Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrial-targeted nuclear genes in concert with reduced signaling via PPAR/PGC-1 and other transcriptional regulators. In cultured myocytes Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO, but not by increasing PGC-1. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.
Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.
Age, Specimen part
View SamplesInfection is a major complication and cause of mortality and morbidity after acute stroke however the mechanisms are poorly understood. After experimental stroke the microarchitecture and cellular composition of the spleen are extensively disrupted resulting in deficits to immune function.
Experimental Stroke Differentially Affects Discrete Subpopulations of Splenic Macrophages.
Specimen part, Treatment
View SamplesWe access the activity-dependent genes in olfactory neuron cells with unilateral naris occlusion model with mouse. Overall design: mRNA profile of olfactory epithelia between closed and open sides of mice naris was compared
Activity-Dependent Gene Expression in the Mammalian Olfactory Epithelium.
Specimen part, Cell line, Subject
View SamplesEffect of SDHB silencing using siRNA methodologies in the tumor phenotype
Cells silenced for SDHB expression display characteristic features of the tumor phenotype.
No sample metadata fields
View SamplesWhen making treatment decisions, oncologists often stratify breast cancers into a low-risk group (ER+, low grade); an intermediate-risk group (ER+, high grade); and a high-risk group that includes Her2+ and triple-negative (ER-/PR-/Her2-) tumors. None of the currently available gene signatures correlates to this clinical classification. We aimed to develop a test that is practical for the oncologists, that offers both molecular characterization of BCs, and improved prediction of prognosis and treatment response. We investigated the molecular basis of such clinical practice by grouping Her2+ and triple-negative breast cancers together during clustering analyses on the genome-wide gene expression profiles of our training cohort, mostly derived from fine needle aspiration biopsies (FNABs) of 149 consecutive evaluable Breast cancers. The analyses consistently divided these tumors into a three-cluster pattern, similar to clinical risk-stratification groups, that was reproducible in published microarray databases (n=2487) annotated with clinical outcomes. The clinicopathologic parameters of each of these three molecular groups were also similar to clinical classification. The low-risk group had good outcomes and benefited from endocrine therapy. Both intermediate- and high-risk groups had poor outcomes and were resistant to endocrine therapy. The latter demonstrated the highest rate of complete pathological response to neoadjuvant chemotherapy; the highest activities in MYC, E2F1, Ras, -Catenin and IFN- pathways; and poor prognosis predicted by 14 independent prognostic signatures. Based on a multivariate analysis, this new gene signature, termed ClinicoMolecular Triad Classification, predicted recurrence and treatment response better than all pathologic parameters and other prognostic signatures.
A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis.
Specimen part
View SamplesTo measures the comparability and concordance of Illumina microarray, a series of 30 samples of Universal Human Reference RNA (UHRR) were set as controls for every single chip of total 30 Human-Ref V2 BeadChips. The average bead number of the 30 arrays was 42.38.1 for any bead type over the 22,184 probes. A high average correlation coefficient (r) value was obtained as 0.99080077 relative to each other of the expression intensity values from the 30 duplicate UHRR samples.
A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis.
Disease
View SamplesGenetic variation modulating risk of sporadic Parkinson's disease (PD) has been primarily explored through genome wide association studies (GWAS). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal timepoints. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a novel postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including known PD genes and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1 null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research. Overall design: 473 single cell RNA-Seq samples from sorted mouse Th-eGFP+ dopaminergic neurons collected at two timepoints from three distinct brain regions.
Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.
Specimen part, Subject
View SamplesThe goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in 5 brain regions of alcohol-nave iP and P.NP rats.
Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats.
Specimen part
View SamplesA highly significant quantitative trait locus (QTL) that influenced alcohol preference was identified in the iP/iNP rats on chromosome 4.
Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains.
No sample metadata fields
View SamplesWe demonstrated recently that both constitutive and FAS-triggered apoptosis of human neutrophils are profoundly impaired by Francisella tularensis, but how this is achieved is largely unknown. To test the hypothesis that changes in neutrophil gene expression contribute to this phenotype, we used human oligonucleotide microarrays to identify differentially regulated genes in cells infected with F. tularensis strain LVS compared with uninfected controls.
Francisella tularensis alters human neutrophil gene expression: insights into the molecular basis of delayed neutrophil apoptosis.
Specimen part, Time
View Samples