Background: Although TNF inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. TNF is known to modulate neurogenesis by decreasing cell proliferation, increasing apoptosis of precursor cells, and impairing neuronal differentiation. TNF can also influence the formation of the hippocampus, with long-lasting effects on cognition. Materials and methods: To clarify whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the brains of E13.5, P7, and adult TNF +/+ and TNF-/- mice and measured changes in gene and protein expression and monoamine levels in adult TNF+/+ and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, selective soluble TNF inhibitor XPro1595, or nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult TNF+/+ and TNF-/- mice and anti-TNF treated mice with behavioral tasks.
TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex.
Sex, Specimen part
View SamplesIRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Though regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. In order to investigate the role of IRAK-4 kinase function in vivo, knock-in mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase deficient IRAK-4 protein (IRAK-4 KD). Analysis of bone marrow macrophages obtained from WT and IRAK-4 KD mice with a number of experimental techniques demonstrated that the IRAK-4 KD cells greatly lack responsiveness to stimulation with the Toll-like receptor 4 (TLR4) agonist LPS. One of the techniques used, microarray analysis, identified IRAK-4 kinase-dependent LPS response genes and revealed that the induction of LPS-responsive mRNAs was largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in TLR4-mediated induction of inflammatory responses.
IRAK-4 kinase activity-dependent and -independent regulation of lipopolysaccharide-inducible genes.
No sample metadata fields
View SamplesIRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Though regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. In order to investigate the role of IRAK-4 kinase function in vivo, knock-in mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase deficient IRAK-4 protein (IRAK-4 KD). Analysis of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice with a number of experimental techniques demonstrated that they greatly lack responsiveness to stimulation with IL-1b or a Toll-like receptor 7 (TLR7) agonist. One of the techniques used, microarray analysis, identified IRAK-4 kinase-dependent IL-1b response genes in mouse embryonic fibroblasts and revealed that the induction of IL-1b-responsive mRNAs was largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in IL-1R/TLR7-mediated induction of inflammatory responses.
IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression.
No sample metadata fields
View SamplesB cells from human tonsil and blood were sorted using flow cytometry. The human samples were processed immediately ex-vivo using markers for known B cell subsets.
Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.
No sample metadata fields
View SamplesSorted B cells using flow cytometry
Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.
No sample metadata fields
View SamplesExpression profiling of stem cell lines derived from the early embryo representing the trophoblast, primitive endoderm, early epiblast (inner cell mass E3.5) and late post-implantation epiblast (E5.5).
Cell-surface proteomics identifies lineage-specific markers of embryo-derived stem cells.
Sex, Specimen part, Cell line
View SamplesThis study analyzes transcriptome profiles in pre-germinated seeds and hypoxia-treated seedlings of Arabidopsis thaliana wild type (Col-0) and homozygous mutants (prt6-1 and ate1 ate2). This dataset includes CEL files, RMA signal values and MAS5 P/M/A calls. For pre-germinated seeds, seeds imbibed for 24 h were used for total RNA extraction. For hypoxia treatment, 7-d-old seedlings were incubated in a hypoxia chamber for 2 h and the entire seedling was subjected to RNA extraction. Quantitative profiling of cellular mRNAs was accomplished with the Affymetrix ATH1 platform. Changes in the transcriptome during early seed germination stage and in response to hypoxia in seedlings were evaluated. The data led to identification of mRNAs with abundance regulated by PRT6 and ATE1 / ATE2, which are essential components for the N-end rule pathway of targeted proteolysis (NERP). A combination of genetic, biochemical and molecular analyses reveal that NERP coordinates the stability of key ethylene responsive factor (ERF) family transcription factors, which regulate expression of core hypoxia response genes and tolerance to low oxygen stress. This indicates that the NERP functions as a homeostatic sensor of low oxygen in plants.
Homeostatic response to hypoxia is regulated by the N-end rule pathway in plants.
Age, Specimen part, Treatment
View SamplesCircular RNAs (circRNAs) are a class of noncoding RNAs produced by a non-canonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA-seq data from colorectal cancer cell lines (HCT116, RKO and SW48) in the presence or absence of DNA damage. Surprisingly, unlike the strong p53-dependent induction of hundreds of p53-induced mRNAs, only a few circRNAs were induced from the p53-induced genes. Circ-MDM2, an annotated circRNA from the MDM2 locus, was one of the handful of circRNAs that originated from a p53-induced gene. Given the central role of MDM2 in suppressing p53 protein levels and p53 activity, we investigated the function of circ-MDM2. Knocking down circ-MDM2 with siRNAs that targeted the circ-MDM2 junction and had no effect on linear MDM2 mRNA, resulted in increased basal p53 levels and growth defects in vitro and in vivo. Consistent with these results, transcriptome profiling showed increased expression of several direct p53 targets, reduced Rb phosphorylation and defects in G1-S progression upon silencing circ-MDM2. Our results reveal the role of a novel circRNA by which the MDM2 locus suppresses p53 levels and cell cycle progression.
A Circular RNA from the <i>MDM2</i> Locus Controls Cell Cycle Progression by Suppressing p53 Levels.
Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.
Sex, Age, Specimen part, Disease
View SamplesGene expression profiling of liver biopsies collected from 33 healthy liver donors ranging from 13 to 90 years old. The Affymetrix HG-U133 Plus 2.0 GeneChip platform was used to evaluate gene-expression.
Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.
Sex, Age, Specimen part, Disease
View Samples