Enhancement of Allele Discrimination by Introduction of Nucleotide Mismatches into siRNA in Allele-Specific Gene Silencing by RNAi
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Mendeley | Further Information

{"title"=>"Enhancement of allele discrimination by introduction of nucleotide mismatches into siRNA in allele-specific gene silencing by RNAi", "type"=>"journal", "authors"=>[{"first_name"=>"Yusuke", "last_name"=>"Ohnishi", "scopus_author_id"=>"8319887400"}, {"first_name"=>"Yoshiko", "last_name"=>"Tamura", "scopus_author_id"=>"16319549400"}, {"first_name"=>"Mariko", "last_name"=>"Yoshida", "scopus_author_id"=>"7601543131"}, {"first_name"=>"Katsushi", "last_name"=>"Tokunaga", "scopus_author_id"=>"55066408600"}, {"first_name"=>"Hirohiko", "last_name"=>"Hohjoh", "scopus_author_id"=>"7003341768"}], "year"=>2008, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "pmid"=>"18493311", "scopus"=>"2-s2.0-48249098892", "doi"=>"10.1371/journal.pone.0002248", "sgr"=>"48249098892", "pui"=>"352069197"}, "id"=>"77ea1b04-7e29-3329-baaf-8d085690967a", "abstract"=>"Allele-specific gene silencing by RNA interference (RNAi) is therapeutically useful for specifically inhibiting the expression of disease-associated alleles without suppressing the expression of corresponding wild-type alleles. To realize such allele-specific RNAi (ASP-RNAi), the design and assessment of small interfering RNA (siRNA) duplexes conferring ASP-RNAi is vital; however, it is also difficult. In a previous study, we developed an assay system to assess ASP-RNAi with mutant and wild-type reporter alleles encoding the Photinus and Renilla luciferase genes. In line with experiments using the system, we realized that it is necessary and important to enhance allele discrimination between mutant and corresponding wild-type alleles. Here, we describe the improvement of ASP-RNAi against mutant alleles carrying single nucleotide variations by introducing base substitutions into siRNA sequences, where original variations are present in the central position. Artificially mismatched siRNAs or short-hairpin RNAs (shRNAs) against mutant alleles of the human Prion Protein (PRNP) gene, which appear to be associated with susceptibility to prion diseases, were examined using this assessment system. The data indicates that introduction of a one-base mismatch into the siRNAs and shRNAs was able to enhance discrimination between the mutant and wild-type alleles. Interestingly, the introduced mismatches that conferred marked improvement in ASP-RNAi, appeared to be largely present in the guide siRNA elements, corresponding to the 'seed region' of microRNAs. Due to the essential role of the 'seed region' of microRNAs in their association with target RNAs, it is conceivable that disruption of the base-pairing interactions in the corresponding seed region, as well as the central position (involved in cleavage of target RNAs), of guide siRNA elements could influence allele discrimination. In addition, we also suggest that nucleotide mismatches at the 3'-ends of sense-strand siRNA elements, which possibly increase the assembly of antisense-strand (guide) siRNAs into RNA-induced silencing complexes (RISCs), may enhance ASP-RNAi in the case of inert siRNA duplexes. Therefore, the data presented here suggest that structural modification of functional portions of an siRNA duplex by base substitution could greatly influence allele discrimination and gene silencing, thereby contributing to enhancement of ASP-RNAi.", "link"=>"http://www.mendeley.com/research/enhancement-allele-discrimination-introduction-nucleotide-mismatches-sirna-allelespecific-gene-silen", "reader_count"=>46, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>12, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>12, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>11, "Materials Science"=>1, "Agricultural and Biological Sciences"=>28, "Medicine and Dentistry"=>4, "Neuroscience"=>1, "Business, Management and Accounting"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Neuroscience"=>{"Neuroscience"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>28}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}}, "reader_count_by_country"=>{"United States"=>1, "South Africa"=>3, "France"=>1}, "group_count"=>2}

Scopus | Further Information

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  • {"month"=>"8", "year"=>"2019", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"4"}
  • {"month"=>"9", "year"=>"2019", "pdf_views"=>"2", "xml_views"=>"0", "html_views"=>"6"}
  • {"month"=>"10", "year"=>"2019", "pdf_views"=>"1", "xml_views"=>"0", "html_views"=>"0"}

Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/931122"], "description"=>"<p>(A) Schematic drawing of conventional and forked siRNA duplexes. Each box represents a ribonucleotide, and antisense-stranded siRNA elements are indicated by gray boxes. (B)-(E) Comparison of ASP-RNAi activities between conventional (Conv.) and forked (Fork) siRNA duplexes. Assessment of conventional and forked siRNA duplexes against the London <i>V717I</i> (B), <i>V717F</i> (C), and <i>V717G</i> (D) <i>APP</i> mutants and the Swedish (E) <i>APP</i> mutant was carried out as described previously <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#pone.0002248-Ohnishi1\" target=\"_blank\">[17]</a>. The ratios of mutant and wild-type luciferase activities in the presence of siRNA duplexes were normalized against the control ratio obtained in the presence of siControl duplex. Data are averages of at least three independent determinations. Error bars represent standard deviations.</p>", "links"=>[], "tags"=>["forked", "sirna", "duplexes", "aps-rnai"], "article_id"=>601568, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002248.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_forked_siRNA_duplexes_on_APS_RNAi_against_APP_mutants_/601568", "title"=>"Effects of forked siRNA duplexes on APS-RNAi against <i>APP</i> mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-21 00:26:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/931056"], "description"=>"<p>(A) sh102(T9), sh102(T9)-12C, sh102(T9)-14U, sh102(T9)-15U and shCont shRNA expression plasmids for production of siPrnp102(T9), (T9)-12C, (T9)-14U and (T9)-15U duplexes and siControl duplex, respectively, were constructed with reporter alleles and their effects on ASP-RNAi were examined as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#pone-0002248-g001\" target=\"_blank\">Figure 1</a>. Western blot analysis of the wild-type (B) and P102L (C) PRNP polypeptides was carried out as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#pone-0002248-g002\" target=\"_blank\">Figure 2</a>.</p>", "links"=>[], "tags"=>["mismatched", "shrna", "plasmids"], "article_id"=>601499, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002248.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ASP_RNAi_with_mismatched_shRNA_expression_plasmids_against_the_PRNP_P102L_mutant_/601499", "title"=>"ASP-RNAi with mismatched shRNA expression plasmids against the <i>PRNP-P102L</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-21 00:24:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/458839", "https://ndownloader.figshare.com/files/458869", "https://ndownloader.figshare.com/files/458902", "https://ndownloader.figshare.com/files/458933", "https://ndownloader.figshare.com/files/458972", "https://ndownloader.figshare.com/files/459023", "https://ndownloader.figshare.com/files/459064", "https://ndownloader.figshare.com/files/459105", "https://ndownloader.figshare.com/files/459143", "https://ndownloader.figshare.com/files/459180"], "description"=>"<div><p>Allele-specific gene silencing by RNA interference (RNAi) is therapeutically useful for specifically inhibiting the expression of disease-associated alleles without suppressing the expression of corresponding wild-type alleles. To realize such allele-specific RNAi (ASP-RNAi), the design and assessment of small interfering RNA (siRNA) duplexes conferring ASP-RNAi is vital; however, it is also difficult. In a previous study, we developed an assay system to assess ASP-RNAi with mutant and wild-type reporter alleles encoding the <em>Photinus</em> and <em>Renilla luciferase</em> genes. In line with experiments using the system, we realized that it is necessary and important to enhance allele discrimination between mutant and corresponding wild-type alleles. Here, we describe the improvement of ASP-RNAi against mutant alleles carrying single nucleotide variations by introducing base substitutions into siRNA sequences, where original variations are present in the central position. Artificially mismatched siRNAs or short-hairpin RNAs (shRNAs) against mutant alleles of the human <em>Prion Protein</em> (<em>PRNP</em>) gene, which appear to be associated with susceptibility to prion diseases, were examined using this assessment system. The data indicates that introduction of a one-base mismatch into the siRNAs and shRNAs was able to enhance discrimination between the mutant and wild-type alleles. Interestingly, the introduced mismatches that conferred marked improvement in ASP-RNAi, appeared to be largely present in the guide siRNA elements, corresponding to the ‘seed region’ of microRNAs. Due to the essential role of the ‘seed region’ of microRNAs in their association with target RNAs, it is conceivable that disruption of the base-pairing interactions in the corresponding seed region, as well as the central position (involved in cleavage of target RNAs), of guide siRNA elements could influence allele discrimination. In addition, we also suggest that nucleotide mismatches at the 3′-ends of sense-strand siRNA elements, which possibly increase the assembly of antisense-strand (guide) siRNAs into RNA-induced silencing complexes (RISCs), may enhance ASP-RNAi in the case of inert siRNA duplexes. Therefore, the data presented here suggest that structural modification of functional portions of an siRNA duplex by base substitution could greatly influence allele discrimination and gene silencing, thereby contributing to enhancement of ASP-RNAi.</p></div>", "links"=>[], "tags"=>["enhancement", "allele", "nucleotide", "mismatches", "sirna", "allele-specific", "rnai"], "article_id"=>150403, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0002248.s001", "https://dx.doi.org/10.1371/journal.pone.0002248.s002", "https://dx.doi.org/10.1371/journal.pone.0002248.s003", "https://dx.doi.org/10.1371/journal.pone.0002248.s004", "https://dx.doi.org/10.1371/journal.pone.0002248.s005", "https://dx.doi.org/10.1371/journal.pone.0002248.s006", "https://dx.doi.org/10.1371/journal.pone.0002248.s007", "https://dx.doi.org/10.1371/journal.pone.0002248.s008", "https://dx.doi.org/10.1371/journal.pone.0002248.s009", "https://dx.doi.org/10.1371/journal.pone.0002248.s010"], "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Enhancement_of_Allele_Discrimination_by_Introduction_of_Nucleotide_Mismatches_into_siRNA_in_Allele_Specific_Gene_Silencing_by_RNAi/150403", "title"=>"Enhancement of Allele Discrimination by Introduction of Nucleotide Mismatches into siRNA in Allele-Specific Gene Silencing by RNAi", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-05-21 00:06:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/930954"], "description"=>"<p>(A) Schematic drawing of reporter alleles. Reporter alleles were constructed by inserting synthetic oligonucleotides of mutant and wild-type allelic sequences into the 3′-UTRs of the reporter genes driven by the same TK promoter (indicated by arrows). Assessment of designed siRNA duplexes against the mutant allele was carried out as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#s4\" target=\"_blank\">Materials and Methods</a>. Effects of designed siRNA duplexes against the <i>PRNP-P102L</i> (B), <i>PRNP -P105L</i> (C), and <i>PRNP -D178N</i> (D) mutants on ASP-RNAi. Reporter alleles, synthetic siRNA duplexes against the mutant alleles (indicated) and the <i>β-galactosidase</i> gene (control) were cotransfected into HeLa cells. Twenty-four hours after transfection, expression levels of the reporter genes were examined. Levels of either mutant allele (pink boxes) or wild-type allele (blue boxes) luciferase activity were normalized against the levels of β-galactosidase activity, and the ratios of mutant and wild-type luciferase activities in the presence of siRNA duplexes were normalized against the control ratios obtained in the presence of siControl duplex (siCont). Data are averages of at least three independent determinations. Error bars represent standard deviations.</p>", "links"=>[], "tags"=>["asp-rnai"], "article_id"=>601396, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002248.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Assessment_of_ASP_RNAi_with_reporter_alleles_/601396", "title"=>"Assessment of ASP-RNAi with reporter alleles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-21 00:23:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/931008"], "description"=>"<p>(A, E) Nucleotide sequences of wild-type and mutant <i>PRNP</i> mRNAs and designed siRNAs. The wild-type and mutant <i>PRNP</i> mRNA sequences around the P102L (A) and P105L (E) variations are shown and the variations are indicated in red. Designed siRNAs (indicated) are represented based on the sequence of the sense-strand (passenger) siRNA element; mismatched nucleotides (introduced base substitutions) and the original variations are indicated in blue and red, respectively. The same sequences as the siPrnp102(T9) or siPrnp105(T10) are represented by thin lines. (B, F) Effects of mismatched siPrnp102(T9) and siPrnp105(T10) on ASP-RNAi. Mismatched siPrnp102(T9) (B) and siPrnp105(T10) (E) duplexes (indicated) were examined as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#pone-0002248-g001\" target=\"_blank\">Figure 1</a>. The ratio of wild-type allele-luciferase activity against the mutant allele-luciferase activity (WT/Mut) was also examined to evaluate the improvement in ASP-RNAi. Data are averages of at least three independent determinations. Error bars represent standard deviations. Expression of the wild-type (C, G) and mutant [P102L (D) and P105L (H)] PRNP polypeptides (PRNPmut102-V5 and PRNPmut102-V5) in the presence of indicated siRNA duplexes was investigated by Western blotting using anti-V5 antibody. Expression of α-tubulin was examined as the control.</p>", "links"=>[], "tags"=>["mismatched", "duplexes"], "article_id"=>601450, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002248.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Assessment_of_mismatched_siPrnp102_T9_and_siPrnp105_T10_duplexes_on_ASP_RNAi_/601450", "title"=>"Assessment of mismatched siPrnp102(T9) and siPrnp105(T10) duplexes on ASP-RNAi.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-21 00:24:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/931188"], "description"=>"<p>(A) Nucleotide sequences of <i>HOXB8</i> mRNA, miR-196a and miR-196b. The <i>HOXB8</i> mRNA sequence, which is nearly complementary to miR-196a, together with mature miR-196a and miR-196b are aligned. Perfect base-pairing and G:U wobble base-pairing are indicated by the horizontal bars and dot, respectively. The mismatched base in miR-196b is indicated in red. (B) Effects of miR-196a and miR-196b on gene silencing against <i>HOXB8</i>. The miR-196a and miR-196b duplexes were chemically synthesized, as described previously <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#pone.0002248-Yekta1\" target=\"_blank\">[31]</a>. The synthetic miRNA duplexes, together with a reporter plasmid carrying a part of the <i>HOXB8</i> gene (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002248#s4\" target=\"_blank\">Materials and Methods</a>), were cotransfected into HeLa cells and the expression of reporter gene was examined. Ratios of normalized target (<i>Renilla</i>) luciferase activity to control (<i>Photinus</i>) luciferase activity are shown. Data are averages of at least three independent experiments. Error bars represent standard deviations.</p>", "links"=>[], "tags"=>["knockdown", "potencies", "mir-196a"], "article_id"=>601635, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002248.g005", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Different_knockdown_potencies_against_HOXB8_between_miR_196a_and_miR_196b_/601635", "title"=>"Different knockdown potencies against <i>HOXB8</i> between miR-196a and miR-196b.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-21 00:27:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/931235"], "description"=>"<p>Guide siRNA elements in RISCs are indicated by gray bars, in which nucleotide variation and the seed region are indicated by red and blue boxes, respectively. Introduced base substitutions are indicated by green boxes. Mutant and wild-type allelic transcripts are indicated by red and blue lines, respectively. (A) When designed siRNA targeting the mutant allele has potential for potent gene silencing, not only the mutant but also the wild-type alleles may be inhibited by RNAi mediated by the siRNA, i.e., double knockdown against both alleles may occur. (B) When a one-base substitution is introduced into the seed region of an siRNA conferring double knockdown, the resultant (guide) siRNA generates one and two mismatches against the mutant and wild-type alleles, respectively, thereby possibly gaining the ability to induce ASP-RNAi.</p>", "links"=>[], "tags"=>["allele-specific", "mismatched"], "article_id"=>601682, "categories"=>["Genetics", "Neuroscience"], "users"=>["Yusuke Ohnishi", "Yoshiko Tamura", "Mariko Yoshida", "Katsushi Tokunaga", "Hirohiko Hohjoh"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002248.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_summary_of_allele_specific_gene_silencing_with_mismatched_siRNA_/601682", "title"=>"Schematic summary of allele-specific gene silencing with mismatched siRNA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-21 00:28:02"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"8", "full-text"=>"5", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"16", "full-text"=>"19", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
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  • {"unique-ip"=>"5", "full-text"=>"6", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"9", "full-text"=>"11", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"20", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"10", "full-text"=>"8", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"5", "full-text"=>"6", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}

Relative Metric

{"start_date"=>"2008-01-01T00:00:00Z", "end_date"=>"2008-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[324, 674, 863, 1015, 1146, 1259, 1360, 1452, 1540, 1621, 1704, 1776, 1843, 1905, 1968, 2029, 2097, 2162, 2233, 2289, 2352, 2412, 2476, 2538, 2601, 2655, 2714, 2777, 2841, 2894, 2946, 2998, 3047, 3103, 3151, 3201, 3258, 3317, 3369, 3424, 3471, 3521, 3583, 3625, 3687, 3743, 3788, 3838, 3896, 3953, 4015, 4075, 4148, 4201, 4275, 4347, 4420, 4486, 4535, 4592, 4660, 4731, 4792, 4845, 4901, 4971, 5027, 5089, 5148, 5200, 5261, 5318, 5374]}, {"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[303, 640, 835, 987, 1125, 1245, 1347, 1439, 1513, 1610, 1694, 1763, 1823, 1883, 1949, 2011, 2076, 2137, 2198, 2258, 2326, 2372, 2430, 2512, 2565, 2617, 2681, 2735, 2795, 2850, 2907, 2966, 3033, 3081, 3129, 3177, 3224, 3279, 3334, 3382, 3435, 3489, 3547, 3587, 3634, 3695, 3756, 3810, 3861, 3912, 3984, 4046, 4109, 4169, 4236, 4288, 4346, 4417, 4463, 4536, 4587, 4681, 4731, 4787, 4858, 4910, 4993, 5046, 5100, 5168, 5233, 5283, 5351]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[329, 686, 873, 1009, 1130, 1239, 1337, 1426, 1509, 1585, 1667, 1746, 1816, 1880, 1937, 1999, 2058, 2120, 2179, 2245, 2311, 2374, 2437, 2511, 2565, 2616, 2671, 2723, 2783, 2844, 2902, 2958, 3017, 3056, 3104, 3169, 3206, 3249, 3298, 3354, 3428, 3479, 3526, 3579, 3628, 3679, 3727, 3771, 3819, 3865, 3927, 4006, 4075, 4116, 4164, 4250, 4323, 4380, 4436, 4492, 4547, 4599, 4652, 4708, 4761, 4811, 4889, 4966, 5025, 5071, 5134, 5186, 5258]}]}
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