HIF- and Non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in Drosophila melanogaster
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{"title"=>"HIF- and Non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in Drosophila melanogaster", "type"=>"journal", "authors"=>[{"first_name"=>"Yan", "last_name"=>"Li", "scopus_author_id"=>"54179422400"}, {"first_name"=>"Divya", "last_name"=>"Padmanabha", "scopus_author_id"=>"55583924200"}, {"first_name"=>"Luciana B.", "last_name"=>"Gentile", "scopus_author_id"=>"23090903100"}, {"first_name"=>"Catherine I.", "last_name"=>"Dumur", "scopus_author_id"=>"6602260385"}, {"first_name"=>"Robert B.", "last_name"=>"Beckstead", "scopus_author_id"=>"36805409600"}, {"first_name"=>"Keith D.", "last_name"=>"Baker", "scopus_author_id"=>"7401611414"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84873515115", "doi"=>"10.1371/journal.pgen.1003230", "sgr"=>"84873515115", "isbn"=>"1553-7404 (Electronic)\\n1553-7390 (Linking)", "pmid"=>"23382692", "issn"=>"15537390", "pui"=>"368295331"}, "id"=>"df1c6b3c-a38e-33c3-bf3f-de942f8ab732", "abstract"=>"Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila melanogaster development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in sima mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIFa and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFa in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs.", "link"=>"http://www.mendeley.com/research/hif-nonhifregulated-hypoxic-responses-require-estrogenrelated-receptor-drosophila-melanogaster", "reader_count"=>54, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>15, "Student > Master"=>8, "Other"=>1, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>3, "Researcher"=>11, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>15, "Student > Master"=>8, "Other"=>1, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>6}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>14, "Materials Science"=>1, "Agricultural and Biological Sciences"=>31, "Medicine and Dentistry"=>3, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>31}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>14}, "Unspecified"=>{"Unspecified"=>4}}, "reader_count_by_country"=>{"Spain"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/497756"], "description"=>"<p>(A) GST-pulldown experiment showing GST-fused dERR LBD association with full-length dHIFa, which is diminished when the final 11 amino acids of the LBD are deleted (ΔAF-2). Similarly, when the LXXLL motif in dHIFa is mutated, binding with the ERR LBD and ΔAF-2 proteins is lessened, but not eliminated when compared to GST alone. (B) <i>dERR</i> mutant animals are sensitive to H exposure and fail to successfully progress to the molt when challenged with 4% O<sub>2</sub>. Shown also are the results of <i>w<sup>1118</sup></i> animals and <i>sima</i> mutants. The L1 stage takes ∼24 hrs to progress through in N at 25°C, but the allotted time was extended to 48 hrs to account for developmental delays that are caused by H treatment. For more details and additional data, see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s009\" target=\"_blank\">Table S3</a>.</p>", "links"=>[], "tags"=>["binds", "dhifa", "hypoxic"], "article_id"=>168272, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g006", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_dERR_binds_to_dHIFa_and_is_essential_for_hypoxic_survival_/168272", "title"=>"dERR binds to dHIFa and is essential for hypoxic survival.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:17:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/497824"], "description"=>"<p>(A) HIF-independent (HI), HIF-dependent (HD), ERR-dependent (ED), and ERR&HIF-dependent (DM) gene sets identified by microarray schemes outlined in Figures S1 and S2. Circles are scaled to size by number of transcripts in each set. (B) A Venn diagram demonstrating the overlap of the HI/HD/ED H-genes sets. Note, HI and HD genes sets are, by definition, mutually exclusive. The asterisks indicate that the overlap is significant (<i>p</i>-value<0.05), as determined by hypergeometric probability. (C) A Venn diagram demonstrating the overlap of the HD/ED/DM H-genes sets. qRT-PCR analysis of hypoxia-regulated genes falling into specific Venn overlaps, as indicated by arrows. (D) The top ten affected transcripts, as assessed by the H-responses measured in the control background, for each of the seven Venn categories shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen-1003230-g007\" target=\"_blank\">Figure 7C</a>. Hypoxic expression for each transcript in the different mutant backgrounds (compared to <i>w<sup>1118</sup></i>) is reported as fold-change difference. Additionally shown is the N/H ratio obtained for <i>w<sup>1118</sup></i> animals. (E) Normoxic and hypoxic expression of each of the six genes (<i>Pfk, fatiga, spermine oxidase, NMNAT, LDH, ALAS</i>) was determined using RNA collected from animals of the indicated genotypes at late-L3. Samples were collected in triplicate and are independent from those used in the microarrays. Values are normalized to <i>rp49</i> expression and are reported relative to the value obtained for <i>w<sup>1118</sup></i> in normoxia.</p>", "links"=>[], "tags"=>["derr", "dhifa", "hypoxic"], "article_id"=>168336, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g007", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_influence_of_dERR_and_dHIFa_on_hypoxic_transcripts_/168336", "title"=>"The influence of dERR and dHIFa on hypoxic transcripts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:18:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/497144"], "description"=>"<p>(A) Hypoxic treatment regimen of <i>w<sup>1118</sup></i> animals that were allowed to develop in normoxia (N) until they reached one of three developmental stages, at which point they were treated for 6 hours in N or hypoxia (H) (4% O<sub>2</sub>). (B–D) qRT-PCR analysis was performed to assess the expression of <i>fatiga</i>, <i>LDH</i>, and <i>Pfk</i> at 18–24 hr AEL, mid-L2, or partial clear-gut larvae in late-L3. All experiments were performed in triplicate from pools of biological replicates. Values are normalized to <i>rp49</i> expression and are reported as the relative fold-change of H/N. Error bars are the SEM. * = <i>p</i>-value<0.05.</p>", "links"=>[], "tags"=>["hypoxic"], "article_id"=>167663, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Temporal_dependent_hypoxic_responses_/167663", "title"=>"Temporal-dependent hypoxic responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:07:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/497662"], "description"=>"<p>(A) Unlike the <i>w<sup>1118</sup></i> response, <i>sima</i> mutants are not able to mobilize glycogen stores in response to 6-hr H-treatment in late-L3. (B) ATP levels are significantly depleted upon H-challenge by <i>w<sup>1118</sup></i> animals. Although sima animals showed a similar trend, the decrease observed was not significant. Levels of glycogen and ATP are normalized to total protein. (C) Shown is a metabolic heat map of individual metabolites measured by GC/MS or LC/MS from late-L3 <i>w<sup>1118</sup></i> animals or <i>sima</i> mutants subject to N (left two columns) or H (right two columns). Six replicates were measured for each treatment group. Each replicate has ∼250 independently collected and pooled animals. Metabolite levels are expressed as log<sub>2</sub> transformations of the average values, which are plotted relative to the normoxic level obtained in the WT background. The data are normalized to total protein content. Red indicates an elevated metabolite level, green indicates a diminished level, and black no/little change. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s008\" target=\"_blank\">Table S2</a> for further information and statistics. (D) qRT-PCR analysis showing <i>amylase</i> expression increases in hypoxia in control animals. Although <i>sima</i> mutants have an elevated constitutive level of <i>amylase</i> expression, they do not induce expression in hypoxia. (E) Integrated snapshot of the transcriptional and metabolic response to hypoxia at 6-hr. Shown, are the metabolites and enzymes of stored sugar and circulating sugar as they feed into glycolysis. When significant H-induced changes were noted (fold-change >1.5, FDR <1%) for transcripts in microarray experiments, those changes are noted in brackets next to the enzyme names. HD or HI status, as classified in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s007\" target=\"_blank\">Table S1</a> is also noted. Metabolite levels from mass spec analysis are additionally shown as box and whisker plots. The upper and lower boundaries of the box note the upper and lower quartile values, while the ends of the vertical line indicate the maximum and minimum values. The average value is the noted by the horizontal line within the box. Error bars are the SEM. * = <i>p</i>-value<0.05.</p>", "links"=>[], "tags"=>["molecular biology", "Biochemistry"], "article_id"=>168176, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g005", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIF_dependent_effects_on_carbohydrate_catabolism_/168176", "title"=>"HIF-dependent effects on carbohydrate catabolism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:16:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/497315"], "description"=>"<p>(A–B) Gene ontology (GO) analysis was performed on HIF-independent (HI) and HIF-dependent (HD) gene sets that were derived from microarray analysis of H- or N-treated control (<i>w<sup>1118</sup></i>) animals or <i>sima</i> mutants collected at the partial clear-gut late-L3 time. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s001\" target=\"_blank\">Figure S1</a> for the analysis scheme. GO categories are listed in order of statistical significance. The numbers of H-regulated genes affected are shown along with the total number of genes in each category. All transcripts are up- or downregulated at least 1.5-fold and have a false discovery rate (FDR) of <1%. (C) A heat map was created to illustrate the similarity or dissimilarity of hypoxic responses for major GO categories impacted by H-treatment in control animals and <i>sima</i> mutants. Red (upregulated), green (downregulated), or white (no significant change) values represent hypoxic responses observed in the backgrounds indicated. For this analysis, FDR stringency was <1%, unless otherwise noted with * for a particular genotype, where a relaxed gate was used (1–5%).</p>", "links"=>[], "tags"=>["hif-independent", "hypoxic"], "article_id"=>167832, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIF_dependent_and_HIF_independent_hypoxic_response_genes_/167832", "title"=>"HIF-dependent and HIF-independent hypoxic response genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:10:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/497413"], "description"=>"<p>(A–E) Developmental hypoxic response profiles from qRT-PCR analyses are shown for transcripts that display HIF-dependent (A – <i>fatiga</i>, B – <i>spermine oxidase</i>, C – <i>sequoia</i>, D – <i>branchless</i>) or largely HIF-dependent expression (E – <i>CG31769</i>). Control (<i>w<sup>1118</sup></i>) animals or <i>sima</i> mutants were challenged for 6-hrs with 4% O<sub>2</sub>. Animals were challenged at: 0–6 hr after egg laying (AEL) (not for mutant), 6–12 hr AEL, 12–18 hr AEL, 18–24 hr AEL, mid-L1, mid-L2, mid-L3, −10–−4 hr relative to pupariation (RTP) L3, 0 hr RTP, +12 hr RTP, +72 hr RTP, and 1-day old males. All values are from experiments performed in triplicate from pools of biological replicates. Values are normalized to <i>rp49</i> expression and are reported as the relative fold-change of H/N. The dotted line represents no net change in response, or a value of 1.0. The vertical black line in late-L3 is when microarray analysis was performed. Error bars are the SEM. Separate normoxic and hypoxic traces for each transcript surveyed are shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["hif-dependent", "hypoxic"], "article_id"=>167929, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Temporal_expression_of_HIF_dependent_hypoxic_response_genes_/167929", "title"=>"Temporal expression of HIF-dependent hypoxic response genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:12:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/497930"], "description"=>"<p>For HIF-dependent genes (taken from the top 20 down-regulated transcripts in the HD H-genes set), transcripts are sorted according to normalized microarray values obtained when comparing <i>w<sup>1118</sup></i> hypoxia samples with <i>sima</i> hypoxia samples. For the HIF-independent genes (taken from the top 20 up-regulated HI H-genes set), transcripts are sorted according to the normalized microarray values obtained when comparing <i>sima</i> normoxia with <i>sima</i> hypoxia samples. For comparative purposes, the respective hypoxic changes observed in <i>w<sup>1118</sup></i> control animals are reported in the last column. Additionally, the first four columns show the Affymetrix probe set ID, CG number, gene title, and the putative process/function of the encoded protein.</p>", "links"=>[], "tags"=>["20", "transcripts", "changes", "hypoxic", "dhif-dependent", "-independent"], "article_id"=>168439, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.t001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_List_of_20_top_transcripts_whose_expression_changes_in_response_to_hypoxic_challenge_in_a_dHIF_dependent_or_independent_fashion_/168439", "title"=>"List of 20 top transcripts whose expression changes in response to hypoxic challenge in a dHIF-dependent or -independent fashion.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-31 02:20:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/480571", "https://ndownloader.figshare.com/files/480574", "https://ndownloader.figshare.com/files/480578", "https://ndownloader.figshare.com/files/480581", "https://ndownloader.figshare.com/files/480585", "https://ndownloader.figshare.com/files/480588", "https://ndownloader.figshare.com/files/480593", "https://ndownloader.figshare.com/files/480594", "https://ndownloader.figshare.com/files/480596"], "description"=>"<div><p>Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout <em>Drosophila melanogaster</em> development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in <em>sima</em> mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIFa and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFa in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs.</p> </div>", "links"=>[], "tags"=>["hif-", "non-hif-regulated", "hypoxic", "responses", "estrogen-related", "receptor"], "article_id"=>155160, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003230.s001", "https://dx.doi.org/10.1371/journal.pgen.1003230.s002", "https://dx.doi.org/10.1371/journal.pgen.1003230.s003", "https://dx.doi.org/10.1371/journal.pgen.1003230.s004", "https://dx.doi.org/10.1371/journal.pgen.1003230.s005", "https://dx.doi.org/10.1371/journal.pgen.1003230.s006", "https://dx.doi.org/10.1371/journal.pgen.1003230.s007", "https://dx.doi.org/10.1371/journal.pgen.1003230.s008", "https://dx.doi.org/10.1371/journal.pgen.1003230.s009"], "stats"=>{"downloads"=>15, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/HIF_and_Non_HIF_Regulated_Hypoxic_Responses_Require_the_Estrogen_Related_Receptor_in_Drosophila_melanogaster__/155160", "title"=>"HIF- and Non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in <em>Drosophila melanogaster</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-01-31 01:26:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/497513"], "description"=>"<p>(A–H) Developmental hypoxic response profiles from qRT-PCR analyses are shown for transcripts that display HIF-independent (A – <i>LDH</i>, B – <i>phosphofructokinase</i>, C – <i>NMNAT</i>, D – <i>Alas</i>, E – <i>Cyp9b1</i>, F – <i>Cyp6a17</i>, G – <i>Cyp6a22</i>) or largely HIF-independent expression (H – <i>Peroxiredoxin 2540-2</i> – we note that <i>Prx2540-2</i> displays HD expression for probe set 1631628_s_at in the microarray and is thus classified as such; however, a second, non-overlapping probe set, 1633471_at, which is much more robustly induced in H appears to be from HI action, although its variability is too great to classify in this manner (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s007\" target=\"_blank\">Table S1</a>). Our qPCR primer set favors HI expression.) Control (<i>w<sup>1118</sup></i>) animals or <i>sima</i> mutants were challenged for 6-hrs with 4% O<sub>2</sub>. Developmental challenge times are identical to those from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen-1003230-g003\" target=\"_blank\">Figure 3</a>. All values are from experiments performed in triplicate from pools of biological replicates. Values are normalized to <i>rp49</i> expression and are reported as the relative fold-change of H/N. The dotted line represents no net change in response, or a value of 1.0. The vertical black line in late-L3 is when microarray analysis was performed. Error bars are the SEM. Separate normoxic and hypoxic traces for each transcript surveyed is shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003230#pgen.1003230.s004\" target=\"_blank\">Figure S4</a>.</p>", "links"=>[], "tags"=>["hif-independent", "hypoxic"], "article_id"=>168033, "categories"=>["Molecular Biology", "Biochemistry"], "users"=>["Yan Li", "Divya Padmanabha", "Luciana B. Gentile", "Catherine I. Dumur", "Robert B. Beckstead", "Keith D. Baker"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003230.g004", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Temporal_expression_of_HIF_independent_hypoxic_response_genes_/168033", "title"=>"Temporal expression of HIF-independent hypoxic response genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-31 02:13:53"}

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Relative Metric

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