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null (Ed.)Abstract Purpose Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. Methods Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t -distributed stochastic neighbor embedding (t-SNE). Results OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals ( p = 1.8 × 10 −13 to 4 × 10 −8 ). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 ( p = 2.8 × 10 −13 ), IL6R ( p = 1.1 × 10 −9 ), TNFR1 ( p = 2.5 × 10 −10 ), and TNFR2 ( p = 5.7 × 10 −9 ), levels indistinguishable from controls ( p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. Conclusions Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients.more » « less
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Summary Cell differentiation is driven by changes in the activity of transcription factors (
TF s) and subsequent alterations in transcription. To study this process, differences inTF binding between cell types can be deduced by probing chromatin accessibility. We used cell type‐specific nuclear purification followed by the assay for transposase‐accessible chromatin (ATAC ‐seq) to delineate differences in chromatin accessibility andTF regulatory networks between stem cells of the shoot apical meristem (SAM ) and differentiated leaf mesophyll cells inArabidopsis thaliana . Chromatin accessibility profiles ofSAM stem cells and leaf mesophyll cells were very similar at a qualitative level, yet thousands of regions having quantitatively different chromatin accessibility were also identified. Analysis of the genomic regions preferentially accessible in each cell type identified hundreds of overrepresentedTF ‐binding motifs, highlighting sets ofTF s that are probably important for each cell type. Within these sets, we found evidence for extensive co‐regulation of target genes by multipleTF s that are preferentially expressed in each cell type. Interestingly, theTF s within each of these cell type‐enriched sets also showed evidence of extensively co‐regulating each other. We further found that preferentially accessible chromatin regions in mesophyll cells tended to also be substantially accessible in the stem cells, whereas the converse was not true. This observation suggests that the generally higher accessibility of regulatory elements in stem cells might contribute to their developmental plasticity. This work demonstrates the utility of cell type‐specific chromatin accessibility profiling for the rapid development of testable models of regulatory control differences between cell types.