Our hypothesis was that at any given point in time, islets will contain differing populations of beta cells at different stages of their lifecycle, with further changes occurring with metabolic stress and aging. We examined subpopulations of beta cells isolated from MIP-GFP mice on the basis of their insulin transcriptional activity and in their expression of p16Ink4a. In addition, using aging C57Bl/6 mice as a model, markers of beta cell aging were identified and validated: Igf1r and Cd99 expression increased with age, whereas Kcnq5 was decreased with age. These markers were correlated with an age-related decline in function. The functional aging of beta cells was accelerated by S961, an antagonist to the insulin receptor, which induced insulin resistance. Particularly surprising was the finding of marked islet heterogeneity as demonstrated with the marked staining differences of the markers: Igf1r, Cd99 and Kcnq5. These novel findings about beta cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions that must be addressed about the pathogenesis of type 2 diabetes. The present study has identified new markers of aging in beta cells and found that the expression of these and other markers can be increased by insulin resistance. This provides insight into how insulin resistance might accelerate the death of beta cells. In addition, striking heterogeneity among islets was found, which opens up new ways to think about islet biology and the pathogenesis of T2D.
β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance.
Age, Specimen part
View SamplesWe report gene expression changes in Cul3 deficient thymic CD4+ T cells
A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation.
Specimen part
View SamplesARC (NSC 188491, SMA-491), 4-amino-6-hydrazino-7-beta-d-ribofuranosyl-7H-pyrrolo-(2,3-d)-pyrimidine-5-carboxamide, is a nucleoside analog with profound in vitro anti-cancer activity. First identified in a high-throughput screen for inhibitors of p21 mRNA expression, subsequent experiments showed that ARC also repressed expression of hdm2 and survivin, leading to its classification as a global inhibitor of transcription 1. The following Hu U133 plus 2.0 arrays represent single time point (24 hour) gene expression analysis of transcripts altered by ARC treatment. Arrays for the other compounds (sangivamycin and doxorubicin) are included as comparators.
ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC.
No sample metadata fields
View SamplesWe measured gene expression of D. melanogaster female heads and abdomens after mating with males from six populations evolved under either enforced monogamy (no male-male competition, 3 populations) or sustained polygamy (intense male-male competition, 3 populations). Overall design: Three samples of virgin female heads and six samples of mated female heads (one each per male evolved population, of which there are three monogamous and three polygamous), for nine libraries. Also, three samples of virgin female abdomens and six samples of mated female abdomens (one each per male evolved population, of which there are three monogamous and three polygamous), for nine libraries. In total, eighteen libraries sequenced in 8 lanes.
Sexual conflict drives male manipulation of female postmating responses in <i>Drosophila melanogaster</i>.
Sex, Specimen part, Subject
View SamplesHomodimerization of Mpl can also be accomplished in the absence of Tpo, by binding of a synthetic ligand (Chemical inducer of dimerization, CID) to a constitutively expressed fusion protein F36VMpl consisting of a ligand binding domain (F36V) and the intracellular signaling domain of Mpl. In contrast to Tpo stimulation, F36VMpl dimerization in human CD34+ progenitor cells generates robust erythropoiesis.
Novel pathways to erythropoiesis induced by dimerization of intracellular C-Mpl in human hematopoietic progenitors.
Specimen part
View SamplesDevelopment of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice receiving non-toxic and toxic LNA gapmers after a single and repeat administration.
Comparison of hepatic transcription profiles of locked ribonucleic acid antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated toxicity in mice.
Sex, Specimen part
View SamplesIdentify shear and side-specific miRNAs in Human Aortic Valvular Endothelial Cells using the following conditions: 1) fHAVEC exposed to OS (FO), 2) vHAVEC exposed to OS (VO), 3) fHAVEC exposed to LS (FL), and 4) vHAVEC exposed to LS (VL).
Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells.
Specimen part
View SamplesGermline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) dramatically increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed histotype. Other risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation. To test whether mtBRCA1 or mtBRCA2 FTE cells respond differently to peri-ovulatory follicular fluid (FF) exposure than control patient FTE, gene expression profiles from primary FTE cultures were compared at baseline, 24h after FF exposure, and 24h after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Analysis revealed increased NFB and EGFR signaling at baseline, with increased interferon signaling after recovery from FF exposure in mtBRCA1 samples. Inhibition of EGFR signaling and ISGylation by increased BRCA1 expression was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1. Suppression of ISG15 and ISGylated protein levels by BRCA1 expression was found to be mediated by decreased NFB signaling and was transiently suppressed by FF exposure. This study demonstrates increased NFB signaling associated with decreased BRCA1 expression resulting in increased ISG15 and ISGylation following FF exposure, which could represent potential targets for chemoprevention.
BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells.
Specimen part, Time
View SamplesXenograft models remain a cornerstone technology in the development of anti-cancer agents. The ability of immunocompromised rodents to support the growth of human tumors provides an invaluable transition between in vitro testing and clinical trials. Therefore, approaches to improve model selection are required. In this study, cDNA microarray data was generated for a collection of xenograft models at in vivo passages 1, 4 and 10 (P1, P4 and P10) along with originating cell lines (P0). These data can be mined to determine transcript expression 1) relative to other models 2) with successive in vivo passage and 3) during the in vitro (P0) to in vivo (P1) transition.
Gene expression profiling of 49 human tumor xenografts from in vitro culture through multiple in vivo passages--strategies for data mining in support of therapeutic studies.
No sample metadata fields
View SamplesTranscriptomic studies of human tumor xenografts are complicated by the presence of murine cellular mRNA. As such, it is useful to know the extent to which mouse mRNA cross-hybridizes to any given array platform. In this study, murine cDNA samples from diverse sources were hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays. In this regard it is possible to identify specific probes that are potential targets of cross-species interference.
Gene expression profiling of 49 human tumor xenografts from in vitro culture through multiple in vivo passages--strategies for data mining in support of therapeutic studies.
Specimen part, Cell line
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