The accumulation of irreparable cellular damage restricts healthy lifespan after acute stress or natural aging. Senescent cells are thought to impair tissue function and their genetic clearance can successfully delay features of aging. Identifying how senescent cells avoid apoptosis would allow for the prospective design of anti-senescence compounds to address whether homeostasis can be restored. Here, we identify FOXO4 as a pivot in the maintenance of senescent cell viability. We designed a FOXO4-based peptide which selectively competes for interaction of FOXO4 with p53. In senescent cells, this results in p53 nuclear exclusion and cell-intrinsic apoptosis. Importantly, under conditions where it was well tolerated, the FOXO4 peptide restored liver function after Doxorubicin-induced chemotoxicity. Moreover, in fast aging XpdTTD/TTD, as well as in naturally aged mice the FOXO4 peptide could counteract the loss of fitness, fur density and renal function. Thus, it is possible to therapeutically target senescent cells and thereby effectively counteract senescence-associated loss of tissue homeostasis. Overall design: mRNA expression levels are compared between IR-induced senescent and proliferating IMR90 cells in triplicate
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.
Specimen part, Cell line, 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.
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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 SamplesArabidopsis seedlings, of both wild-type and an ARF7/ARF19 double knockout mutant, were grown to 7 days post-germination. The roots were then dissected into 5 developmental zones, the meristem, early elongation zone, late elongation zone, mature root and lateral root zone. The sections then underwent transcriptional profiling to identify processes and regulatory events specific and in common to the zones.
A novel aux/IAA28 signaling cascade activates GATA23-dependent specification of lateral root founder cell identity.
Age, Specimen part
View SamplesDifferent inbred strains of rats differ in their susceptibility to OIR, an animal model of human retinopathy of prematurity. We examined gene expression profiles in Fischer 344 (F344, resistant to OIR) and Sprague Dawley (SD, susceptible to OIR) rats at the early time point of day 3 to identifying gene pathways related to the underlying genetic cause of phenotypic differences between strains.
Gene expression microarray analysis of early oxygen-induced retinopathy in the rat.
No sample metadata fields
View SamplesEnhanced prenatal fatty streak formation in human fetuses has been associated with maternal hypercholesterolemia. However, the possible roles of maternal genetic background and in utero environment on development of atherosclerosis in adult life have not been unraveled. We generated genetically identical heterozygous apoE-deficient mice offspring with a different maternal background to study the intrauterine effect of maternal genotype and associated hypercholesterolemia on the developing vascular system. As read out for increased atherosclerosis development in adult life, a constrictive collar was placed around the carotid artery to induce lesion formation. A significant increase in endothelial cell activation and damage was detected in the carotid arteries of heterozygous apoE-deficient fetuses with apoE-deficient mothers compared with offspring from wild type mothers, but no fatty streak formation was observed. Postnatally, all carotid arteries revealed normal morphology. In adult offspring with maternal apoE-deficiency, the constrictive collar resulted in severe lesion (9/10) development compared with no to only minor lesions (2/10) in offspring of wild type mothers. Microarray analysis showed no effect of maternal apoE-deficiency on gene expression in adult offspring. We conclude that maternal apoE-deficiency not only affects fetal arteries, but also increases the susceptibility for development of collar-induced atherosclerosis in adult life.
Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life.
No sample metadata fields
View SamplesRNA-seq analysis was performed between WT and alphaT-cat KO mouse cerebella aiming to discover gene transcripts altered by the loss of alphaT-cat These altered gene transcripts could be associated with several neurologic disease-relevant pathways Overall design: Total RNA extracted of cerebellar tissue (n=3) from the brains of WT ad alphaT-cat KO mice
αT-catenin in restricted brain cell types and its potential connection to autism.
Specimen part, Subject
View SamplesPurpose: Our lab has previously shown that Scleraxis (Scx) is require for proper valve development in vivo. In order to fully explore gene networks regulated by Scx during the vital stages of valve remodeling , high throughput RNA-squencing was performed. Results:There were a total of 18,810 genes were detected. A total of 864 genes were differentially expressed Scx null AVC regions: 645 being upregulated and 217 downregulated. Overall design: In this data set, we include expression data from atrioventricular canal (AVC) regions from Scx null and wild-type littermate controls at embryonic day 15.5. A total of 6 samples were analyzed; 3 valve regions from E15.5 Scx-/- mice, and 3 from E15.5 Scx+/+ wild-type littermate controls. Differential expression read counts are ranked based on p-value (<0.05).
RNA-seq analysis to identify novel roles of scleraxis during embryonic mouse heart valve remodeling.
No sample metadata fields
View SamplesWe have analysed a family with an autosomal recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship.
Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.
Sex, Specimen part
View SamplesImmune cell-specific expression is one indication of the importance of a gene's role in the immune response.
Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data.
Specimen part
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