Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

Knowledge of how valvular interstitial cells (VICs) interact with the extracellular matrix (ECM) would aid in not only better understanding the etiology of valvular disease, but also constructing appropriate environments for valve tissue engineering. In this work, the calcification of VICs cultured on ECM coatings (fibronectin, fibrin, collagen, laminin) or ECM-derived peptide sequences (RGDS, YIGSR, DGEA) was quantified via several techniques. Neutralizing antibodies to specific adhesion receptors were also applied, followed by quantification of phenotypic markers related to valve calcification. The calcification of VICs varied with the ECM component or peptide that was presented on the culture substrate. VICs calcified the most on RGDS and least on YIGSR and DGEA, while blocking specific receptors revealed that disruption of VIC binding via the α 5 β 1 integrin or the 67kDa laminin receptor had a dramatic calcification-stimulating effect. Binding via the α 2 β 1 integrin did not alter calcification or VIC phenotype. These findings were translated to 3-D peptide-modified scaffold environments that demonstrated varying levels of disease expression by VICs. Thus, specific adhesion receptors play a significant role in mediating the interactions between VICs and ECM that lead to calcification, which provides important information regarding the mechanisms of valvular disease and scaffold design for valve tissue engineering.

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The mitochondrial pathway of apoptosis is controlled by the ratio of anti-and pro-apoptotic members of the Bcl-2 family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger apoptosis remains unclear. We report here that human 17-b-estradiol (E2) and its related steroid hormones induce apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers apoptosis. The SLFN12 protein and an apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related hormones are high, and dynamic cell turnover by apoptosis is critical for successful implantation and placenta development.

Much remains to be discovered about the etiology of heart valve disease and the molecular level mechanisms that drive it. The MAPK/ERK pathway influences calcification in many cell types and has been linked to the expression of a contractile phenotype in valvular interstitial cells (VICs). However, a direct correlation between MAPK/ERK pathway activity and VIC calcification has not been previously described. Thus the role of the MAPK pathway in the calcification of VIC cultures was investigated by measuring ERK activation in both calcifying and noncalcifying VIC environments and then, conversely, analyzing the effects of ERK pathway inhibition on VIC calcification and phenotype. Prolonged elevation of phosphorylated ERK-1/2 was found in calcifying VIC cultures, whereas directly blocking phosphorylation of ERK-1/2 resulted in a dramatic decrease in nodule number, nodule size, and total calcified area. Application of the ERK pathway inhibitor was also associated with a dramatic decrease in apoptosis, which may have contributed to the decreased nodule formation obtained via ERK inhibition. Real-time PCR analysis revealed that calcified samples exhibited significantly elevated expression of several myofibroblastic and osteoblastic markers, while ERK inhibition substantially reduced the expression of these markers, often to levels comparable to the noncalcifying control. These data suggest that the MAPK pathway plays an important role in regulating the phenotype and calcification of VICs, wherein sustained pathway activation is associated with increased VIC calcification. These findings may be used to further elucidate the mechanisms of valvular disease and identify potential treatment targets.

Diabetic foot ulcer (DFU) caused by impaired wound healing is a common vascular complication of diabetes. The current study revealed that plasma levels of pigment epithelium-derived factor (PEDF) were elevated in type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contribute to skin wound-healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved the functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF-deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous microvessels, increased skin thickness, improved numbers and functions of circulating EPCs, and accelerated wound healing compared with wild-type mice. Overexpression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chlorideinduced Wnt signaling activation downstream of the PEDF interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound-healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing in the process of angiogenesis and vasculogenesis through the inhibition of Wnt/b-catenin signaling.

Community-acquired pneumonia (CAP) contributes substantially to morbidity and mortality in children under the age of 5 years. In examining bronchoalveolar lavages (BALs) of children with CAP, we found that interleukin-17 (IL-17) production was significantly increased in severe CAP. Immune profiling showed that mucosal-associated invariant T (MAIT) cells from the BALs, but not blood, of CAP patients actively produced IL-17 (MAIT17). Single-cell RNA-sequencing revealed that MAIT17 resided in a BAL-resident PLZF hi CD103 + MAIT subset with high expression of hypoxia-inducible factor 1α (HIF-1α), reflecting the hypoxic state of the inflamed tissue. CAP BALs also contained a T-bet + MAIT1 subset and a novel DDIT3 + (DNA damage-inducible transcript 3-positive) MAIT subset with low expression of HIF1A. Furthermore, MAIT17 differed from T-helper type 17 (Th17) cells in the expression of genes related to tissue location, innateness, and cytotoxicity. Finally, we showed that BAL monocytes were hyper-inflammatory and elicited differentiation of MAIT17. Thus, tissue-resident MAIT17 cells are induced at the infected respiratory mucosa, likely influenced by inflammatory monocytes, and contribute to IL-17-mediated inflammation during CAP.Mucosal Immunology _#####################_ ; https://doi.

Estradiol enhances COX-2 expression and prostaglandin biosynthesis in TSC2-deficient cells via a rapamycin-insensitive, mTORC2-dependent mechanism.