Hua Guo

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10,000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Chinese tongue sole is a marine fish with ZW sex determination. Genome sequencing suggested that the Z-linked dmrt1 is a putative male determination gene, but direct genetic evidence is still lacking. Here we show that TALEN of dmrt1 efficiently induced mutations of this gene. The ZZ dmrt1 mutant fish developed ovary-like testis, and the spermatogenesis was disrupted. The female-related genes foxl2 and cyp19a1a were significantly increased in the gonad of the ZZ dmrt1 mutant. Conversely, the male-related genes Sox9a and Amh were significantly decreased. The dmrt1 deficient ZZ fish grew much faster than ZZ male control. Notably, we obtained an intersex ZW fish with a testis on one side and an ovary on the other side. This fish was chimeric for a dmrt1 mutation in the ovary, and wild-type dmrt1 in the testis. Our data provide the first functional evidence that dmrt1 is a male determining gene in tongue sole.

The compound 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), an alternative to perfluorooctanesulfonate (PFOS) in the metal-plating industry, has been widely detected in various environmental matrices. However, its hepatotoxicity has yet to be clarified. Here, male mice were exposed to 0.04, 0.2, or 1 mg/kg/day of 6:2 Cl-PFESA for 56 days. Results demonstrated that relative liver weight increased significantly in the 0.2 and 1 mg/kg/day 6:2 Cl-PFESA groups, whereas liver lipid accumulation increased in all 6:2 Cl-PFESA groups. Serum enzyme activities of alanine transaminase and alkaline phosphatase were increased. Serum triglycerides and low-density lipoprotein cholesterol both increased, whereas serum total cholesterol and high-density lipoprotein cholesterol decreased following 6:2 Cl-PFESA exposure. A total of 264 differentially expressed proteins (127 up-regulated and 137 down-regulated), mainly involved in lipid metabolism, xenobiotic metabolism, and ribosome biogenesis, were identified by quantitative proteomics. Bioinformatics analysis highlighted the de-regulation of PPAR and PXR, which may contribute to the hepatotoxicity of 6:2 Cl-PFESA. Additionally, 6:2 Cl-PFESA induced both cell apoptosis and proliferation in the mouse liver. Compared to the overt toxicity of PFOS, 6:2 Cl-PFESA exhibited more-serious hepatotoxicity. Thus, caution should be exercised in the application of 6:2 Cl-PFESA as a replacement alternative to PFOS in industrial areas.

Graves' disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4(+)CD25(+)FOXP3(+) Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4(+)CD25(+) Treg cells in an IFN-α-dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-α secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4(+)CD25(+) Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD.