EMBO/sd-character-level-ner huggingface dataset:
Fig.Figure 5(A) Amounts of rRNA were from uninfected Caco-2 cells or cells infected with indicated strains. *P<0.05 (when compared to the uninfected Caco-2 cells). (B) Amounts of rRNA in uninfected or infected Caco-2 cells transfected with control (siNC) or EBP2-targeting (siEBP2) siRNAs. *P<0.05 (when compared to the siNC-transfected cells that are infected with vopZ'ΔvscN1). (C) Amounts of RNA polymerase I (POLR1A) were from uninfected Caco-2 cells or cells infected with indicated strains. *P<0.05 (when compared to the uninfected Caco-2 cells). (D). Amounts of rRNA in intestinal homogenates from infant rabbits infected with indicated strains 18 and 38 h after infection. *P<0.05 (when compared to the uninfected rabbits at 18 hours). ΔP<0.05 (when compared to the uninfected rabbits at 38 hours post infection).
Noc associates with the membrane in a ΔΨ‐sensitive manner A–H Effect of CCCP on the localisation of Noc and NocNΔ10.Figure 1A-H Effect of CCCP on the localisation of Noc and NocNΔ10. Cellular localisation of Noc‐mYFP (DWA206) and NocNΔ10‐mYFP (DWA382) either with no additions (NA) or after CCCP treatment (5 min; 100 μM), as indicated. Scale bar, 2.5 μm. I-L Effect of Noc overproduction on cell division. Exponentially growing cultures of DWA119 (Δnoc, Pspac(hy)‐noc) and DWA282 (Δnoc, Pspac(hy)‐nocNΔ10) were examined after growth for 1 h with 1 mM IPTG. Cell membranes and DNA were stained with FM5‐95 and DAPI, respectively. Insets show corresponding phase contrast light microscopy images. Scale bar, 5 μm. M Complementation of noc in a Δnoc ΔminCD background. Strains DWA564 (Δnoc, ΔminCD, Pxyl‐noc‐myfp) and 566 (Δnoc, ΔminCD, Pxyl‐nocNΔ10‐myfp) were streaked on nutrient agar (NA) plates in the presence of 0.5% w/v xylose and incubated at 30 and 39°C, as indicated. N Effect of Noc and NocNΔ10 overproduction on sporulation. Strains DWA119 (Δnoc, Pspac(hy)‐noc) and DWA282 (Δnoc, Pspac(hy)‐nocNΔ10) were streaked on NA plates in the absence and presence of 1 mM IPTG, as indicated, and photographed after 48 h at 37°C. O Western blot analysis of cellular fractions (T, total; C, cytosolic; M, membrane) of strains DWA119 and 282 expressing Noc or NocNΔ10, respectively. Proteins were detected using polyclonal antibodies against Noc, DnaA and PBP2B. Antibodies were used at a dilution of 1:10,000.
Figure 4Immunoblot images show EphA2 (A; total, pS897 and pY588) and corresponding pS897/pY588 ratios (B) of TYK-nu and TYK-nu.R after treatment with 0-10 μM cisplatin for 72 h . N = 5. EphA2 (total and phosphorylated) in the cells treated with 0-80 μM carboplatin for 72 h. EphA2 (total and phosphorylated) in the cells EphA2 (total and pS897) in TYK-nu after treatment with inhibitors against MEK (UO126, 10 μM), PKA (H89.2HCl, 10 μM), PI3K (LY294002, 10 μM) or its alpha subunit (BYL-719, 5 μM) and RSK (BI-D1870, 10 μM) in combination with 0-10 μM cisplatin for 72 h (E). Corresponding EphA2-pS897 quantification for BI-D1870 treatment (F) N = 5. EphA2 (total and pS897) in TYK-nu.R treated with 0-20 μM cisplatin without or with 10 μM BI-D1870 for 72 h. EphA2, RSK and ERK1/2 (total and phosphorylated) in TYK-nu (H) and OVCAR4 (I) treated with 0-30 μM carboplatin without or with 50 μM LJH685 for 72 h.
Figure 6A-I. Immunofluorescence staining of spinal cords and brains from non-transgenic (Non-Tg), SOD1 transgenic, or Sig1R−/−mice. Transverse sections of mousespinal cords (A, D-I) or sagittal sections of mouse brains (B, C) were stained using anti-Sig1R (white), βIII-tubulin (red) and IP3R3 (green) antibodies. Note that Sig1R and IP3R3 are co-localized in the motor neurons of the anterior horn (A) and the hypoglossal nucleus (B), and IP3R3 was not expressed in hippocampal neurons (C). Mutant SOD1 induced aggregation of Sig1R and mislocalization of IP3R3 in anterior horn neurons (D-G), while their abnormalities were not observed in SOD1WTmotor neurons (H). Mislocalization of IP3R3 was also observed in Sig1R−/−mouse spinal cords (I). Scale bars: 50 µm. J and K. Representative electron micrographs of the MAM (J) (double-headed arrows) in motor neurons of 12 months-old Non-Tg, SOD1G85R or Sig1R−/−mice. Note that ER-mitochondria contacted areas were reduced in both SOD1G85R or Sig1R−/−mice. Quantification of the mitochondria surface associated to ER was calculated in K. For quantification, 13-19 motor neurons and 224-316 mitochondria with MAM in each animal (n = 2) were analyzed. Data are expressed as mean ± SEM. Double asterisk means p < 0.0001 vs Non-Tg. A one-way ANOVA with subsequent post hoc Tukey's test. Scale bars: 300 nm. L. The levels for IP3R3 and calreticulin were decreased in the MAM fractions of Sig1R−/−mouse brains. MAM fractions and whole tissue lysates of Sig1R+/+ or Sig1R−/−mouse brains were immunoblotted. Representative blots from three independent experiments are shown.
Figure 7NAT4 expression levels and N-terminal acetylation on Histone H4 are reduced under Calorie Restriction conditions. Lower levels of N-acH4 affect the methylation status at H4R3, with this arginine being a key regulator of the lifespan extension induced by the CR pathway. Under these conditions several stress-response genes, including PNC1, are induced. Lifespan extension is probably an effect of increased Pnc1 activity and the hormesis effect caused by enhanced stress protection previously described. Calorie Restriction also extends lifespan through rDNA stability and decrease in translation, pathways that are independent of Nat4.
Fig.Figure 2A. The hydrolytic cleavage of UBE2N-Ub by MvcA into UBE2N and ubiquitin (Q40E variant). Reactions containing the indicated proteins were allowed to proceed for 30 min and samples resolved by SDS-PAGE were detected by CBB staining (left). Mass spectrometric analysis of the protein band corresponding to ubiquitin produced by MvcA from UBE2N-Ub (right). The ubiquitin product is the Glu40 variant of ubiquitin. B. Proposed catalytic mechanism for isopeptide bond cleavage catalyzed by MvcA. Nucleophile attack of the isopeptide bond by the thiol from the catalytic center of MvcA leads to the release of UBE2N and formation of a thioester linked MvcA-Ub intermediate, which is further attacked by a nucleophilic water to produce UbQ40E and to regenerate the active enzyme. C. Dose-dependent cleavage of UBE2N-Ub by MvcA. A series of reactions containing UBE2N-Ub and MvcA at the indicated molar ratios were established and the reactions were allowed to proceed for 30 min before SDS-PAGE and CBB staining. Note that the activity was detectable in a reaction starting at the molar ratio of between UBE2N-Ub and MvcA is 2048:1. D. Time-dependent cleavage of UBE2N-Ub by MvcA. UBE2N-Ub was incubated with MvcA at the molar ratio of 128. Samples taken at the indicated time points were resolved by SDS-PAGE and detected by CBB staining. E. UBE2N produced from UBE2N-Ub via MvcA catalyzed deubiquitination is active in catalyzing the formation of polyubiquitin chains. UBE2N-Ub was preincubated with MvcA or its inactive mutant for 30 min. Then a cocktail containing E1, UBE2V2, 3xHA-ubiquitin, the E3 enzyme TRAF6 and ATP was added into reactions. Ubiquitination was allowed to proceed for 30 min. Proteins in samples resolved by SDS-PAGE were transferred onto nitrocellulose membranes and blotted with the HA specific antibody. Note the robust formation of polyubiquitin chains in the reaction receiving MvcA (middle lane).
Figure 1(A) Experimental setup: Mouse germinal vesicle oocytes (GVOs) were isolated and injected with Morpholinos (MOs) designed to target Tet1-3 mRNAs. After in vitro maturation (IVM), MII oocytes were fertilized by in vitro fertilization (IVF). Zygotes derived from knockdown (KD) and control-MO injected oocytes were analyzed by I) non-invasive time-lapse imaging to monitor the developmental potential of KD embryos, II) immunofluorescence to analyze changes in DNA methylation reprogramming and III) by single 2-cell embryo RNA-Seq & BS-Seq to study the impact of Tet enzymes on embryonic gene activation (EGA) and DNA methylation reprogramming in the totipotent 2-cell embryo. (B-C) Representative time-lapse images of (B) Tet1-3 triple KD (Tet-TKD), (C) Tet3-KD and control embryos at 3.5 days post fertilization. Scale bar = 100 µm. (D-E) Developmental rates of (D) control (control-MO injected), Tet1-, Tet2- and Tet3-single KD and Tet-TKD embryos and (E) control (control-MO + Tet2 mRNA co-injected), Tet2-KD2 (Tet2 MO2 injected), Tet2-KD2 + GFP mRNA and Tet2-KD2 + Tet2 mRNA embryos until blastocyst stage. Indicated p-values were calculated using log rank (Mantel-Cox) test against (D) control embryos or (E) Tet2-KD2 embryos or as indicated (ns = non-significant, * = p < 0.05, **** = p < 0.0001; numbers of analyzed embryos for each condition are indicated in parenthesis).
IIS inhibition affects the transcriptome and proteome of mitochondrial deficient nematodes.Figure 2(A) Left panel: Venn Diagram of the number of genes significantly dysregulated in age-1; gas-1 versus wt (green) and gas-1 versus wt (red). Right panel: Scatter-plots of the expression of genes significantly downregulated (left) or upregulated (right) in gas-1 and age-1; gas-1 mutants compared to wt. In black: expression levels of genes that are significantly up- or down-regulated in gas-1 mutants compared to wt. In red: expression levels of the same genes in age-1; gas-1 mutants compared to wt. (B) IPA analysis indicating the overrepresented canonical pathways in age-1; gas-1 versus gas-1 mutants. (C) Representative lifespans of the indicated strains with average median lifespans ± SEM from all replicates indicated beneath representative curves (D) Volcano plot of TMT/iTRAQ-based quantitative proteomic analysis. In red, proteins significantly dysregulated in age-1; gas-1 compared to gas-1 (FDR< 20%; |log2 (fold change)| >0.47). Dashed lines indicate cutoffs. Proteins involved in carbohydrate (green) and lipid (blue) metabolism are labeled. (E) STRING analysis on dysregulated proteins in age-1; gas-1 vs gas-1 nematodes (20% FDR; |log2(fold change)| >0.47). (F) IPA analysis of TMT/iTRAQ scan results and prediction of downstream effects. Legend indicates color-coding of molecules and connections. Shades of red and green are proportional to fold change, whereas shades of blue and orange are proportional to the strength of the prediction, as calculated by IPA. (G) STRING network for proteins involved in carbohydrate (green) and lipid (blue) metabolism. Legend indicates the nature of each indicated connection. (H) Left panel: Glucose quantification in wt, gas-1 and age-1; gas-1 nematode lysates with NMR, n=7, ns= non-significant, Mann Whitney U test. Right panel: Quantification of total carbohydrates in the indicated strains with phenol-sulfuric assay. Error bars: mean ± SEM, 2 biological replicates (5 technical replicates each), normalized to wt and number of animals used. **p value < 0.01, ns= non-significant, Mann-Whitney U test.
a, Sequence–structure alignment of S.f2a, Sequence-structure alignment of S. flexneri IpaJ with members of C39-peptidase-like family identified by HHPred. IpaJ possesses invariant catalytic triad residues Cys 64, His 206 and Asp 218 (red). The conserved Gln 58, which helps form the oxyanion hole found in many proteases, is shown in green. Invariant residues and core hydrophobic residues found in the C39-family are shown in blue and magenta, respectively. Characterized C39-family member (GCN5-acyetyl transferase) and a C1-family member (Papain) are shown. b, Fluorescence microscopy of HeLa cells transfected with the indicated IpaJ mutants. The cis-Golgi (GM130, green) and F-actin (red) are shown. Scale bar, 10 µm. c, IpaJ or its catalytic mutants were expressed from a galactose-inducible promoter (pGal413 vector) and assayed for a growth arrest phenotype on galactose or glucose (control) carbon source. d, Illustration of the yeast genomic clones isolated from the IpaJ suppressor screen. ARF1p, ARF2p and VPS15p are highlighted. e, Yeast strain harbouring a galactose-inducible IpaJ gene were transformed with a multi-copy vector containing the indicated genes. Yeast were assayed for a growth arrest phenotype on galactose or glucose (control) carbon source.
Figure 3Schematic illustration of full-length and chimeric Rad54 and Rdh54 protein constructs. Images of GFP-tagged Rad54, Rdh54NRad54, Rdh54 and Rad54NRdh54 (1, 3, 10 and 30 nM each) bound to Rad51-ssDNA molecules. Images of GFP-tagged Rad54, Rdh54NRad54, Rdh54 and Rad54NRdh54 (1, 3, 10 and 30 nM each) bound to Rad51-ssDNA molecules in the presence of 30 nM Hed1. Quantification of the integrated GFP signal intensity for GFP-tagged Rad54 (N = 75), Rdh54NRad54 (N = 46), Rdh54 (N = 50) and Rad54NRdh54 (N = 35; 1, 3, 10 and 30 nM each) bound to Rad51-ssDNA molecules. The data was fit by non-linear regression and error bars represent s.d. for individual DNA molecules. Comparison of fold binding inhibition for GFP-tagged Rad54, Rdh54NRad54, Rdh54 and Rad54NRdh54 in reactions conducted in the presence of 30 nM Hed1. The dot represents the mean and the error bars represent the range for two independent experiments.
Figure 4Representative double immunofluorescence confocal images of coronal sections of the dorsal striatum showing p62 immunolabelling (red) in choline acetyltransferase (ChAT)-positive (cyano) ChIs of Tor1a+/+ and Tor1a+/- mice. A1) Two representative ChIs identified by the white box in the low magnification images (bar = 20 µm) are shown at higher magnification in (A2) (bar = 5 µm). A3) The graph reporting mean ± SEM values of p62/ChAT signal overlap in ChIs, normalized to Tor1a+/+ values of the same experiment, shows a significant increase of p62 in Tor1a+/- neurons (Tor1a+/+ n=20 cells, N=6 mice; Tor1a+/- n=20 cells, N=6 mice, t test ***P=0.00008)
Developmental increase of miR-29a regulates the expression of extracellular and epigenetic remodeling factors.Figure 1a) Venn diagram showing the intersection between putative miR-29a target genes (grey) and age-upregulated (green, bottom) or age-downregulated (red, top) genes. Ellipse area is proportional to the size of the sets. The numbers indicate the numerosity of the sets. 1051 miR-29a predicted targets by Targetscan, 5429 genes downregulated with age; 554 genes in the intersection, odds ratio 4.40; Fisher exact test, p< 0.0001; 4339 upregulated genes with age; 164 genes in the intersection, odds ratio 0.93; Fisher exact test p=0.427. b) Box plot showing the distribution of log2(FC) of all or selected miR-29a targets in the Data ref: Mazziotti et al, 2017 dataset of age-regulated genes in the visual cortex. Notches represent confidence intervals for the median. Whiskers indicate 95th and 5th percentile, the box marks the 25th and 75th percentile. Significance vs. all detected genes was assessed by Wilcoxon's test (miR-29a targets p=4.9x10-14, top 200 miR-29a targets p=3.7x10-38). c) DAVID functional annotation clustering analysis showing the most significantly overrepresented GO terms in age-downregulated miR-29 targets. (d,e) Mature miR-29a (n=3/4 mice for each age; one-way ANOVA, p<0.0001; post hoc Tukey's test ***p<0.001, ****p<0.0001, ns not significant) and Dnmt3a expression level (normalized to P10) at different ages measured by qPCR (n=3/4 mice for each age; one-way ANOVA, p<0.0001; post hoc Tukey's test: *p<0.05, **p<0.01, ****p<0.0001, ns not significant). One way ANOVA p-values are reported. Error bars represent ±SEM. f) Scatter plot showing correlation of miR-29a and Dnmt3a levels in the visual cortex display a strong negative correlation (Pearson correlation: r=-0.817, p<0.001). Each circle represents data from a single animal. g) Representative examples of in situ hybridization on visual cortex (left P25, right P120) using a LNA probe against miR-29a. Scale bar 180 µm. Cortical layers are delimited by roman numerals and brackets h) Example of co-staining for PV (green), miR-29a (red) and nuclear marker (blue) in a P120 mouse. White triangles represent PV+/miR-29a+ cells. Scale bar 20 µm.
Figure 1A Turbidity and bright-field microscope images of indicated groups (left) and the quantitative analysis of turbidity of samples were measured by absorbance at 600 nm (right). 10 μM cGAS, 5 μM G3BP1, 5 μM BSA and 100 nM dsDNA (60 bp) were used in these assays. n = 3 biological replicates. Data information: Representative images are shown Error bars, mean with s.d. , *P < 0.05, ****P < 0.0001, two-tailed t-test. NS, non-significant. Scale bars, 10 μm B cGAMP production assays. Recombinant cGAS (10 μM) and G3BP1 (10 μM) were incubated with 100 nM dsDNA. The produced cGAMP was quantitatively analyzed by Liquid Chromatography-Mass Spectrometry/Multiple Reaction Monitoring (LC-MS/MRM). ND, not detected. n = 3 technical replicates. C Bright-field microscope images of cGAS (10 μM) with indicated concentrations of BSA or G3BP1 (left) and a quantitative analysis of the total area of condensates (right). n = 3 biological replicates. Data information: Representative images are shown Error bars, mean with s.d. , *P < 0.05, ****P < 0.0001, two-tailed t-test. NS, non-significant. Scale bars, 10 μm D Time-lapse imaging of liquid droplets fusion after mixing 10 μM cGAS-mCherry with 1 μM FAM-labeled dsDNA. Data information: Representative images are shown Error bars, mean with s.d. Scale bars, 5 μm (D) E Time-lapse imaging of liquid droplets fusion after mixing 40 μM cGAS-mCherry with 10 μM G3BP1-mEGFP. Data information: Representative images are shown Scale bars 3 μm (E) F FRAP analysis of DNA-induced droplets of cGAS (1 μM dsDNA, 10 μM cGAS-mCherry), the yellow dotted circle indicated the region of photobleaching. G FRAP curve of (F). n = 3 biological replicates. H FRAP analysis of cGAS-G3BP1 droplets. 10 μM cGAS-mCherry and 5 μM G3BP1 were used. The yellow dotted circle indicated the region of photobleaching. I FRAP curve of (H). n = 3 biological replicates. Data information: Representative images are shown (A, Error bars, mean with s.d. , *P < 0.05, ****P < 0.0001, two-tailed t-test. NS, non-significant. FRAP, Fluorescence recovery after photobleaching. Scale bars, 2 μm (F and H).
Determination of the threshold pHi for alkaline‐evoked Ca2+ influxChanges in pHi evoked by mixing with pHi‐clamp solutions (see explanation in the text); sperm were loaded with the pHi indicator BCECF.Figure 3A Changes in pHi evoked by mixing with pHi‐clamp solutions (see explanation in the text); sperm were loaded with the pHi indicator BCECF. ΔR/R (%) indicates the change in the BCECF fluorescence emission ratio (ΔR = F494/F540) with respect to the basal ratio (R, mean of the first 3-5 data points).B Steady‐state change (at t = 14 s) of BCECF fluorescence for the pHi signals shown in (A). The intercept of the fitted straight line with the x‐axis yields the resting pHi; the slope of the straight line yields the ΔR/R (%) × ΔpH−1. Inset: calibrated changes in pHi evoked by various pHi‐clamp solutions. C Ca2+ signals evoked by mixing of sperm with pHi‐clamp solutions. D Dose-response relation for the Ca2+ signals shown in (C). E Calibrated pHi increase (red) and respective Ca2+ response (black) evoked by mixing of sperm with a pHi 7.6‐clamp solution; depicted are, on an extended time scale, the first 500 ms of the respective pHi increase and Ca2+ signal shown in (B, inset) and (C), respectively. The threshold pHi for CatSper activation was deduced from the latency of the Ca2+ signal.F Threshold pHi and latency of Ca2+ signals evoked by various pHi‐clamp solutions (mean ± SD; n ≥ 3).
Figure 3A Serum free fatty acid (FFA) levels and triacylglycerol levels in WT and FADD-D mice fed a HFD for 20 days (n = 5 for each genotype). Data are expressed as means ± SEM. *P = 0.0059, **P = 0.0012 (Student's t-test). B Serum levels of leptin in WT and FADD-D mice (n = 4 for each genotype) fed a SD or a HFD. Data are expressed as means ± SEM. *P = 0.0032, **P = 0.0003, ***P = 0.0038 (one-way ANOVA). C Morphology of inguinal WAT, BAT, and liver from WT and FADD-D mice fed a HFD for 20 days. WAT and BAT were stained with hematoxylin and eosin. Liver tissues were stained with Oil red O to demonstrate lipid accumulation and counterstained with hematoxylin. Scale bars = 50 μm. Shown are typical results from four different fields and three different experiments. D Comparison of cell size in WAT of WT and FADD-D mice maintained on SD and HFD (n = 5 for each genotype). E FADD-D mice lost more weight as compared with WT on 20-h fasting (n = 4 for each genotype). Data are expressed as means ± SEM. *P = 0.0085 (Student's t-test). F Whole-body oxygen consumption rate (VO2) during 24 hr in WT and FADD-D mice fed a SD (n = 4 for each genotype). Data are expressed as means ± SEM. *P = 0.0055, **P = 0.0081 (Student's t-test). G Average respiratory exchange ratio (VCO2/VO2) (RER) for the dark and light period in WT and FADD-D mice (n = 5 for each genotype). Data are expressed as means ± SEM. *P = 0.0042, **P = 0.0079 (Student's t-test). H Rectal temperature (n = 5 for each genotype). Data are expressed as means ± SEM. *P = 0.0217 (Student's t-test). I Average values of energy expenditure (EE) for the 24 hr period in WT and FADD-D mice (n = 5 for each genotype). Data are expressed as means ± SEM. *P = 0.0054 (Student's t-test). J Physical activity for the dark and light period in WT and FADD-D mice (n = 5 for each genotype). Data are expressed as means ± SEM. NS, not statistically significant (Student's t-test).
IFN-I, Myd88 and IFN-γ activate distinct sets of genes in mouse pDC during MCMV infection (A) Generation of mixed bone marrow chimera mice (MBMC); CTR, control; TST, test.Figure 1 (A) Generation of mixed bone marrow chimera mice (MBMC); CTR, control; TST, test. Recipient CD45.1 (5.1) mice were irradiated, then reconstituted with equal proportions of bone marrow cells isolated from indicated mice. Mice were used at least 8 weeks after reconstitution  (B) Gating strategy. pDC were identified as lineage (TCRb, CD19, Ly6G, NK1.1)- CD11b- CD11clow/int CD317high cells. 5.2 vs 5.1 cells were finally discriminated within the pDC gate 5.2+ pDC were isolated by sorting from MBMC reconstituted with BM cells from WT B6 (CTR), Ifnar1-/- or Myd88-/- deficient (TST) mice. Their 5.1+ WT counterparts were isolated from the same mice. Two independent experiments were performed for each experimental condition (i.e. with Ifnar1-CTR and -TST MBMC on the one hand, versus Myd88-CTR and TST MBMC on the other hand). Samples from uninfected animals are shown as empty symbols and those from MCMV-infected mice as filled symbols. Altogether, this led to 14 biological replicates for WT pDC, irrespective of their CD45 allotypic status and of the type of MBMC they originated from, both for uninfected and MCMV-infected MBMC. pDC isolated from uninfected or MCMV-infected C57BL/6 mice were included as internal control. Unsupervised hierarchical clustering (HC) and principal component analysis (PCA) were performed on all the probe sets of the microarrays. For HC, Pearson correlation distance and Ward's method linkage were used.  (E) Venn diagram showing the overlap between the lists of genes significantly upregulated in WT pDC of infected mice (n=14) as compared to WT pDC of uninfected animals (n=14) (grey circle), or downregulated in Ifnar1-KO (n=2) (red circle) or Myd88-KO (n=2) (green circle) pDC isolated from infected TST MBMC, as compared to WT pDC (n=6) isolated from the same TST or from their matched CTR infected MBMC  (F) Enrichment of the gene modules identified in (E) for independent gene sets previously established from the analysis of other microarray datasets (blue font), belonging to specific signaling pathways (red font), associated to specific functions or diseases (violet font) or regulated by the indicated upstream regulators (black font), as assessed by using Ingenuity Pathway Analysis (IPA). Data are represented as a heatmap, with gene modules identified in panel E as columns and gene sets as rows. The colored cells indicate the significance of the enrichment of each gene module for each gene set, as computed by IPA analysis and according to the color scale shown below the heatmap