We aimed to identify specific biomarkers of IFN-beta bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFN-beta. Nine genes followed patterns in gene expression over time similar to the MX1 and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments revealed specific induction of selected biomarkers by IFN-beta but not IFN-gamma, and several markers, in particular USP18 and HERC5, were significantly induced at lower IFN-beta concentrations and more selective than the MX1 as biomarkers of IFN-beta bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p=0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFN-beta bioactivity, and to further explore their implication in MS pathogenesis.
Search for specific biomarkers of IFNβ bioactivity in patients with multiple sclerosis.
Sex, Age, Specimen part, Disease, Disease stage, Treatment, Subject, Time
View Samplesrae1 is an essential gene and encodes one of nuclear pore complex. rae1-167 mutant cells show rapid accumulation of polyA-RNA in the nucleus at 36C followed by protein accumulation, suggesting that accumulated nuclear mRNA influences nucelar cytooplasmic transport.
A systematic genomic screen implicates nucleocytoplasmic transport and membrane growth in nuclear size control.
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View SamplesComparison of acetylcholine receptor immunization between RIIIS/J and B10.RIII mice.
Periodic gene expression program of the fission yeast cell cycle.
Specimen part
View SamplesWe established a novel in vitro tissue culture system (named VISUAL), in which xylem and phloem differentiation can be induced with Arabidopsis thaliana cotyledons
Vascular Cell Induction Culture System Using Arabidopsis Leaves (VISUAL) Reveals the Sequential Differentiation of Sieve Element-Like Cells.
Age, Specimen part, Time
View SamplesWe established a novel in vitro tissue culture system (named VISUAL), in which xylem and phloem differentiation can be induced with Arabidopsis thaliana cotyledons
Vascular Cell Induction Culture System Using Arabidopsis Leaves (VISUAL) Reveals the Sequential Differentiation of Sieve Element-Like Cells.
Specimen part, Time
View SamplesAfter activation, CD4+ helper T (Th) cells differentiate
Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages.
Specimen part
View SamplesT follicular helper (Tfh) cells play a pivotal role in germinal center reactions, which requires Bcl6 transcription factor. To analyze their relationships with other effector T cell lineages and their stability in vivo, we developed and analyzed a new Bcl6 reporter mouse alone or together with other lineage reporter systems. Assisted with genome-wide transcriptome analysis, we show substantial plasticity of T cell differentiation in the early phase of immune response. At this stage, CXCR5 appears to be expressed in a Bcl6-independent manner. Once Bcl6 is highly expressed, Tfh cells can persist in vivo and some of them develop into memory cells. Together, our results indicate Bcl6 as a bona fide marker for Tfh polarized program.
Bcl6 expression specifies the T follicular helper cell program in vivo.
Sex, Specimen part
View SamplesMemory CD4+ T helper (Th) cells are crucial for acquired immunity and protection from infectious microorganisms, and also drive pathogenesis of chronic inflammatory diseases, such as asthma. ST2hi memory-type Th2 cells have been identified as a pathogenic subpopulation capable of directly inducing eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amounts of IL-5 upon stimulation via their TCR, but not in response to IL-33. In contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). We investigated the molecular mechanism that controls the innate function of IL-33-induced cytokine production, and identified a MAPK phosphatase Dusp10, as a key negative regulator of IL-33–induced cytokine production in Th2 cells. We found that Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production by preventing GATA3 activity through inhibition of p38 MAPK phosphorylation. Strikingly, deletion of Dusp10 rendered ST2hi Th2 cells able to directly respond to IL-33 exposure and produce IL-5. Thus, DUSP10 constrains IL-33–induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-mediated GATA3 function. Overall design: Functions of Dusp10, a family of dual specificity protein phosphatase, are assessed by RNA-seq.
DUSP10 constrains innate IL-33-mediated cytokine production in ST2<sup>hi</sup> memory-type pathogenic Th2 cells.
Specimen part, Cell line, Subject
View SamplesSequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10 and C18) and parental PEO1 (P1 and P2) cells was performed in order to determine mechanisms of acquired resistance in the resistant cell lines. PEO1 parental cell lines were authenticated prior to sequencing. PEO1 parental were confirmed to be BRCA2-mutated (5139C>G). Olaparib PEO1 resistant cells were generated through a step-wise escalation of olaparib (10nM to 8uM olaparib). In olaparib resistant lines an increase canonical Wnt signaling and loss of of non-canonical Wnt signaling was observed. Overall design: Sequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10, and C18) and parental PEO1 cells was performed in order to determine mecahnisms of acquired resistance.
Activation of Wnt signaling promotes olaparib resistant ovarian cancer.
Cell line, Subject
View SamplesRecent studies have shown that stem cell memory T (TSCM) cell-like properties are important for the successful adoptive immune therapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine activated T cells are converted into stem cell memory-like T (iTSCM) cells by co-culture with stromal OP9 cells expressing the NOTCH-ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converts conventional human CAR-T cells into TSCM-like CAR-T, “CAR-iTSCM” cells, and that the mitochondrial metabolic reprogramming plays a key role in this conversion. The NOTCH signals promote mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. We identified fork head box M1 (FOXM1) as a downstream target of NOTCH, which is responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possess superior antitumor potential compared to conventional CAR-T cells. We propose that the NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy.
The NOTCH-FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory-like CAR-T Cells.
Sex, Specimen part
View Samples