Gene expression from bone-marrow drived macrophages of WT and SREBP-1a deficient mice
Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a.
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View SamplesSalmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the cecum of streptomycin pre-treated mice. We determined global changes in gene expression elicited by serotype Typhimurium in the cecal mucosa. The gene expression profile was dominated by T cell derived cytokines and genes whose expression is known to be induced by these cytokines. Markedly increased mRNA levels of interferon (IFN-gamma), interleukin-22 (IL-22) and IL-17 were detected by quantitative real-time PCR. Furthermore, mRNA levels of genes whose expression is induced by IFN-gamma, IL-22 or IL-17, including macrophage inflammatory protein 2 (MIP-2), inducible nitric oxide synthase (Nos2), lipocalin-2, MIP-1alpha, MIP-1beta, and keratinocyte-derived cytokine (KC), were also markedly increased. To assess the importance of T cells in orchestrating this pro-inflammatory gene expression profile, we depleted T cells using a monoclonal antibody prior to investigating cecal inflammation caused by serotype Typhimurium in streptomycin pre-treated mice. Depletion of CD3+ T cells resulted in a dramatic reduction in gross pathology, a significantly reduced recruitment of neutrophils and a marked reduction in mRNA levels of IFN-gamma, IL-22, IL-17, iNOS, lipocalin-2 and KC. Our results suggest that T cells play an important role in amplifying inflammatory responses induced by serotype Typhimurium in the cecal mucosa.
T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa.
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View SamplesTo adapt the lives of organisms to the day-night cycle, evolution has built a complex machinery, whose molecular components are able to anticipate and drive changes in organism behavior and metabolism. A mutual bidirectional interaction exists between circadian abnormalities and development of diseases.
Circadian clock regulates the host response to Salmonella.
Age, Specimen part
View SamplesSalmonella enterica serotype Typhimurium cause a localized enteric infection in immunocompetent patients while human immunodeficiency virus (HIV)-infected patients develop a life threatening bacteremia. We used a rhesus macaque ileal loop model to study how simian immunodeficiency virus (SIV) infection triggers defects in mucosal barrier function that enhance S. Typhimurium dissemination. SIV infection resulted in significant depletion of CD4+ T cells in the intestinal mucosa. Gene expression profiling revealed a defective TH17 response (with suppression of IL-17 and IL-22 expression) and impaired homeostasis of the intestinal epithelium in SIV-infected animals during NTS infection. These findings correlated with an impaired ability of lamina propria CD4+ T cells from SIV-infected macaques to produce IL-17 upon ex vivo stimulation, while production of IFN-gamma was not affected. This cytokine imbalance in SIV-infected animals was associated with reduced expression of genes required for intestinal epithelial maintenance and repair, increased fluid secretion during NTS infection, epithelial damage and translocation of a non-invasive S. Typhimurium mutant. Although no defects in neutrophil recruitment were noted, the ileum of SIV-infected animals contained lower levels of the enzyme myeloperoxidase, which may indicate defects in neutrophil killing capacity. S. Typhimurium was recovered in markedly increased numbers from the mesenteric lymph nodes of SIV-infected macaques, illustrating the increased potential for systemic dissemination during co-infection. Our data suggest that SIV-infection causes a multi-factorial defect in mucosal barrier function that promotes bacterial dissemination.
Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut.
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View SamplesPlant immune responses to pathogen attack involve various defense mechanisms and among them, the Hypersensitive Response (HR), a form of programmed cell death occurring at invasion sites. AtMYB30, a transcription factor acts as a positive regulator of a cell death pathway conditioning the HR.
A MYB transcription factor regulates very-long-chain fatty acid biosynthesis for activation of the hypersensitive cell death response in Arabidopsis.
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View SamplesNeuroprotective therapies for retinal degeneration may be used to rescue retinal cells and preserve vision. Hypoxic preconditioning stabilizes the transcription factor HIF-1 in the retina and strongly protects photoreceptors in an animal model of light-induced retinal degeneration.
Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection.
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View SamplesAlveolar soft-part sarcoma (ASPS) is an extremely rare, highly vascular soft tissue sarcoma affecting predominantly adolescents and young adults. In an attempt to gain insight into the pathobiology of this enigmatic tumor, we performed the first genome-wide gene expression profiling study.
Gene expression profiling of alveolar soft-part sarcoma (ASPS).
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View SamplesThe infant leukemia-associated gene, Ott1(Rbm15), has broad regulatory effects within the murine hematopoiesis. However, germline Ott1 deletion results in fetal demise prior to E10.5, indicating additional developmental requirements for Ott1. The spen gene family, to which Ott1 belongs, has a transcriptional activation/repression domain and RNA recognition motifs, and in Drosophila has a significant role in the development of the head and thorax. Early Ott1-deficient embryos show growth retardation and incomplete closure of the notochord. Further analysis demonstrated placental defects in the spongiotrophoblast and syncytiotrophoblast layers, resulting in an arrest of vascular branching morphogenesis. Rescue of the placental defect using a conditional allele with a trophoblast-sparing cre transgene allowed embryos to form a normal placenta and survive gestation. This result shows that the process of vascular branching morphogenesis in Ott1-deficient animals is regulated by the trophoblast compartment rather than the fetal vasculature. Mice surviving to term manifested hyposplenia and abnormal cardiac development. Analysis of global gene expression of Ott1-deficient embryonic hearts shows enrichment of hypoxia-related genes and significant alteration of several candidate genes critical for cardiac development. Thus, Ott1-dependent pathways in addition to being implicated in leukemogenesis, may also be important in the pathogenesis of placental insufficiency and cardiac malformations.
Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen.
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View SamplesThe infant leukemia-associated gene, Ott1 (Rbm15), has broad regulatory effects on embryonic development and hematopoiesis. Embryonic deletion of Ott1 results in defects to the placenta, spleen and heart. Conditional deletion within the adult hematopoietic compartment demonstrates a requirement in pre-B development and inhibitory roles in myeloid progenitor and megakaryocyte populations. Ott1-deleted bone marrow has an expansion of the Lin- Sca-1+ c-Kit+ (LSK) population which includes the hematopoietic stem cell (HSC) population. Functional HSC testing through competitive repopulation of irradiated recipients demonstrated however, a severe defect in Ott1-deficient HSCs, despite adequate numbers of immunophenotypically identified long term HSCs. Although mice deleted in situ for Ott1 are able to maintain hematopoiesis in steady state over a normal lifetime, but when subjected to proliferative stress, the HSC population loses the self-renewing, G0 fraction and undergoes bone marrow failure.
Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress.
Specimen part
View SamplesC/EBP (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBP responsible for ALK-mediated oncogenesis. C/EBP was knocked down in ALK+ ALCL cell lines with a C/EBP-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBP. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBP was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBP-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBP in ALK-mediated oncogenesis.
Identification of C/EBPβ target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.
Sex, Cell line
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