Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways
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{"title"=>"Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways", "type"=>"journal", "authors"=>[{"first_name"=>"Charlie W.", "last_name"=>"Lees", "scopus_author_id"=>"13609265600"}, {"first_name"=>"William J.", "last_name"=>"Zacharias", "scopus_author_id"=>"16679951100"}, {"first_name"=>"Mark", "last_name"=>"Tremelling", "scopus_author_id"=>"13609025000"}, {"first_name"=>"Colin L.", "last_name"=>"Noble", "scopus_author_id"=>"12789909500"}, {"first_name"=>"Elaine R.", "last_name"=>"Nimmo", "scopus_author_id"=>"6602749202"}, {"first_name"=>"Albert", "last_name"=>"Tenesa", "scopus_author_id"=>"8247573400"}, {"first_name"=>"Jennine", "last_name"=>"Cornelius", "scopus_author_id"=>"24340633800"}, {"first_name"=>"Leif", "last_name"=>"Torkvist", "scopus_author_id"=>"55882038700"}, {"first_name"=>"John", "last_name"=>"Kao", "scopus_author_id"=>"55383842700"}, {"first_name"=>"Susan", "last_name"=>"Farrington", "scopus_author_id"=>"8385319900"}, {"first_name"=>"Hazel E.", "last_name"=>"Drummond", "scopus_author_id"=>"7005501505"}, {"first_name"=>"Gwo Tzer", "last_name"=>"Ho", "scopus_author_id"=>"8783979400"}, {"first_name"=>"D. R.", "last_name"=>"Ian Arnott", "scopus_author_id"=>"25957637000"}, {"first_name"=>"Henry D.", "last_name"=>"Appelman", "scopus_author_id"=>"7005774727"}, {"first_name"=>"Lauri", "last_name"=>"Diehl", "scopus_author_id"=>"7006349336"}, {"first_name"=>"Harry", "last_name"=>"Campbell", "scopus_author_id"=>"7202318417"}, {"first_name"=>"Malcolm G.", "last_name"=>"Dunlop", "scopus_author_id"=>"7101629955"}, {"first_name"=>"Miles", "last_name"=>"Parkes", "scopus_author_id"=>"56553841600"}, {"first_name"=>"E. M.", "last_name"=>"Sarah Howie", "scopus_author_id"=>"25957801000"}, {"first_name"=>"Deborah L.", "last_name"=>"Gumucio", "scopus_author_id"=>"7005490506"}, {"first_name"=>"Jack", "last_name"=>"Satsangi", "scopus_author_id"=>"7006615924"}], "year"=>2008, "source"=>"PLoS Medicine", "identifiers"=>{"isbn"=>"1549-1676 (Electronic)\\r1549-1277 (Linking)", "scopus"=>"2-s2.0-58149464866", "pui"=>"354059888", "doi"=>"10.1371/journal.pmed.0050239", "sgr"=>"58149464866", "pmid"=>"19071955", "issn"=>"15491277"}, "id"=>"afcde179-2028-328a-9e9c-c5ee24d05dd0", "abstract"=>"BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.\\n\\nMETHODS AND FINDINGS: Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.\\n\\nCONCLUSIONS: HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.", "link"=>"http://www.mendeley.com/research/analysis-germline-gli1-variation-implicates-hedgehog-signalling-regulation-intestinal-inflammatory-p", "reader_count"=>50, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>7, "Researcher"=>14, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>3, "Student > Bachelor"=>3, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>7, "Researcher"=>14, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>3, "Student > Bachelor"=>3, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Medicine and Dentistry"=>18, "Agricultural and Biological Sciences"=>25, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>18}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>25}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}}, "reader_count_by_country"=>{"Korea (South)"=>1, "United States"=>1, "Japan"=>1, "United Kingdom"=>2, "Portugal"=>1, "Germany"=>1}, "group_count"=>4}

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  • {"files"=>["https://ndownloader.figshare.com/files/914172"], "description"=>"<div><p>(A) Kaplan-Meier survival curve. WT animals are 100% viable over the 6-d treatment period (<i>n</i> = 14). Nearly 50% of <i>Gli1<sup>+/lacZ</sup></i> animals (four out of nine) die in response to 3% DSS treatment for 6 d.</p>\n <p>(B) <i>Gli1<sup>+/lacZ</sup></i> animals display markedly more severe symptoms than WT animals after 4 or 6 d of 3% DSS treatment. 1, diarrhoea; 2, bloody diarrhoea; 4, severe bleeding/death. Each dot represents an individual animal and the solid line shows the mean observation in each cohort.</p>\n <p>(C) <i>Gli1<sup>+/lacZ</sup></i> animals (<i>n</i> = 9) lose weight more rapidly than their WT littermates (<i>n</i> = 10). *, <i>p</i> < 0.05 by Student's <i>t</i>-test.</p></div>", "links"=>[], "tags"=>["animals", "dss"], "article_id"=>584609, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gli1_lacZ_Animals_Show_Mortality_Severe_Clinical_Symptoms_and_Profound_Weight_Loss_after_DSS_Treatment_/584609", "title"=>"<i>Gli1<sup>+/lacZ</sup></i> Animals Show Mortality, Severe Clinical Symptoms, and Profound Weight Loss after DSS Treatment", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:16:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/914564"], "description"=>"<div><p>(A–C) No DSS treatment.</p>\n <p>(D–F) 4 d of 3% DSS.</p>\n <p>(A, D) Few CD3+ T lymphocytes respond to Hh signalling during colonic homeostasis. Infiltrating T cells in DSS-induced ulcers do not express Gli1 or respond to Hh signalling.</p>\n <p>(B, E) Many but not all CD11b+ myeloid cells respond to Hh signalling and express LacZ. After 4 d of DSS, ulcers in <i>Gli1<sup>+/lacZ</sup></i> animals are filled with myeloid cells, many of which respond to Hh signals.</p>\n <p>(C, F) CD11c+ dendritic cells respond directly to Hh signals during homeostasis and inflammation. Nuclear DAPI staining was performed but has been omitted to allow clear visualization of co-expression of nuclear LacZ and cell surface markers.</p></div>", "links"=>[], "tags"=>["myeloid", "cells", "hh", "signalling", "homeostasis"], "article_id"=>584995, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g006", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Intestinal_Myeloid_Cells_Respond_Directly_to_Hh_Signalling_during_Homeostasis_and_Inflammation_/584995", "title"=>"Intestinal Myeloid Cells Respond Directly to Hh Signalling during Homeostasis and Inflammation", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:23:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/914051"], "description"=>"<div><p>(A) PTCH, HHIP, and GLI1 mRNA levels increase along the length of the healthy adult colon, from ascending colon (AC) to descending colon (DC) and sigmoid colon (SC).</p>\n <p>(B) HH protein expression in terminally differentiated enterocytes at the luminal surface, is greater in the distal colon compared with the proximal (vertical and horizontal arrows represent these gradients).</p>\n <p>(C) Quantitative analysis of mRNA levels of IHH, PTCH, GLI1, and HHIP in UC compared with noninflamed HC (HC N-I). To account for the gradients identified along the length of the healthy colon (a-b), the data from SC only are shown. QPCR data is presented for IHH as this gene was not present on the Agilent microarray chip.</p>\n <p>(D) GLI1 expression in CD versus HC (N-I) and non-IBD inflammation (HC I) versus HC. Disease specimens are subcategorised into noninflamed (N-I) and inflamed (I) tissues. There was no change in levels of desert HH (DHH), PTCH2, GLI2, GLI3, SUFU, or DISP1 in either UC or CD compared with HC, or in non-IBD inflammation (unpublished data). Analysis of SHH mRNA demonstrated a mild increase in expression levels related to inflammation that is consistent with the known expression of SHH in inflammatory cells (<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-sg004\" target=\"_blank\">Figure S4</a>) [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-b021\" target=\"_blank\">21</a>]. Individual data points are plotted with horizontal lines representing the medians for each dataset. <i>p</i>-Values presented are derived from Kruskal-Wallis test, comparing levels in AC, DC, and SC, and from Mann-Whitney <i>U</i>-tests (UC versus HC (N-I)).</p></div>", "links"=>[], "tags"=>["hh", "signalling", "components", "colon"], "article_id"=>584484, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g003", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_HH_Signalling_Components_in_the_Healthy_Human_Adult_Colon_HC_and_UC_/584484", "title"=>"Expression of HH Signalling Components in the Healthy Human Adult Colon (HC) and UC", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:14:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/451879", "https://ndownloader.figshare.com/files/451924", "https://ndownloader.figshare.com/files/451959", "https://ndownloader.figshare.com/files/451981", "https://ndownloader.figshare.com/files/452028", "https://ndownloader.figshare.com/files/452085", "https://ndownloader.figshare.com/files/452176", "https://ndownloader.figshare.com/files/452200", "https://ndownloader.figshare.com/files/452214", "https://ndownloader.figshare.com/files/452229", "https://ndownloader.figshare.com/files/452247"], "description"=>"<div><h3>Background</h3><p>Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in <em>GLI1</em> (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.</p> <h3>Methods and Findings</h3><p>Using a gene-wide haplotype-tagging approach, germline <em>GLI1</em> variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, <em>GLI1</em> was associated with IBD, predominantly UC, in Scotland and England (<em>p</em> < 0.0001). A nonsynonymous SNP (rs2228226C→G), in exon 12 of <em>GLI1</em> (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09–1.31, <em>p</em> = 0.0002). <em>GLI1</em> variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, <em>Gli1<sup>+/lacZ</sup></em> mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. <em>Gli1<sup>+/lacZ</sup></em> mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.</p> <h3>Conclusions</h3><p>HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.</p> </div>", "links"=>[], "tags"=>["germline", "gli1", "implicates", "hedgehog", "signalling", "intestinal", "inflammatory", "pathways"], "article_id"=>149039, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.0050239.sg001", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg002", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg003", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg004", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg005", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg006", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg007", "https://dx.doi.org/10.1371/journal.pmed.0050239.sg008", "https://dx.doi.org/10.1371/journal.pmed.0050239.st001", "https://dx.doi.org/10.1371/journal.pmed.0050239.st002", "https://dx.doi.org/10.1371/journal.pmed.0050239.sd001"], "stats"=>{"downloads"=>42, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Analysis_of_Germline_GLI1_Variation_Implicates_Hedgehog_Signalling_in_the_Regulation_of_Intestinal_Inflammatory_Pathways/149039", "title"=>"Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-12-09 02:30:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/913736"], "description"=>"<div><p>(A) IBD versus HCs.</p>\n <p>(B) UC versus HCs. There was no evidence of heterogeneity in the contribution of rs2228226 between the three cohorts (<i>p</i> = 0.825). 95% CIs for individual populations are represented by horizontal lines and population sizes by square boxes. The diamond represents the pooled OR (fixed effect model) with 95% CIs delineated by the diamond's width. Note the different range of the <i>x</i>-axis for (A) and (B).</p></div>", "links"=>[], "tags"=>["nonsynonymous", "snp", "rs2228226", "sweden", "mantel-haenszel"], "article_id"=>584148, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g001", "stats"=>{"downloads"=>6, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Meta_Analysis_of_Nonsynonymous_GLI1_SNP_rs2228226_tSNP_4_in_Scotland_Cambridge_and_Sweden_Using_Mantel_Haenszel_Method_n_5_352_Individuals_/584148", "title"=>"Meta-Analysis of Nonsynonymous <i>GLI1</i> SNP rs2228226 (tSNP<sub>4</sub>) in Scotland, Cambridge, and Sweden Using Mantel-Haenszel Method (<i>n</i> = 5,352 Individuals)", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:09:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/913903"], "description"=>"<div><p>(A) Conservation of known functional domains in the Gli1 protein. Previously described Sufu binding, DNA binding, and transactivation domains [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-b034\" target=\"_blank\">34</a>,<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-b057\" target=\"_blank\">57</a>,<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-b058\" target=\"_blank\">58</a>] are shown schematically. Amino acid conservation of each domain is represented numerically and by shading of the bar below the domain. Red boxes indicate regions known to regulate GLI1 protein stability [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-b049\" target=\"_blank\">49</a>]. The conserved C-terminal domain that includes Q1100E is adjacent to a known transactivation domain.</p>\n <p>(B) Alignment of the C terminus of mammalian Gli1 proteins. This region (AA 1080–1106) is highly conserved in mammalian lineages.</p>\n <p>(C, D) GLI1 Q1100 and E1100 have similar cellular localization in 293T cells.</p>\n <p>(E) GLI1 E1100 is deficient in driving activation of the 8xGli-Luciferase reporter compared to GLI1 Q1100. GLI2ΔN is a strong activator of 8xGli-Luciferase and serves as a positive control for GLI1 activation. The m8xGli-Luciferase construct contains eight mutant Gli binding sites and serves as a negative control. Data are shown from six triplicate experiments done using two different plasmid preparations (<i>n</i> = 18). Bar heights indicate mean fold activation above baseline, and error bars indicate standard error of the mean. <i>p</i>-Values were calculated using the Student's <i>t</i>-test.</p></div>", "links"=>[], "tags"=>["disrupts", "conserved", "gli1", "transcriptional"], "article_id"=>584335, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Q1100E_Disrupts_a_Conserved_Region_of_the_GLI1_Protein_and_Reduces_GLI1_Transcriptional_Activity_/584335", "title"=>"Q1100E Disrupts a Conserved Region of the GLI1 Protein and Reduces GLI1 Transcriptional Activity", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:12:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/914756"], "description"=>"<div><p>(A, B) Cytokine and chemokine expression normalized to GAPDH is plotted on the <i>y</i>-axis for <i>Gli1<sup>+/lacZ</sup></i> mice, and on the <i>x</i>-axis for WT animals. Gene expression levels that are statistically different are shown with stars. The dotted diagonal trend line indicates identical expression levels between WT and <i>Gli1<sup>+/lacZ</sup></i> mice. (A) Cytokine and chemokine expression in WT and <i>Gli1<sup>+/lacZ</sup></i> animals (<i>n</i> = 3) without DSS treatment. Cytokine and chemokine expression is low and very similar between WT and <i>Gli1<sup>+/lacZ</sup></i> animals.</p>\n <p>(B) Cytokine expression in WT and <i>Gli1<sup>+/lacZ</sup></i> animals (<i>n</i> = 4) after 6 d of 3% DSS treatment. Many pro-inflammatory cytokines and chemokines are significantly more highly expressed in <i>Gli1<sup>+/lacZ</sup></i> animals compared to WT. Note the difference in axes in panels (A) and (B).</p>\n <p>(C) Fold change of cytokine expression from baseline to inflamed for WT and <i>Gli1<sup>+/lacZ</sup></i> animals. We detect dramatic up-regulation of T<sub>h</sub>17 and T<sub>h</sub>1 pathway cytokines and chemokines in <i>Gli1<sup>+/lacZ</sup></i> animals. *, <i>p</i> < 0.05; **, <i>p</i> < 0.01 by the Student's <i>t</i>-test.</p></div>", "links"=>[], "tags"=>["wt", "mice", "dss", "treatments", "demonstrates", "robust", "pro-inflammatory", "cytokine"], "article_id"=>585181, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g007", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cytokine_Analysis_of_Gli1_lacZ_and_WT_Mice_after_DSS_Treatments_Demonstrates_Robust_Pro_inflammatory_Cytokine_Activation_/585181", "title"=>"Cytokine Analysis of <i>Gli1<sup>+/lacZ</sup></i> and WT Mice after DSS Treatments Demonstrates Robust Pro-inflammatory Cytokine Activation", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:26:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/914350"], "description"=>"<div><p>(A, B) WT and <i>Gli1<sup>+/lacZ</sup></i> animals demonstrate normal thickness and structure of colonic mucosa in the absence of DSS.</p>\n <p>(C) WT animals (<i>n</i> = 4) exhibit mild colonic inflammation but do not develop substantial epithelial or ulcerative inflammatory pathology within 4 d of DSS treatment.</p>\n <p>(D) <i>Gli1<sup>+/lacZ</sup></i> animals (<i>n</i> = 4) develop significant inflammatory infiltration, epithelial damage, and ulceration within 4 d of DSS treatment.</p>\n <p>(E) WT animals (<i>n</i> = 14) demonstrate ulceration following DSS treatment.</p>\n <p>(F) <i>Gli1<sup>+/lacZ</sup></i> animals develop profound intestinal inflammation in response to 3% DSS treatment, with severe epithelial damage in long stretches of their colonic mucosa (<i>n</i> = 9).</p>\n <p>(G) Blinded histological scoring of colonic damage after 6 d of DSS treatment. Standard lengths of tissue from the mid colon and distal descending colon were scored in each animal. <i>Gli1<sup>+/lacZ</sup></i> animals (<i>n</i> = 6) have more overall inflammatory foci and more long foci (10+ crypt units affected) than WT animals (<i>n</i> = 6). Each dot represents the number of observed foci in an individual animal; the solid line shows the mean observation in each cohort. Red dots indicate the animals that were analyzed for cytokine expression.</p>\n <p>(H) Comprehensive colitis scoring [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050239#pmed-0050239-b029\" target=\"_blank\">29</a>] of WT and <i>Gli1<sup>+/lacZ</sup></i> animals after 4 and 6 d of DSS treatment. <i>p</i>-Values for (G) and (H) calculated by the Student's <i>t</i>-test.</p></div>", "links"=>[], "tags"=>["animals", "intestinal", "inflammation", "wt", "littermates", "dss"], "article_id"=>584766, "categories"=>["Chemistry", "Genetics", "Immunology"], "users"=>["Charlie W Lees", "William J Zacharias", "Mark Tremelling", "Colin L Noble", "Elaine R Nimmo", "Albert Tenesa", "Jennine Cornelius", "Leif Törkvist", "John Kao", "Susan Farrington", "Hazel E Drummond", "Gwo-Tzer Ho", "Ian D. R Arnott", "Henry D Appelman", "Lauri Diehl", "Harry Campbell", "Malcolm G Dunlop", "Miles Parkes", "Sarah E. M Howie", "Deborah L Gumucio", "Jack Satsangi"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.0050239.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gli1_lacZ_Animals_Demonstrate_More_Severe_Intestinal_Inflammation_than_WT_Littermates_in_Response_to_DSS_Treatment_/584766", "title"=>"<i>Gli1<sup>+/lacZ</sup></i> Animals Demonstrate More Severe Intestinal Inflammation than WT Littermates in Response to DSS Treatment", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-12-09 01:19:26"}

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Relative Metric

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