seq.: Gene Bank accession number; symbol: encoded protein, e.g. <sup>*</sup>Serotonin-TP  =  Serotonin transporter; PC: protein class (TF  =  transcription factor; RB  =  ribosomal protein; PK  =  kinase; MP  =  membrane protein; IM  =  immunomodulator; and two other proteins); length: size of open reading frame in base pairs; CAI (codon adaptation index) <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017596#pone.0017596-Graf3\" target=\"_blank\">[19]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017596#pone.0017596-Sharp1\" target=\"_blank\">[48]</a>: measure for the “relative adaptability” of the codon usage of the gene of interest to codons used in highly expressed genes. The CAI represents the geometric mean of the relative adaptiveness values of the used codons. The relative adaptiveness value of a synonymous codon represents the ratio of the frequency of this codon in the codon usage of a given expression system and the frequency of the most frequent synonymous codon for the specific amino acid, leading to a value of 1.0 for the optimal codon and less frequently used codons are scaled down accordingly. %GC: percentage of GC-content in the respective transgene; codons altered (n): total number of codons altered in the open reading frame; codons altered (%): percentage of codons altered in the open reading frame; ratio expression wt: opt: mean expression from three independent transfections of wildtype genes were set to 1 and then compared to the mean expression of optimized genes; expression statistics: wtopt: −. Average variations ≥10% were considered an improvement in expression (<b>+</b>).</p>", "links"=>[], "tags"=>["levels", "50", "wildtype", "sequence-optimized"], "article_id"=>464857, "categories"=>["Biotechnology", "Molecular Biology", "Biochemistry", "Genetics"], "users"=>["Stephan Fath", "Asli Petra Bauer", "Michael Liss", "Anne Spriestersbach", "Barbara Maertens", "Peter Hahn", "Christine Ludwig", "Frank Schäfer", "Marcus Graf", "Ralf Wagner"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017596.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Direct_comparison_of_expression_levels_of_50_wildtype_and_sequence_optimized_human_genes_/464857", "title"=>"Direct comparison of expression levels of 50 wildtype and sequence-optimized human genes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-03 01:20:57"}

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  • {"unique-ip"=>"29", "full-text"=>"32", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
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  • {"unique-ip"=>"32", "full-text"=>"30", "pdf"=>"12", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
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  • {"unique-ip"=>"58", "full-text"=>"81", "pdf"=>"13", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"63", "full-text"=>"78", "pdf"=>"25", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"44", "full-text"=>"54", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
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  • {"unique-ip"=>"36", "full-text"=>"78", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"20", "supp-data"=>"1", "cited-by"=>"2", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"22", "full-text"=>"23", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
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Relative Metric

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