Aged humans and rodents are susceptible to infection with Streptococcus pneumoniae bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines and increased production of interleukin (IL)-10 by macrophages (Mphi) from aged mice. To understand the molecular basis of cytokine dysregulation in aged mouse Mphi, a microarray analysis was performed on RNA from resting and lipopolysaccharide (LPS)-stimulated Mphi from aged and control mice using the Affymetrix Mouse Genome 430 2.0 gene chip. Two-way ANOVA analysis demonstrated that at an overall P < 0.01 level, 853 genes were regulated by LPS (169 in only the young, 184 in only the aged, and 500 in both). Expression analysis of systematic explorer revealed that immune response (proinflammatory chemokines, cytokines, and their receptors) and signal transduction genes were specifically reduced in aged mouse Mphi. Accordingly, expression of Il1 and Il6 was reduced, and Il10 was increased, confirming our previous results. There was also decreased expression of interferon-gamma. Genes in the Toll-like receptor-signaling pathway leading to nuclear factor-kappaB activation were also down-regulated but IL-1 receptor-associated kinase 3, a negative regulator of this pathway, was increased in aged mice. An increase in expression of the gene for p38 mitogen-activated protein kinase (MAPK) was observed with a corresponding increase in protein expression and enzyme activity confirmed by Western blotting. Low doses of a p38 MAPK inhibitor (SB203580) enhanced proinflammatory cytokine production by Mphi and reduced IL-10 levels, indicating that increased p38 MAPK activity has a role in cytokine dysregulation in the aged mouse Mphi.
Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages.
Specimen part
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Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice.
Sex, Specimen part
View SamplesLatexin is a hematopoietic stem cell (HSC) regulatory gene. Its deletion leads to the expansion of HSC population. The underlying mechanims are largely unknown.
Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice.
Sex, Specimen part
View SamplesLatexin is a hematopoietic stem cells (HSCs) and progenitor cells (HPCs) regulatory gene. Its deletion leads to the expansion of HSC and HPC population. The underlying mechanims are largely unknown.
Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice.
Sex, Specimen part
View SamplesThe transcriptional coactivator Yap promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. Here we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair. Overall design: Totally sixteen samples
Two-signal requirement for growth-promoting function of Yap in hepatocytes.
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YY1 is indispensable for Lgr5+ intestinal stem cell renewal.
Specimen part
View SamplesCrypts were isolated from either control or YY1f/f; Vil-Cre-ERT2 mice treated with tamoxifen for 4 days to induce knockout
YY1 is indispensable for Lgr5+ intestinal stem cell renewal.
Specimen part
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Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.
Specimen part, Treatment
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Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells.
Specimen part
View SamplesEfficient in vitro generation of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) holds great promise for cell-based therapies of hematological diseases. To date, HoxB4 remains to be the most effective transcription factor (TF) whose over-expression in ESCs confers long-term repopulating ability to ESC-derived HSCs. Despite its importance, the components and dynamics of the HoxB4 transcriptional regulatory network is poorly understood, hindering efforts to develop a more efficient protocol for in vitro derivation of HSCs. Towards this goal, we performed global gene expression profiling and chromatin immunoprecipitation coupled with deep sequencing (ChIP-Seq) at four stages of the HoxB4-mediated HSC development. Joint analyses of ChIP-Seq and gene expression profiles unveil a number of global features of the HoxB4 regulatory network.
Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells.
Specimen part
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