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Fetal lung maturation induced by chorioamnionitis and its interaction with antenatal corticosteroids in rhesus macaque fetuses

ABSTRACT: Purpose: Our goal was to evaluate the pathways through which chorioamnionitis induces fetal lung maturation and how it interacts with a low-dose treatment with antenatal corticosteroids to further enhance fetal lung maturation. Methods: We treated pregnant rhesus macaque at 132 days (80% gestation) with intre-amniotic bacterla lipopolissacharide to model chorioamnionitis or a low-dose antenatal corticosteroids treatment with betamethasone-acetate (Beta-Ac 0.125mg/kg) or both treatments. Fetuses were delivered by c-section after 5 days and RNA-sequencing of whole lung tissue was performed. Another group of fetuses exposed to LPS was delivered 16h after treatment. Preterm controls were delivered at 132 days and term controls were delivered at 155 days and received no intervention. Results: Treatment with Beta-Ac in the setting of chorioamnionitis improves lung compliance and increases surfactant production relative to either treatment alone. RNA sequencing shows that these changes are mediated by suppression of proliferation and induction of mesenchymal cellular death. The combined exposure results in a mature-like transcriptomic profile with inhibition of extracellular matrix development by suppression of collagen genes and regulators of lung development. ACS and inflammation also suppressed signature genes associated with proliferative mesenchymal progenitors similar to the term lung. Conclusion: Treatment with ACS in the setting of inflammation may result in early respiratory advantage to preterm infants, but this advantage may come at a cost of abnormal extracellular matrix development which may be associated with increased risk of chronic lung disease.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE148645 | GEO | 2021/02/01

REPOSITORIES: GEO

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Next-generation sequencing of rhesus macaques lung after treatment with a low-dose or clinical antenatal corticosteroid treatment

Project description:Purpose: Evaluate fetal lung maturation and transcriptome after clinical treatment with antenatal corticosteroids compared to an alternative treatment with a slow release low-dose formulation. Methods: Lung mRNA profiles of rhesus macaques were generated by RNA sequencing. Reads that met quality thresholds were aligned to the rhesus macaque genome and number of reads per gene was counted. RNA-sequencing of the hippocampus was done. Differential expression analysis was done using read counts. Results: A relatively low dose of Beta-Ac increased lung compliance, surfactant concentration and relative airspace of the fetal lung equivalent to the clinical drug. By transcriptome analyses, the early suppression of genes associated with immune responses and the downregulation of genes associated with developmental pathways were less changed by Beta-Ac than the clinical drug. There were no significant differences between Beta-Ac and control while the clinical drug suppressed maturational pathways including genes involved in neurogenesis, neuronal differentiation and stem cell fate commitment. Conclusions: We report that low-dose betamethasone-acetate has decreased impact on lung transcriptome compared to the clinical treatment.

2019-06-21 | GSE118438 | GEO

Fetal lung maturation induced by chorioamnionitis and its interaction with antenatal corticosteroids in rhesus macaque fetuses

Project description:Fetal lung maturation induced by chorioamnionitis and its interaction with antenatal corticosteroids in rhesus macaque fetuses

| PRJNA625272 | ENA

Identification of novel candidate target genes at 3q26.2-q29 in squamous cell carcinoma of the lung

2009-06-19 | GSE16597 | GEO

Resident Macrophages are Locally Programmed for Silent Clearance of Apoptotic Cells

Project description:Although apoptotic cells (ACs) contain nucleic acids that can be recognized by Toll-like receptors (TLRs), engulfment of ACs does not initiate inflammation in healthy organisms. To better understand this phenomenon, we identified and characterized macrophage populations that continually engulf ACs in several distinct tissues. These macrophages share characteristics compatible with immunologically silent clearance of ACs, including high expression of AC recognition receptors, low expression of TLR9, and reduced TLR responsiveness to nucleic acids. When removed from tissues, these macrophages lose many of these characteristics and generate inflammatory responses to AC-derived nucleic acids, suggesting that cues from the tissue microenvironment are required to program macrophages for silent AC clearance. We show that KLF2 and KLF4 control expression of many genes within this AC clearance program. Coordinated expression of AC receptors with genes that limit responses to nucleic acids may represent a central feature of tissue macrophages that ensures maintenance of homeostasis.

2017-11-15 | GSE93820 | GEO

Expression profiling defines a recurrence signature in lung adenocarcinoma

Project description:Lung cancer remains the leading cause of cancer death worldwide. Overall 5-year survival is about 10-15% and despite curative intent surgery, treatment failure is primarily due to recurrent disease. Conventional prognostic markers are unable to determine which patients with completely resected disease within each stage group are likely to relapse. To identify a gene signature associated with recurrent adenocarcinoma (AC) of lung, we analyzed primary tumour gene expression for a total of 48 stage I ACs on 22,323 element microarrays, comparing expression profiles for individuals who remained disease-free for a minimum of 36 months with those from individuals whose disease recurred within 18 months of complete resection. Genome-wide profiling has revealed a distinct gene expression profile for recurrent lung AC which may be clinically useful as a prognostic tool. Keywords: non-small cell lung carcinoma, squamous cell, tumor recurrence, expression profiling

2007-05-01 | GSE5843 | GEO

Formation of artificial chromosomes in Caenorhabditis elegans and analyses of their segregation in mitosis, DNA sequence composition and holocentromere organization

Project description:To investigate how exogenous DNA concatemerizes to form episomal artificial chromosomes (ACs), acquire equal segregation ability and maintain stable holocentromeres, we injected DNA sequences with different features, including sequences that are repetitive or complex, and sequences with different AT-contents, into the gonad of Caenorhabditis elegans to form ACs in embryos, and monitored AC mitotic segregation. We demonstrated that AT-poor sequences (26% AT-content) delayed the acquisition of segregation competency of newly formed ACs. We also co-injected fragmented Saccharomyces cerevisiae genomic DNA, differentially expressed fluorescent markers and ubiquitously expressed selectable marker to construct a less repetitive, more complex AC. We sequenced the whole genome of a strain which propagates this AC through multiple generations, and de novo assembled the AC sequences. We discovered CENP-AHCP-3 domains/peaks are distributed along the AC, as in endogenous chromosomes, suggesting a holocentric architecture. We found that CENP-AHCP-3 binds to the unexpressed marker genes and many fragmented yeast sequences, but is excluded in the yeast extremely high-AT-content centromeric and mitochondrial DNA (> 83% AT-content) on the AC. We identified A-rich motifs in CENP-AHCP-3 domains/peaks on the AC and on endogenous chromosomes, which have some similarity with each other and similarity to some non-germline transcription factor binding sites.

2021-08-22 | GSE145600 | GEO

Molecular and functional features of synucleinopathy-associated astrocytes

Project description:Astrocyte (AC) involvement is a common neuropathological feature in human synucleinopathy-associated neurodegeneration. However, our understanding of the in vivo characteristics of reactive ACs in synucleinopathy remained limited. Here we report the transcriptomic and functional features of a unique synucleinopathy-associated AC (SAA) subtype in a mouse model. SAAs share a convergent transcriptomic state across synucleinopathy-laden brain regions, and are at least partially reliant on microglia for their phenotypic maintenance in vivo. Intravital imaging revealed that an upregulation of the excitatory amino acid transporter 2 (EAAT2) in synucleinopathy-affected ACs is associated with depressed neuronal activities. This is potentially mediated via increased AC glutamate uptake, as pharmacological induction of EAAT2 reproduced the same effect. With cross-species comparative analysis, we showed that the core SAA transcriptomic features are present in human aged and synucleinopathy-affected midbrain ACs, while important distinct characteristics also exist. Collectively, our results uncovered complex reactive AC changes that likely play important adaptive roles in synucleinopathy.

2023-06-30 | GSE205511 | GEO

Oral dosing for antenatal corticosteroids in the rhesus macaque

Project description:Oral dosing for antenatal corticosteroids in the rhesus macaque

| PRJNA542881 | ENA

Identification of novel candidate target genes at 3q26.2-q29 in squamous cell carcinoma of the lung

Project description:High-resolution array-CGH was performed to identify differences in the patterns of genomic imbalances between SCC and AC of non-small cell lung cancer (NSCLC). On a genome-wide profile, SCCs showed higher frequency of gains than ACs (p = 0.067). More specifically, statistically significant differences were observed across the histologic subtypes for gains at 2q14.2, 3q26.2-q29, 12p13.2-p13.33, and 19p13.3, as well as losses at 3p26.2-p26.3, 16p13.11, and 17p11.2 in SCC, and gains at 7q22.1 and losses at 15q22.2-q25.2 occurred in AC (P < 0.05). The most striking difference between SCC and AC was gains at 3q26.2-q29, occurring in 86% (19/22) of SCCs, but in only 21% (3/14) of ACs. Array-CGH was performed to compare the different patterns of genetic alterations. DNA from NSCLC patients (n=36) and human reference DNA (Promega) were differentially labeled and cohybridized on the array. The Fisher exact test utilized two categories, normal and abnormal (loss and gain), with the null hypothesis that the relative proportions of each of the two imbalance categories would be expected to be the same in the groups. The counts of abnormal versus normal were summarized by subtype of NSCLC for each BAC, providing 2x2 tables for analysis. A multiple testing correction (Benjamini-Hochberg false discovery rate (FDR)) was applied to correct for the high number of false positive calls.

2010-05-18 | E-GEOD-16597 | biostudies-arrayexpress

Mouse retinal cell atlas: molecular identification of sixty-three amacrine cell types

Project description:Amacrine cells (ACs) are a diverse class of interneurons that modulate input from photoreceptors to retinal ganglion cells (RGCs), rendering each RGC type selectively sensitive to particular visual features, which are then relayed to the brain. While many AC types have been identified morphologically and physiologically, they have not been comprehensively classified or molecularly characterized. We used high-throughput single-cell RNA sequencing (scRNA-seq) to profile >32,000 ACs from mice of both sexes, and applied computational methods to identify 63 AC types. We identified molecular markers for each type, and used them to characterize the morphology of multiple types. We show that they include nearly all previously known AC types as well as many that had not been described. Consistent with previous studies, most of the AC types expressed markers for the canonical inhibitory neurotransmitters GABA or glycine, but several expressed neither or both. In addition, many expressed one or more neuropeptides, and two express glutamatergic markers. We also explored transcriptomic relationships among AC types and identified transcription factors expressed by individual or multiple closely related types. Noteworthy among these were Meis2 and Tcf4, expressed by most GABAergic and most glycinergic types, respectively. Together, these results provide a foundation for developmental and functional studies of ACs, as well as means for genetically accessing them. Along with previous molecular, physiological and morphological analyses, they establish the existence of at least 130 neuronal types and nearly 140 cell types in mouse retina.

2020-06-22 | GSE149715 | GEO

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