JAK/STAT and Hox Dynamic Interactions in an Organogenetic Gene Cascade
Publication Date
July 31, 2015
Journal
PLOS Genetics
Authors
Pedro B. Pinto, Jose Manuel Espinosa Vázquez, María Luísa Rivas & James Castelli Gair Hombría
Volume
11
Issue
7
Pages
e1005412
DOI
https://dx.plos.org/10.1371/journal.pgen.1005412
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1005412
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26230388
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521708
Europe PMC
http://europepmc.org/abstract/MED/26230388
Web of Science
000360622200057
Scopus
84938785068
Mendeley
http://www.mendeley.com/research/jakstat-hox-dynamic-interactions-organogenetic-gene-cascade
Events
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Mendeley | Further Information

{"title"=>"JAK/STAT and Hox Dynamic Interactions in an Organogenetic Gene Cascade", "type"=>"journal", "authors"=>[{"first_name"=>"Pedro B.", "last_name"=>"Pinto", "scopus_author_id"=>"56767618500"}, {"first_name"=>"Jose Manuel", "last_name"=>"Espinosa-Vázquez", "scopus_author_id"=>"36087271700"}, {"first_name"=>"María Luísa", "last_name"=>"Rivas", "scopus_author_id"=>"15061914700"}, {"first_name"=>"James Castelli Gair", "last_name"=>"Hombría", "scopus_author_id"=>"9942375000"}], "year"=>2015, "source"=>"PLoS Genetics", "identifiers"=>{"pmid"=>"26230388", "sgr"=>"84938785068", "doi"=>"10.1371/journal.pgen.1005412", "scopus"=>"2-s2.0-84938785068", "pui"=>"605567957", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "issn"=>"15537404"}, "id"=>"56672c40-b777-3827-838b-d6e3750ee3a3", "abstract"=>"Organogenesis is controlled by gene networks activated by upstream selector genes. During development the gene network is activated stepwise, with a sequential deployment of successive transcription factors and signalling molecules that modify the interaction of the elements of the network as the organ forms. Very little is known about the steps leading from the early specification of the cells that form the organ primordium to the moment when a robust gene network is in place. Here we study in detail how a Hox protein induces during early embryogenesis a simple organogenetic cascade that matures into a complex gene network through the activation of feedback and feed forward interaction loops. To address how the network organization changes during development and how the target genes integrate the genetic information it provides, we analyze in Drosophila the induction of posterior spiracle organogenesis by the Hox gene Abdominal-B (Abd-B). Initially, Abd-B activates in the spiracle primordium a cascade of transcription factors and signalling molecules including the JAK/STAT signalling pathway. We find that at later stages STAT activity feeds back directly into Abd-B, initiating the transformation of the Hox cascade into a gene-network. Focusing on crumbs, a spiracle downstream target gene of Abd-B, we analyze how a modular cis regulatory element integrates the dynamic network information set by Abd-B and the JAK/STAT signalling pathway during development. We describe how a Hox induced genetic cascade transforms into a robust gene network during organogenesis due to the repeated interaction of Abd-B and one of its targets, the JAK/STAT signalling cascade. Our results show that in this network STAT functions not just as a direct transcription factor, but also acts as a \"counter-repressor\", uncovering a novel mode for STAT directed transcriptional regulation.", "link"=>"http://www.mendeley.com/research/jakstat-hox-dynamic-interactions-organogenetic-gene-cascade", "reader_count"=>22, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>2, "Researcher"=>6, "Student > Ph. D. Student"=>12, "Student > Master"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>2, "Researcher"=>6, "Student > Ph. D. Student"=>12, "Student > Master"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>12, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}}, "reader_count_by_country"=>{"Brazil"=>1, "United Kingdom"=>1, "France"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2196845"], "description"=>"<p>(A) The <i>ems0</i>.<i>35</i> enhancer (blue) drives expression to the posterior spiracles (B). (C) Expression of <i>ems0</i>.<i>35-Z</i> is maintained in <i>Df(1)os1A</i> mutant embryos lacking JAK/STAT pathway activity. (D) Fusion of the <i>crb</i> STAT-binding and repressor modules (red and green) to <i>ems0</i>.<i>35</i> (<i>crb313-ems0</i>.<i>35)</i> does not affect spiracle expression in wild type embryos (E), but abolishes spiracle expression in <i>Df(1)os1A</i> embryos (F). (G) When the STAT-binding sites are mutated in this construct (<i>crb313 MUT-ems0</i>.<i>35</i>) spiracle activity is lost (H). Note that the <i>crb313-ems0</i>.<i>35</i> fusion construct generates a novel gut pattern of expression that is STAT independent as it is unaffected in <i>Df(1)os1A</i> mutants or when the STAT sites are mutated. Arrowheads: posterior spiracle primordium.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499392, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g003", "stats"=>{"downloads"=>4, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_repressor_domain_functions_as_an_independent_regulatory_module_/1499392", "title"=>"The repressor domain functions as an independent regulatory module.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196846"], "description"=>"<p>Activation of the <i>crb</i> enhancer variants determined by <i>in situ</i> using <i>lacZ</i> RNA probes. While the spatial expression of the three reporters is similar, expression of <i>crb305</i> (C-C”) starts at an earlier developmental stage than <i>crb43</i>.<i>2</i> (A-A”) and <i>crb518</i> (B-B”), indicating that the repressor element regulates <i>crb</i>’s CRM temporal activation (compare A and B with C). Arrowheads: posterior spiracle primordium.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499393, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g004", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_repressor_module_regulates_the_temporal_activation_of_crb518_/1499393", "title"=>"The repressor module regulates the temporal activation of <i>crb518</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196847"], "description"=>"<p>Expression of <i>crb305-Z</i> in <i>Abd-B</i><sup><i>M1</i></sup> null homozygous mutant embryos (A), or <i>Df(1)os1A</i> embryos lacking all three Upd ligands (B). Ectopic expression of Abd-Bm in the ectoderm drives ectopic activation of <i>crb305</i> in all trunk segments in wild type embryos (C) but fails to do so in embryos lacking the Upd ligands (D). Ectopic expression of Upd, induces ectopic activation of <i>crb305</i> exclusively in the posterior segments (E). This activation is dependent on Abd-B function since ectopic expression of Upd in <i>Abd-B</i><sup><i>M1</i></sup> mutant embryos fails to activate <i>crb305</i> (F). Arrowheads: posterior spiracle primordium.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499394, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g005", "stats"=>{"downloads"=>3, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_the_crb305_posterior_spiracle_enhancer_requires_a_both_Abd_Bm_and_STAT92E_function_/1499394", "title"=>"Activation of the <i>crb305</i> posterior spiracle enhancer requires a both Abd-Bm and STAT92E function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196848"], "description"=>"<p>(A) Chromatin immunoprecipitation shows Abd-B binding to <i>crb</i> in S2 cells. Cells were transfected with pAC-Gal4 to activate the expression of UAS constructs, and either with pUAST-Abd-Bm-HA or empty pUAST as a control. ChIP was performed using an anti-HA antibody. (B) Localization of putative Abd-B binding sites in <i>crb305</i> (asterisks) and oligos used to test direct binding of Abd-B in EMSAs; (S) indicates the position of the consensus STAT92E binding sites. (C) EMSAs showing binding of Abd-B to wild type oligos (lanes 1–4, 9–12, 21–24, 29–32, 37–40, 45–48, 57–60, 65–68, black arrows) but not to oligos with the mutated sites (lanes 5–8, 13–20, 25–28, 33–36, 41–44, 49–56, 61–64, 69–76). In oligos containing two Abd-B sites, both have to be mutated to abolish Abd-B binding (lanes 5–20, 41–56, 61–76). Specificity of the observed band shifts was determined by the presence of a super-shift after incubation with anti-Abd-B antibody (grey arrows). White arrows point at unspecific bands. Protein extracts from non-transfected S2 cells were used as negative control. Arrowheads indicate the unbound radioactively labelled oligos.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499395, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g006", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Abd_Bm_binds_multiple_sites_in_crb305_posterior_spiracle_enhancer_/1499395", "title"=>"Abd-Bm binds multiple sites in <i>crb305</i> posterior spiracle enhancer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196849"], "description"=>"<p>(A) Genomic region contained in [CH321-91P18] BAC-<i>Abd-B-gfp</i> and location of the <i>VT42855</i> enhancer sequence. Asterisks represent 3N (red) and 4N (blue) STAT sites present in the <i>VT42855</i>, green boxes and arrows in the scale line mark the position of the control and experimental oligos used in the ChIP experiment below. (B) Endogenous Abd-B protein expression. (C) GFP-tagged Abd-B expression from the BAC-<i>Abd-B-gfp</i> is indistinguishable in the A8 and A9 abdominal segments from the endogenous protein. (D) Ectopic Abd-Bm expression in the embryonic ectoderm using <i>69B-Gal4</i> induces ectopic BAC-<i>Abd-B-gfp</i> activation anterior to A8. (E) In <i>Df(1)os1A</i> embryos lacking JAK/STAT ligands ectopic Abd-Bm expression cannot activate high levels of BAC-<i>Abd-B-gfp</i> anterior to A8. (F) Ectopic Upd expression using <i>69B-Gal4</i> induces ectopic BAC-Abd-B-gfp activation. Note in D and F that the expression observed in A8 and A9 is stronger than the ectopic expression in anterior segments. This is likely due to the BAC element containing several A8-A9 enhancers not all of which will respond to the feedback and become activated ectopically. (G) Posterior spiracle <i>gal4</i> RNA expression (arrowhead) driven by the 2.2kb Abd-B genomic fragment in VT42855-Gal4 line. (H) Posterior spiracle expression in <i>VT42855-Gal4</i> disappears in <i>Df(1)os1A</i> embryos lacking JAK/STAT ligands. Note that central nervous expression is unaffected. (I-K) <i>VT42855-Gal4/+</i>, <i>UAS-lacZ/+</i> embryos double stained with anti-<b>β</b>Gal (green in I, white in K) and anti-Ct (red in I white in J) to prove the posterior spiracle expression (inset) of <i>VT42855</i>. (L) STAT92E-GFP Chromatin immunoprecipitation in S2 cells shows STAT binding to the <i>VT42855</i> region of the <i>Abd-B cis</i> regulatory element compared with the negative control region devoid of STAT sites indicated in A (green boxes). Cells were transfected with pAC-Gal4 to activate the expression of UAS constructs, pAC-Hop<sup>Tum-l</sup> expressing an activated JAK kinase to induce STAT92E activation by phosphorylation and either with pUAST-STAT92E-GFP or empty pUAST as a control. ChIP of STAT92E was performed using an anti-GFP antibody. The position of oligos used to amplify the <i>VT42855</i> region is indicated in (A) by an arrow and their sequences indicated in Materials and Methods. (M) The <i>crb518</i> posterior spiracle enhancer is composed of a specificity module sufficient to drive posterior spiracles expression, a STAT binding module and a repressor module. Early Abd-B expression activates the JAK/STAT Unpaired ligand and other primary posterior spiracle targets, but fails to activate <i>crb518</i> CRM as a result of the repressor module activity. The JAK/STAT pathway plays a key role in the activation of <i>crb</i> by, first, reinforcing Abd-B expression in A8 through a feedback loop mechanism; second, inducing additional activator factors, which together with ABD-B act over the specificity module and finally by direct binding of STAT92E to <i>crb518</i> to counteract the repressor element. Arrowheads in G and H indicate the position of the posterior spiracle primordium; arrows in D and F indicate some of the segments that exhibit ectopic activation of the BAC-<i>Abd-B-gfp</i>.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499396, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g007", "stats"=>{"downloads"=>4, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_JAK_STAT_activates_expression_of_Abd_B_through_a_feedback_loop_/1499396", "title"=>"JAK/STAT activates expression of Abd-B through a feedback loop.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196961", "https://ndownloader.figshare.com/files/2196962", "https://ndownloader.figshare.com/files/2196963", "https://ndownloader.figshare.com/files/2196965", "https://ndownloader.figshare.com/files/2196967", "https://ndownloader.figshare.com/files/2196969", "https://ndownloader.figshare.com/files/2196970", "https://ndownloader.figshare.com/files/2196971", "https://ndownloader.figshare.com/files/2196972"], "description"=>"<div><p>Organogenesis is controlled by gene networks activated by upstream selector genes. During development the gene network is activated stepwise, with a sequential deployment of successive transcription factors and signalling molecules that modify the interaction of the elements of the network as the organ forms. Very little is known about the steps leading from the early specification of the cells that form the organ primordium to the moment when a robust gene network is in place. Here we study in detail how a Hox protein induces during early embryogenesis a simple organogenetic cascade that matures into a complex gene network through the activation of feedback and feed forward interaction loops. To address how the network organization changes during development and how the target genes integrate the genetic information it provides, we analyze in <i>Drosophila</i> the induction of posterior spiracle organogenesis by the Hox gene <i>Abdominal-B</i> (<i>Abd-B</i>). Initially, Abd-B activates in the spiracle primordium a cascade of transcription factors and signalling molecules including the JAK/STAT signalling pathway. We find that at later stages STAT activity feeds back directly into <i>Abd-B</i>, initiating the transformation of the Hox cascade into a gene-network. Focusing on <i>crumbs</i>, a spiracle downstream target gene of Abd-B, we analyze how a modular <i>cis</i> regulatory element integrates the dynamic network information set by Abd-B and the JAK/STAT signalling pathway during development. We describe how a Hox induced genetic cascade transforms into a robust gene network during organogenesis due to the repeated interaction of Abd-B and one of its targets, the JAK/STAT signalling cascade. Our results show that in this network STAT functions not just as a direct transcription factor, but also acts as a \"counter-repressor\", uncovering a novel mode for STAT directed transcriptional regulation.</p></div>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499473, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1005412.s001", "https://dx.doi.org/10.1371/journal.pgen.1005412.s002", "https://dx.doi.org/10.1371/journal.pgen.1005412.s003", "https://dx.doi.org/10.1371/journal.pgen.1005412.s004", "https://dx.doi.org/10.1371/journal.pgen.1005412.s005", "https://dx.doi.org/10.1371/journal.pgen.1005412.s006", "https://dx.doi.org/10.1371/journal.pgen.1005412.s007", "https://dx.doi.org/10.1371/journal.pgen.1005412.s008", "https://dx.doi.org/10.1371/journal.pgen.1005412.s009"], "stats"=>{"downloads"=>17, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_JAK_STAT_and_Hox_Dynamic_Interactions_in_an_Organogenetic_Gene_Cascade_/1499473", "title"=>"JAK/STAT and Hox Dynamic Interactions in an Organogenetic Gene Cascade", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196843"], "description"=>"<p>(A) Constructs designed to analyse the <i>crb518</i> CRM (S and asterisks indicate the position of STAT92E binding sites). (B) <i>crb518</i>-<i>lacZ</i> reporter expression. (C) The <i>crb313</i>-<i>lacZ</i> reporter with the 1–204 bp region deleted loses posterior spiracle expression. (D) The <i>crb101</i>-<i>lacZ</i> reporter containing the STAT92E binding sites is unable to direct expression to the posterior spiracles. (E) The <i>crb305-lacZ</i> reporter is able to direct expression to the posterior spiracle and its expression is downregulated in embryos mutant for the Unpaired JAK/STAT ligands (F). (G) The <i>crb204-lacZ</i> reporter lacking the STAT92E binding sites is able to direct expression in the posterior spiracles and still requires JAK/STAT function as in <i>unpaired</i> null mutants its activity in the posterior spiracles is abolished (H). Arrowheads: posterior spiracle primordium.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499390, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g001", "stats"=>{"downloads"=>4, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Component_modules_of_the_crb518_posterior_spiracle_minimal_enhancer_/1499390", "title"=>"Component modules of the <i>crb518</i> posterior spiracle minimal enhancer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/2196844"], "description"=>"<p>(A) Representation of the dual STAT92E requirement for <i>crb518</i> CRM expression in the posterior spiracles (A’). <i>crb518</i> requires direct STAT92E binding to counteract a repressor, as well as an indirect STAT92E function to induce an activator of the spiracle specificity module. (B) Mutation of the STAT binding sites (<i>crb518</i>-STAT-mt-Z) in the presence of the repressor module downregulates spiracle expression (B’). (C) Mutation of the STAT binding sites in the absence of the repressor module (<i>crb305</i>-STAT-mt-Z) does not affect spiracle expression (C’). (D) Fusion of the specificity and repressor modules in the absence of the STAT-binding module (<i>crb518</i><b>Δ</b><i>101</i>-Z) downregulates spiracle expression (D’). Arrowheads: posterior spiracle primordium.</p>", "links"=>[], "tags"=>["Hox Dynamic Interactions", "jak", "stages STAT activity", "gene network", "network STAT functions", "transcription factors", "network organization changes", "Organogenetic Gene Cascade Organogenesis", "cascade"], "article_id"=>1499391, "categories"=>["Uncategorised"], "users"=>["Pedro B. Pinto", "Jose Manuel Espinosa-Vázquez", "María Luisa Rivas", "James Castelli-Gair Hombría"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005412.g002", "stats"=>{"downloads"=>4, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_STAT92E_binding_sites_are_required_to_release_crb518_from_repression_/1499391", "title"=>"STAT92E binding sites are required to release <i>crb518</i> from repression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-07-31 02:55:12"}

PMC Usage Stats | Further Information

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

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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