Establishing reliable biomarkers for assessing and validating clinical diagnosis at early prodromal stages of Parkinsons disease is crucial for developing therapies to slow or halt disease progression. Here, we present the largest study to date using whole blood gene expression profiling from over 500 individuals to identify an 87-gene blood-based signature. Our gene signature effectively differentiates between idiopathic PD patients and controls in both a validation cohort and an independent test cohort, and further highlights mitochondrial metabolism and ubiquitination/proteasomal degradation as potential pathways disrupted in Parkinsons disease.
Analysis of blood-based gene expression in idiopathic Parkinson disease.
Sex, Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Inflammatory Type 2 cDCs Acquire Features of cDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection.
No sample metadata fields
View SamplesThe phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1-cDC2) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen presenting cells (APC). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of Fc receptor CD64 shared with MCs, and of IRF8 shared with cDC1s. These inflammatory (Inf-)cDC2s were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2 matured in response to cell-intrinsic toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module and acquired antigens via convalescent serum and Fc receptors. Since hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
Inflammatory Type 2 cDCs Acquire Features of cDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection.
No sample metadata fields
View SamplesWe sequenced mRNA from 6 samples of FACsorted telencephalons from E14.5 Sip1|Nkx2-1 knockout and WT|Nkx2-1 control mouse embryos to find differentially expressed genes in the absence of the transcription factor Sip1. Overall design: Examination of mRNA levels in 3 control and 3 Sip1|Nkx2-1 knockout samples
Directed migration of cortical interneurons depends on the cell-autonomous action of Sip1.
Specimen part, Cell line, Subject
View SamplesThe transcriptional profile of A673 parental and SP-2509 Drug resistant cells treated with DMSO and SP-2509 (2uM 48hrs) Overall design: A673 parental and SP-2509 Drug resistant cells treated with DMSO and SP-2509 (2uM 48hrs)
Ewing sarcoma resistance to SP-2509 is not mediated through KDM1A/LSD1 mutation.
Treatment, Subject
View SamplesThe transcriptional profile of A673 parental, and SP-2509 drug resistant washout cells (4 and 6 months) Overall design: Following generation of A673 SP-2509 drug resistant cells (chronic exposure for 7 months), drug was withdrawn with cell pellets collected 4 and 6 months after removal.
Ewing sarcoma resistance to SP-2509 is not mediated through KDM1A/LSD1 mutation.
Disease, Treatment, Subject
View SamplesNumerous microRNAs and their target mRNAs are co-expressed across diverse cell types. However, it is unknown whether they are regulated in a cellular context-independent or -dependent manner. Here, we explored transcriptome-wide targeting and gene regulation by miR-155, whose activation-induced expression plays important roles in innate and adaptive immunity. Through mapping of miR-155 targets using differential Argonaute iCLIP, mRNA quantification with RNA-Seq, and 3'UTR usage analysis using polyadenylation (polyA)-Seq in activated miR-155-sufficient and deficient macrophages, dendritic cells, T and B lymphocytes, we identified numerous targets differentially bound by miR-155. While alternative cleavage and polyadenylation (ApA) contributed to differential miR-155 binding to some transcripts, in a majority of cases identical 3'UTR isoforms were differentially regulated across cell types, suggesting ApA-independent and cellular context-dependent miR-155-mediated gene regulation reminiscent of sequence-specific transcription factors. Our study provides comprehensive maps of miR-155 regulatory RNA networks and offers a valuable resource for dissecting context-dependent and -independent miRNA-mediated gene regulation in key cell types of the adaptive and innate immune systems. Overall design: Primary dendritic cells, B cells, CD4 T cells, and macrophages from C57BL/6J wild type and miR-155 KO mice were cultured in RPMI medium with 10% FBS. Prior to harvesting primary dendritic cells, mice were subcutaneously injected with one million B16 melanoma cells expressing Flt3 ligand for about two weeks. After purification of splenic CD11c+ dendritic cells by CD11c microbeads (Miltenyi Biotec), dendritic cells were activated in a medium containing 100 ng/ml LPS (SIGMA) and 20 ng/ml GMSCF (Tonbo). Splenic primary B cells were purified by negative selection using Dynabeads Mouse CD43 (Invitrogen), and activated in a medium containing 25 ug/ml LPS and 6.5 ng/ml mIL4 (PeproTech). CD4 T cells from lymph node and spleen were purified with Dynabeads FlowComp Kit (Invitrogen). CD4+CD25-CD44- T cells were then activated with Dynabeads Mouse T-Activator CD3/CD28 (Invitrogen). Intraperitoneal macrophages, induced by thioglycollate injection, were harvested and activated with 100 ng/ml LPS.
The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types.
Specimen part, Cell line, Treatment, Subject
View SamplesNumerous microRNAs and their target mRNAs are co-expressed across diverse cell types. However, it is unknown whether they are regulated in a cellular context-independent or -dependent manner. Here, we explored transcriptome-wide targeting and gene regulation by miR-155, whose activation-induced expression plays important roles in innate and adaptive immunity. Through mapping of miR-155 targets using differential Argonaute iCLIP, mRNA quantification with RNA-Seq, and 3'UTR usage analysis using polyadenylation (polyA)-Seq in activated miR-155-sufficient and deficient macrophages, dendritic cells, T and B lymphocytes, we identified numerous targets differentially bound by miR-155. While alternative cleavage and polyadenylation (ApA) contributed to differential miR-155 binding to some transcripts, in a majority of cases identical 3'UTR isoforms were differentially regulated across cell types, suggesting ApA-independent and cellular context-dependent miR-155-mediated gene regulation reminiscent of sequence-specific transcription factors. Our study provides comprehensive maps of miR-155 regulatory RNA networks and offers a valuable resource for dissecting context-dependent and -independent miRNA-mediated gene regulation in key cell types of the adaptive and innate immune systems. Overall design: Primary dendritic cells, B cells, CD4 T cells, and macrophages from C57BL/6J wild type and miR-155 KO mice were cultured in RPMI medium with 10% FBS. Prior to harvesting primary dendritic cells, mice were subcutaneously injected with one million B16 melanoma cells expressing Flt3 ligand for about two weeks. After purification of splenic CD11c+ dendritic cells by CD11c microbeads (Miltenyi Biotec), dendritic cells were activated in a medium containing 100 ng/ml LPS (SIGMA) and 20 ng/ml GMSCF (Tonbo). Splenic primary B cells were purified by negative selection using Dynabeads Mouse CD43 (Invitrogen), and activated in a medium containing 25 ug/ml LPS and 6.5 ng/ml mIL4 (PeproTech). CD4 T cells from lymph node and spleen were purified with Dynabeads FlowComp Kit (Invitrogen). CD4+CD25-CD44- T cells were then activated with Dynabeads Mouse T-Activator CD3/CD28 (Invitrogen). Intraperitoneal macrophages, induced by thioglycollate injection, were harvested and activated with 100 ng/ml LPS. Each condition has 3 sequencing replicates.
The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types.
Specimen part, Cell line, Subject
View SamplesLeft ventricular gene expression profiles from 12-, 16- and 20-months old spontaneously hypertensive rats (SHRs) were compared with left ventricular profiles seen in age-matched Wistar-Kyoto (WKY) rats by screening Affymetrix U34A arrays (there are 4 samples in each timepoint except 3 samples of 20-months old WKYs).
Distinct upregulation of extracellular matrix genes in transition from hypertrophy to hypertensive heart failure.
No sample metadata fields
View SamplesWe undertook an integrative technological approach to compare miRNA detection capability of three high-throughput commercial platforms. Overall design: We artificially introduced human precursor, 2’-O-methyl modified and mature spiked-in miRNAs in a controlled fashion into native human placenta total RNA.
Differences in microRNA detection levels are technology and sequence dependent.
Subject
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