Using measles virus induced T cell suppression as a model, we established that T cell inhibitory protein isoforms can be produced from alternatively spliced pre-mRNAs as a result of virus-mediated ablation of T cell receptor dependent activation of the phosphatidylinositol-3-kinase (PI3K). To asses production of alternative splice variants in response to PI3K abrogation in T cells at a whole cell level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) on T cell suppression. Applying our algorithm on this model 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulated at the level of AS or RG were found enriched in different functional groups with AS targeting e. g. extra cellular matrix (ECM)-receptor interaction and focal adhesion, while cytokine-receptor interaction, Jak-STAT and p53 pathways were mainly RG. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry strongly supporting the notion that PI3K abrogations interferes with key T cell activation processes at both levels, and that candidates represented within both categories bear the potential to actively contribute to T cell suppression
Accumulation of splice variants and transcripts in response to PI3K inhibition in T cells.
Specimen part, Treatment, Subject
View SamplesTuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) frequently complicates combined anti-retroviral therapy (ART) and anti-tubercular therapy in HIV-1 co-infected tuberculosis (TB) patients. The immunopathological mechanism underlying TB-IRIS is incompletely defined.
Cytotoxic mediators in paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome.
Specimen part, Subject
View SamplesPatients with HIV-associated TB are known to experience systemic hyperinflammation, clinically known as immune reconstitution inflammatory syndrome (IRIS), following the commencement of antiretroviral therapy (ART). No prognostic markers or biomarkers have been identified to date and little is known about the mechanism mediating the hyperinflammation. We recruited a prospective cohort of 63 patients with HIV-associated TB, 33 of whom developed TB-IRIS. Of which transcriptomic profiling was performed using longitudinal whole blood RNA samples from 15 non-IRIS and 17 TB-IRIS patients. Transcriptomic signatures that distinguish patients who would eventually develop IRIS were identified as early as week 0.5 (2-5 days post-ART) and predicted a downstream activation of proinflammatory cytokines. At the peak of IRIS (week 2), transcriptomic signatures were overrepresented by innate receptor signaling pathways including toll-like receptor, IL-1 receptor and TREM-1.
HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.
Specimen part
View SamplesThe invasion of activated fibroblasts represents a key pathomechanism in fibrotic diseases, carcinogenesis and metastasis. Here, invading fibroblasts contribute to fibrotic extracellular matrix (ECM) formation and the initiation, progression, or resistance of cancer, respectively. To construct a transcriptome-wide signature of fibroblast invasion, we used a multiplex phenotypic 3D invasion assay using murine lung fibroblasts. Microarray-based gene expression profiles of invading and non-invading fibroblasts were highly distinct: 1049 genes were differentially regulated (>1.5-fold). An unbiased pathway analysis (Ingenuity) identified a significant enrichment for the functional clusters invasion of cells, idiopathic pulmonary fibrosis (IPF) and metastasis. Particularly, matrix metalloprotease13 (MMP13), transforming growth factor (TGF)1, Caveolin1 (Cav1), Phosphatase and Tensin Homolog (Pten), and secreted frizzled-related protein1 (Sfrp1) were among the highest regulated genes. In silico analysis by Ingenuity predicted TGF1, epidermal growth factor (EGF), fibroblast growth factor2 (FGF2), and platelet-derived growth factor (PDGF)-BB to induce invasion. As such, these growth factors were tested in the 3D invasion assay and displayed a significant induction of invasion, thus validating the transcriptome profile. Accordingly, our transcriptomic invasion signature describes the invading fibroblast phenotype in unprecedented detail and provides a tool for future functional studies of cell invasion and therapeutic modulation thereof.
Validated prediction of pro-invasive growth factors using a transcriptome-wide invasion signature derived from a complex 3D invasion assay.
Sex
View SamplesAmyotrophic lateral sclerosis (ALS) is a fatal adult-onset neuromuscular disorder characterized by the selective degeneration of upper and lower motor neurons, progressive muscle wasting and paralysis. To define the full set of alterations in gene expression in skeletal muscle during the course of the disease, we performed high-density oligonucleotide microarray analysis of gene expression in hind limb skeletal muscles of sod1(G86R) mice, one of the existing transgenic models of ALS. To monitor denervation-dependent gene expression, we determined the effects of short-term acute denervation on the muscle transcriptome after sciatic nerve axotomy.
Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model.
Sex, Age, Specimen part, Disease, Disease stage, Treatment, Subject, Time
View SamplesRats overexpressing the human renin and angiotensinogen genes die after seven weeks of end organ damage. They develop hypertension, heart hypertrophy and proteinuria.We compared terminal heart failure, these are indeed terminally ill to double transgenic animals suffering on hypertension, proteinuria and heart hypertrophy. In addition, Losartan-treated animals (10 mg/kg/d)showed similar physiological parameters (normotension, no proteinuria and no heart hypertrophy compared to control sprague dawley rats.
Cardiac gene expression profile in rats with terminal heart failure and cachexia.
No sample metadata fields
View SamplesMicroRNAs (miRNAs) are small RNAs that play important regulatory roles in many cellular pathways. MiRNAs associate with members of the Argonaute (Ago) protein family and bind to partially complementary sequences on mRNAs and induce translational repression or mRNA decay. MiRNA expression can be controlled by transcription factors and can therefore be cell type- or tissue-specific. Here we have analyzed miRNA expression profiles in murine monocyte-derived dendritic cells (DCs) and macrophages upon stimulation with LPS, LDL, eLDL and oxLDL to identify not only stimuli-specific miRNA, but also to identify a hierarchical miRNA system involving miR-155. For this, miR-155 knockout dendritic cells and macrophages were also sequenced using the same stimuli. Overall design: Sequencing of murine monocyte-derived dendritic cells and macrophages (each wild type and miR-155 knock out cells) matured and stimulated, respectively, by LPS, oxLDL, eLDL or LDL.
A miR-155-dependent microRNA hierarchy in dendritic cell maturation and macrophage activation.
Specimen part, Cell line, Subject
View SamplesType I IFN-signaling suppresses an excessive IFN-{gamma} response and prevents lung damage and chronic inflammation following Pneumocystis (PC)-infection and clearance in CD4 T cell-competent mice.
Type-I IFN signaling suppresses an excessive IFN-gamma response and thus prevents lung damage and chronic inflammation during Pneumocystis (PC) clearance in CD4 T cell-competent mice.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
The mammalian TRIM-NHL protein TRIM71/LIN-41 is a repressor of mRNA function.
Specimen part, Cell line
View SamplesWe identify mammalian TRIM71 as repressor of mRNAs that inhibits translation and affects mRNA stability.
The mammalian TRIM-NHL protein TRIM71/LIN-41 is a repressor of mRNA function.
Cell line
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