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GSE23802
Drosophila melanogaster
54 Downloadable Samples
Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary but not sufficient for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases.
Publication Title
No associated publication
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 44 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1x10-5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4x10-15, odds ratio[OR]=1.91; rs10994982, P=5.7x10-9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 x10-5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes.
Publication Title
Germline genomic variants associated with childhood acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part, Disease
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix HT MG-430 PM Array Plate (htmg430pm)
Description
Tumor associated macrophages show signs of both, classical pro-inflammatory as well as alternative macrophage activation. The aim of this study was to compare TAMs across tumor types, to characterize their phenotype in detail and to identify the signaling nodules involved regulating classical and alternative activation traits.
Publication Title
Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix HT MG-430 PM Array Plate (htmg430pm)
Description
Recent observations about how cells sense amino acids have argued for preeminent roles of mTOR and the stress kinase GCN2 in allowing cells to estimate their amino acid needs. Here we used models of programmed immune microenvironments where helper T cells have to sense how much amino acids are available to engage in antigen-fueled proliferation. Contrary to current models, T cells activate mTOR in the competency phase of the cell cycle regardless of amino acid amounts, GCN2 or surface TCR. Instead, we found T cells use an amino acid sensing system to target IL-2-induced STAT5 phosphorylation at the restriction point of cell cycle commitment. mTOR activity is subsequently reduced and specifically connected to SREBP activation. T cells can be pushed into cycle by increasing IL-2 even when no amino acids are available. Collectively, our studies reveal helper T cells use sequential and distinct pathways to measure local amino acid concentrations.
Publication Title
Proliferating Helper T Cells Require Rictor/mTORC2 Complex to Integrate Signals from Limiting Environmental Amino Acids.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Pediatric adrenocortical tumors (ACT) are rare and often fatal malignancies; little is known regarding their etiology and biology. To provide additional insight into the nature of ACT, we determined the gene expression profiles of 24 pediatric tumors (five adenomas, 18 carcinomas, and one undetermined) and seven normal adrenal glands. Distinct patterns of gene expression, validated by quantitative real-time PCR and Western blot analysis, were identified that distinguish normal adrenal cortex from tumor. Differences in gene expression were also identified between adrenocortical adenomas and carcinomas. In addition, pediatric adrenocortical carcinomas were found to share similar patterns of gene expression when compared with those published for adult ACT. This study represents the first microarray analysis of childhood ACT. Our findings lay the groundwork for establishing gene expression profiles that may aid in the diagnosis and prognosis of pediatric ACT, and in the identification of signaling pathways that contribute to this disease.
Publication Title
Gene expression profiling of childhood adrenocortical tumors.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
A small subset of T cells also expresses kiler-cell immunoglobulin-like receptors (KIRs). We find that KIR+ T cells primarily reside in the CD56+ T population. However, little is known on how these cells are different from the conventional CD56- T, NK, and iNKT cells.
Publication Title
Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Nitric oxide (NO) produced by macrophages (Ms) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. M arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in Ms. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated Ms. We found that mycobacteria-infected Ms produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected Ms
Publication Title
No associated publication
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Infection is the single greatest threat to survival during cancer chemotherapy because of depletion of bone marrow derived immune cells. In the absence of phagocytes such as neutrophil, vaccine-induced humoral and cellular anti-pathogen immunity are compromised. Using a model of vaccine-induced protection against lethal P. aeruginosa pneumonia in the setting of chemotherapy-induced neutropenia, we found a population of resident lung macrophages in the immunized lung that mediated protection in the absence of neutrophils, bone marrow derived monocytes, or antibodies. These vaccine-induced macrophages (ViMs) expanded after immunization, locally proliferated, and were closely related to alveolar macrophages (AMs) by surface phenotype and gene expression profiles. By contrast to AMs, numbers of ViMs were stable through chemotherapy, show enhanced phagocytic activity, and prolonged survival of neutropenic mice from lethal P. aeruginosa pneumonia upon intratracheal adoptive transfer. Thus, induction of ViMs by tissue macrophage remodeling may become a framework for new strategies to activate immune-mediated reserves against infection in immunocompromised hosts.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Myelopoiesis is impaired in Raptor-deleted mice (CreER-Rptor-flox/flox). To evaluate the transcriptional changes in myeloid precursors , we isolated CMP (LinSca-1c-Kit+CD34+FcRII/IIImid), GMP (LinSca-1c-Kit+CD34+FcRII/IIIhigh) and Lin (B220, Ly6C, Ly6G, CD3, Ter-119) negative cells (Lin) from bone marrow of WT or CreER-Rptor-flox/flox mice. RNA was isolated from CMP and GMP immediately after sorting and Lin- cells were cultured for 12 hours with M-CSF (10 ng/mL) in 10% FBS and 1% P/S DMEM before RNA isolation.
Publication Title
Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 19 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but mechanisms linking them remain elusive. We report that mTORC1 couples microenvironmental cues with metabolic programs in orchestrating reciprocal development of two fundamentally distinct lineages, and T cells. Loss of mTORC1 impairs but promotes T cell development, and disrupts metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, reactive oxygen species (ROS) controlled by mTORC1 serves as a key metabolic signal, and perturbation of redox homeostasis impinges upon fate decisions. Furthermore, singlecell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples