The effect of the downstream pressure (defined here as the wake pressure behind the tail of the reflecting wedge) on shock wave reflection in steady flows is investigated both numerically and analytically. The dependence of the shock wave configurations on the downstream pressure is studied. In addition to the incident-shock-waveangle-induced hysteresis, which was discovered a few years ago, a new downstreampressure-induced hysteresis has been found to exist. The numerical study reveals that when the downstream pressure is sufficiently high, an inverse-Mach reflection wave configuration, which has so far been observed only in unsteady flows, can be also established in steady flows. Very good agreement between the analytical predictions and the numerical results is found.
We previously described the effects and behaviour of the main circulating active androgen testosterone (Testo) in an androgen-sensitive sebocyte cell line. Testosterone and DHT readily induce androgen receptor (AR) translocation, expression of target genes and finally a lipogenic differentiation program. DHEA is not significantly transformed into Testo, had no significant androgenic (agonist), nor anti-androgenic (antagonist) effect by itself in the tested conditions. Here we analysed the activity of reference anti-androgens (Finasteride, Dutasteride, Cyproterone acetate), both at the level of their potential targets (5-alpha-reductase, AR translocation, induced transcripts) and in the functional lipid accumulation assay. As expected, because the 5-alpha-reductase type 1 predominates in this model, Dutasteride was found 100-fold more active than Finasteride in inhibiting DHT production. Cyproterone acetate (CypAc) did not interfere with Testo metabolism. Regarding the effects on testosterone or DHT early-induced gene RASD1(1), CypAc was fully active in the 10 nM range, while Dutasteride and Finasteride were active only over the micromolar range, this when Testo was the inducer. CypAc did not interfere with DHT-induced AR translocation, suggesting that its activity targets the intra-nuclear transcription process. Regarding the diversity of the metabolite profile, and the diversity of the mechanisms it was important to test the potential inhibitors in a functional assay relevant of the biological effects of interest. In the validated 7 days lipid accumulation assay (1), CypAc and Dutasteride were found the most potent, but active concentrations were in the micromolar range. We further used this assay to evaluate other/new potential anti-androgens, as well as miscellaneous compounds that could interfere with androgen-induced lipid accumulation in sebocytes. (1) Barrault et al. (2015) J Steroid Biochem Mol Biol ;152:34-44.
Global regulation of gene expression is essential for appropriate epidermal stratification. One set of global regulators is the histone deacetylase (HDAC) family; HDACs repress transcription by removing acetyl groups from histones. HDAC inhibitors are used to treat cutaneous malignancies, but broadly inhibit all class I HDAC family members and have side effects. Delineating the activities of individual class I HDACs in the skin will be important for the development of improved therapeutics. To address this, we are using loss of function genetic analyses in mice. We find that epidermal deletion of Hdac3 during embryonic life results in failure to form a functional barrier and perinatal lethality; this phenotype is distinct from that caused by deletion of Hdac1/2 but partially overlaps with the effects of loss of the transcription factor KLF4, suggesting a possible interaction of HDAC3 and KLF4. Transcriptional profiling of Hdac3 and Klf4 embryonic mutant epidermis reveals statistically significant overlap in dysregulated genes, including epidermal differentiation and danger response genes. ChIP-seq experiments identify statistically significant overlap in sites bound by HDAC3 and KLF4, and proximity ligation assays reveal direct HDAC3/KLF4 interaction in suprabasal cells. In vitro data suggest that HDAC3 functions in a complex with NCoR/SMRT. To determine whether HDAC3 function is dependent on interaction with NCoR/SMRT in the epidermis in vivo, we have deleted the genes coding for these proteins. Ncor/Smrt double mutants recapitulate the epidermal barrier defect and gene expression changes observed in Hdac3 mutant epidermis. Intriguingly, total HDAC3 protein is severely decreased in Ncor/Smrt mutant epidermis, demonstrating that NCoR/SMRT function to stabilize HDAC3 in keratinocytes. Together, our data indicate that HDAC3 has distinct functions from HDAC1/2 and associates with KLF4 and NCoR/SMRT to repress gene expression in the developing epidermis.
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