Cytokine responses and regulation of interferon-gamma release by human mononuclear cells to Aspergillus fumigatus and other filamentous fungi.

Contains fulltext : 48233.pdf (publisher's version ) (Closed access)There is substantial evidence that the production of proinflammatory cytokines is important in host resistance to invasive aspergillosis. Knowledge of the host response towards other filamentous fungi is scarce, as most studies have focused on Aspergillus fumigatus. In addition, interferon-gamma (IFNgamma) plays a crucial role in the control of invasive aspergillosis, but little is known about the regulation of IFNgamma after stimulation of mononuclear cells by A. fumigatus. Cytokine responses to four different Aspergillus spp., Scedosporium prolificans, and a Rhizopus oryzae strain were compared for their ability to induce the release of tumour necrosis factor-alpha (TNFalpha) and interleukin(IL)-6 by human monocytes. S. prolificans induced significantly more TNFalpha and IL-6 release compared to A. fumigatus, while the various Aspergillus spp. induce comparable levels of these cytokines. By using specific cytokine inhibitors we were able to show that endogenous IL-1, but not IL-18 and TNFalpha was required for IFNgamma and IL-10 release upon stimulation with A. fumigatus hyphae, whereas conidia induced IFNgamma stimulation is independent of these cytokines

AN OPTIMIZATION PROBLEM FOR A PRODUCTION SYSTEM WITH REAL OPTION APPROACH (Nonlinear Analysis and Convex Analysis)

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes