The p53 Inhibitor MDM2 Facilitates Sonic Hedgehog-Mediated Tumorigenesis and Influences Cerebellar Foliation
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{"title"=>"The p53 inhibitor MDM2 facilitates Sonic hedgehog-mediated tumorigenesis and influences cerebellar foliation", "type"=>"journal", "authors"=>[{"first_name"=>"Reem", "last_name"=>"Malek", "scopus_author_id"=>"37098799700"}, {"first_name"=>"Jennifer", "last_name"=>"Matta", "scopus_author_id"=>"25635814300"}, {"first_name"=>"Natalie", "last_name"=>"Taylor", "scopus_author_id"=>"57196957466"}, {"first_name"=>"Mary Ellen", "last_name"=>"Perry", "scopus_author_id"=>"7402948843"}, {"first_name"=>"Susan M.", "last_name"=>"Mendrysa", "scopus_author_id"=>"6603479510"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-79952776026", "sgr"=>"79952776026", "pui"=>"361467840", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"21437245", "doi"=>"10.1371/journal.pone.0017884"}, "id"=>"e1820348-85b3-314e-ab8f-4a7e5cb4e963", "abstract"=>"Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro)), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/-) mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.", "link"=>"http://www.mendeley.com/research/p53-inhibitor-mdm2-facilitates-sonic-hedgehogmediated-tumorigenesis-influences-cerebellar-foliation", "reader_count"=>48, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>4, "Researcher"=>8, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>6, "Student > Bachelor"=>6, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>4, "Researcher"=>8, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>6, "Student > Bachelor"=>6, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>9, "Agricultural and Biological Sciences"=>24, "Medicine and Dentistry"=>11, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>9}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "Canada"=>2, "United States"=>2, "United Kingdom"=>1, "Germany"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/790223"], "description"=>"<p>Midsagittal sections of cerebella from wild-type (A,D,G,J,M), <i>Mdm2<sup>puro/Δ7-9</sup></i> (B,E,H,K,N), and <i>Mdm2<sup>puro/Δ7-9</sup>;p53<sup>−/−</sup></i> (C,F,I,L,O) mice at P7. (A–F) H&E staining shows a thin EGL and sparsely-populated IGL in <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella. (G–I) MDM2 deficiency does not appear to block GNP differentiation as immunohistochemical staining for CyclinD1 selectively marks undifferentiated GNPs of the outer, but not inner, EGL. (J–L) <i>Mdm2<sup>puro/Δ7-9</sup></i> Purkinje cells stained with anti-Calbindin D-28K have stunted arborization of the dendrites and have failed to form a uniform monolayer as seen in wild-type controls. <i>Mdm2<sup>puro/Δ7-9</sup>;p53<sup>−/−</sup></i> (M–O) Immunohistochemical staining for p53 reveals an increase in the number of GNPs staining positively for p53 in the EGL of <i>Mdm2<sup>puro/Δ7-9</sup></i> mice. (C,F,I,L,O) <i>Mdm2<sup>puro/Δ7-9</sup>;p53<sup>−/−</sup></i> mice are phenotypically indistinguishable from wild-type mice, highlighting the importance of MDM2 for limiting p53 function in cerebellar development.</p>", "links"=>[], "tags"=>["abnormalities", "mice", "rescued"], "article_id"=>460589, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cerebellar_abnormalities_of_Mdm2_puro_916_7_9_mice_are_rescued_by_loss_of_p53_/460589", "title"=>"Cerebellar abnormalities of <i>Mdm2<sup>puro/Δ7-9</sup></i> mice are rescued by loss of p53.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:09:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/395352"], "description"=>"<div><p>Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of <em>Mdm2</em> (<em>Mdm2<sup>puro</sup></em>), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 <em>in vivo</em>. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in <em>Mdm2</em>-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in <em>Ptch1<sup>+/−</sup></em> mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.</p> </div>", "links"=>[], "tags"=>["p53", "inhibitor", "mdm2", "facilitates", "sonic", "hedgehog-mediated", "tumorigenesis", "influences", "cerebellar", "foliation"], "article_id"=>138092, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_p53_Inhibitor_MDM2_Facilitates_Sonic_Hedgehog_Mediated_Tumorigenesis_and_Influences_Cerebellar_Foliation/138092", "title"=>"The p53 Inhibitor MDM2 Facilitates Sonic Hedgehog-Mediated Tumorigenesis and Influences Cerebellar Foliation", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-18 02:14:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/790382"], "description"=>"<p>(A,B) Identification of BrdU-positive (red) cells in the EGL (blue) of midsagittal sections of newborn (P0) wild-type (A) and <i>Mdm2<sup>puro/Δ7-9</sup></i> (B) cerebella using ImagePro software as described under <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017884#s2\" target=\"_blank\">Materials and Methods</a>. The EGL of <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella was acellular (blue) and hypoproliferative (red) as revealed by BrdU staining followed by image analysis. (C) Graph of the relative number of EGL cells in wild-type and <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella (<i>n</i> = 3, <i>P</i><0.001). (D,E) High magnification of BrdU label in tip of lobule III in a wild-type (D) and an <i>Mdm2<sup>puro/Δ7-</sup></i><sup><b><i>9</i></b></sup> (E) cerebellum. (F) Graph of relative percentage of BrdU-positive cells in EGL of wild-type and <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella (<i>n</i> = 3, <i>P</i> = 0.082). (G,H) High magnification of TUNEL label in end of lobule III in a wild-type (G) and an <i>Mdm2<sup>puro/Δ7-9</sup></i> (H) cerebellum. (I) Graph of relative percentage of TUNEL-positive cells in EGL of wild-type and <i>Mdm2<sup>puro/Δ7-</sup></i><sup><b><i>9</i></b></sup> cerebella. GNPs in the EGL of <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella are highly apoptotic (<i>n</i> = 3, <i>P</i> = 0.033).</p>", "links"=>[], "tags"=>["proliferation", "apoptosis"], "article_id"=>460756, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g005", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decreased_proliferation_and_increased_apoptosis_in_Mdm2_puro_916_7_9_cerebella_/460756", "title"=>"Decreased proliferation and increased apoptosis in <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:12:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/790740"], "description"=>"<p>(A–C) Shown are H&E stained sagittal sections of cerebella obtained from 3-week-old (A) wild-type, (B) <i>Ptch1<sup>+/−</sup></i>, and (C) <i>Ptch1<sup>+/−</sup></i>;<i>Mdm2<sup>puro/Δ7-9</sup></i> mice. PNLs as indicated by the arrow and outlined by the dashed blue line in (B) are composed of small, round tightly clustered cells with a high nucleus∶cytoplasmic ratio located superficial to the molecular layer either on the surface of the cerebellum or in a fissure between adjacent folia. <i>Ptch1<sup>+/−</sup></i>;<i>Mdm2<sup>puro/Δ7-9</sup></i> mice (C) fail to develop PNLs. (<i>D</i>) Quantification of PNLs observed in 3-week-old <i>Ptch1<sup>+/−</sup></i> and <i>Ptch1<sup>+/−</sup></i>;<i>Mdm2<sup>puro/Δ7-9</sup></i> mice. (E) Model for crosstalk between p53 and Shh pathways in cerebellar development. During GNP development, Shh stimulates proliferation through the positive regulation of the Gli family of transcription factors. P53 promotes apoptosis and concomitantly interferes with Gli function, attenuating the proliferative effects of Shh. Shh regulates MDM2, to keep p53 activity in check, allowing GNPs to expand in response to Shh signaling.</p>", "links"=>[], "tags"=>["pre-neoplastic", "lesion", "cerebellum", "mice", "expressing", "wild-type"], "article_id"=>461102, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g008", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Shh_induced_pre_neoplastic_lesion_PNL_formation_in_the_cerebellum_is_significantly_decreased_in_Ptch1_8722_mice_expressing_30_the_wild_type_level_of_MDM2_/461102", "title"=>"Shh-induced pre-neoplastic lesion (PNL) formation in the cerebellum is significantly decreased in <i>Ptch1<sup>+/−</sup></i> mice expressing ∼30% the wild-type level of MDM2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:18:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/790523"], "description"=>"<p>(A) Expression of Shh target genes (<i>Gli1</i>, <i>NMyc</i>, <i>CyclinD1</i>) and p53 target genes (<i>p21</i>, <i>DAPK</i>, <i>CyclinG</i>) in whole cerebella was determined by real-time PCR and normalized to <i>Tubb5</i>. Graphed is the average fold change in gene expression of Shh- and p53-target genes in whole cerebella of P5 mice with the indicated <i>Mdm2</i> genotype relative to wild-type controls (<i>n</i> = 3, *<i>P</i><0.05). (B) Histogram showing the total number of GNPs isolated from cerebella of mice of the indicated <i>Mdm2</i> genotype at P5 (<i>n</i> = 3–8, * <i>P</i><0.05). (C) WB analysis of Gli1 and Gli2 in GNPs isolated from P5 mice of the indicated <i>Mdm2</i> genotype. WB for actin confirms equal loading.</p>", "links"=>[], "tags"=>["signaling", "attenuated", "concomitant", "p53", "activation"], "article_id"=>460893, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Shh_signaling_is_attenuated_concomitant_with_p53_activation_in_Mdm2_puro_916_7_9_cerebella_/460893", "title"=>"Shh signaling is attenuated concomitant with p53 activation in <i>Mdm2<sup>puro/Δ7-9</sup></i>cerebella.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:14:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/790607"], "description"=>"<p>(A) IHC for BrdU-incorporating cells in vehicle-treated (−Shh) and stimulated (+Shh) GNPs. Total nuclei labeled by DAPI. (B) Graphed is the average fold change in the percentage of GNPs immunoreactive for BrdU in Shh stimulated versus vehicle control cultures (n = 3). (C) Expression of <i>Mdm2</i> and the Shh target gene, <i>Gli1</i>, was quantified by real-time PCR and normalized to <i>Tubb5</i>. Graphed is the relative fold change in expression of <i>Mdm2</i> and <i>Gli1</i> in wild-type GNPs cultured in the presence of Shh (+) or vehicle (−). (B) WB analysis of MDM2 and p-MDM2<sup>S166</sup> in GNPs treated with Shh (+) or vehicle (−). WB for actin confirms equal loading of protein.</p>", "links"=>[], "tags"=>["mdm2", "shh", "cultured", "wild-type"], "article_id"=>460974, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Regulation_of_MDM2_by_Shh_in_cultured_wild_type_GNPs_/460974", "title"=>"Regulation of MDM2 by Shh in cultured wild-type GNPs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:16:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/789821"], "description"=>"<p>(A) Schematic illustrating partial structure of the <i>Mdm2</i> gene surrounding the site of gene targeting, the resulting <i>Mdm2<sup>puro</sup></i> hypomorphic allele, and the <i>Mdm2<sup>Δ7-9</sup></i> null allele generated following Cre-mediated recombination. (B) Immunoprecipitation followed by Western blot (WB) analysis of MDM2 in brains from mice of the indicated <i>Mdm2</i> genotype. (C) WB analysis of MDM2 in GNPs isolated from P5 mice of the indicated <i>Mdm2</i> genotype. WB for actin controls for loading.</p>", "links"=>[], "tags"=>["characterization", "hypomorphic"], "article_id"=>460185, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_and_characterization_of_the_hypomorphic_Mdm2_puro_916_7_9_allele_/460185", "title"=>"Generation and characterization of the hypomorphic <i>Mdm2<sup>puro/Δ7-9</sup></i> allele.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:03:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/790050"], "description"=>"<p>(A–B) Midsagittal sections of newborn (P0) wild-type and <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella stained with H&E. The four principal fissures, denoted by asterisks, are apparent in wild-type cerebella at P0 (A), whereas only two are evident in <i>Mdm2<sup>puro/Δ7-9</sup></i> mice (B). Wild-type pups show two additional fissures, indicated by arrows, whereas mutant pups do not. (C–D) Superimposition of P0 (purple outline), P7 (blue outline), and adult (green outline) cerebella from wild-type (C) or <i>Mdm2<sup>puro/Δ7-9</sup></i> (D) mice. By P7, all four primary fissures, as well as two additional fissures, are evident in <i>Mdm2<sup>puro/Δ7-9</sup></i> mice. Moreover, even in adulthood, the mutant cerebellum does not reach the size or complexity of the wild-type cerebellum. Abbreviations are: prc, precentral; pc, pre-culminate; pr, primary; pp, prepyramidal; sec, secondary; pl, posterolateral fissures.</p>", "links"=>[], "tags"=>["defects", "p0"], "article_id"=>460421, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g003", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Foliation_defects_in_P0_mice_/460421", "title"=>"Foliation defects in P0 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:07:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/789937"], "description"=>"<p>In 4-month-old male and female <i>Mdm2<sup>puro/Δ7-9</sup></i> mice, cerebellar weight (A) is disproportionately reduced from wild-type relative to the decreases in both brain weight (B) and body weight (C) (<i>n</i> = 5–10, <i>P</i><0.001 when comparing wild-type and mutant mice by sex). Gross analysis of whole brains of 1-month-old wild-type (D) and <i>Mdm2<sup>puro/Δ7-9</sup></i> mice (E). The cerebellar vermis in mutant mice, denoted by the asterisk in (E), is reduced in mass thereby exposing more of the colliculi. H&E stained midsagittal sections of 4-month-old wild-type (F) and <i>Mdm2<sup>puro/Δ7-9</sup></i> (G) cerebella. <i>Mdm2<sup>puro/Δ7-9</sup></i> cerebella show a marked agenesis of foliation, with the internal granular layer (IGL) more severely diminished at the anterior and posterior folia. The asterisks in (F) and (G) denote the principal fissures which are shallow in mutant mice.</p>", "links"=>[], "tags"=>["foliation", "defective"], "article_id"=>460310, "categories"=>["Cancer", "Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Reem Malek", "Jennifer Matta", "Natalie Taylor", "Mary Ellen Perry", "Susan M. Mendrysa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017884.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cerebellar_size_and_foliation_are_defective_in_Mdm2_puro_916_7_9_mice_/460310", "title"=>"Cerebellar size and foliation are defective in <i>Mdm2<sup>puro/Δ7-9</sup></i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-18 00:05:10"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"5", "full-text"=>"7", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"2", "full-text"=>"1", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
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Relative Metric

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