The Interaction between Regulatory T Cells and NKT Cells in the Liver: A CD1d Bridge Links Innate and Adaptive Immunity

Regulatory T cells (Tregs) and natural killer T (NKT) cells are two distinct lymphocyte subsets that independently regulate hepatic adaptive and innate immunity, respectively. In the current study, we examine the interaction between Tregs and NKT cells to understand the mechanisms of cross immune regulation by these cells.The frequency and function of Tregs were evaluated in wild type and NKT cell deficient (CD1dko) mice. In vitro lymphocyte proliferation and apoptosis assays were performed with NKT cells co-cultured with Tregs. The ability of Tregs to inhibit NKT cells in vivo was examined by adoptive transfer of Tregs in a model of NKT cell mediated hepatitis.CD1dko mice have a significant reduction in hepatic Tregs. Although, the Tregs from CD1dko mice remain functional and can suppress conventional T cells, their ability to suppress activation induced NKT cell proliferation and to promote NKT cell apoptosis is greatly diminished. These effects are CD1d dependent and require cell to cell contact. Adoptive transfer of Tregs inhibits NKT cell-mediated liver injury.NKT cells promote Tregs, and Tregs inhibit NKT cells in a CD1d dependent manner requiring cell to cell contact. These cross-talk immune regulations provide a linkage between innate and adaptive immunity

Imidazo[1,2-<i>a</i>]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization

A series of imidazo­[1,2-<i>a</i>]­pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent <i>in vitro</i> inhibition of HCV replication (EC₅₀ < 10 nM), direct binding to purified NS4B protein (IC₅₀ < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication

Magnetoresistive Conductive Polyaniline–Barium Titanate Nanocomposites with Negative Permittivity

Polyaniline (PANI) polymer nanocomposites (PNCs) filled with barium titanate (BaTiO 3) were synthesized by a surface initiated polymerization method. Two different particle sizes (100 and 500 nm) were studied. By varying the loading level, size of BaTiO 3 nanoparticles (NPs) and stirring method for the polymerization process, a series of PNCs were obtained and the effects of these parameters on the crystalline structure, thermal stability, morphology, electrical conductivity and dielectric permittivity were systematically studied. FT-IR analysis indicated a strong interaction between the formed PANI and the BaTiO 3 NPs, and TEM observations showed that the BaTiO 3 NPs are well coated with a PANI layer, however, the thickness of the PANI layer decreased with increasing the BaTiO 3 particles loading. The XRD reflection patterns indicated that the crystallinity of the polyaniline part in the PNCs depends on the nanoparticle loading. However, the resistivity does not increase with increasing the crystallinity, and the temperature dependent resistivity result reveals a 3-d variable range hopping (VRH) electron transport mechanism. The BaTiO 3 loading dependent resistivity is interpreted from the dominating space charge on the BaTiO 3/PANI interface and the ferroelectric nature of BaTiO 3 for the PNCs with different particle loadings. Compared with the positive real permittivity for the PNCs prepared from physical mixing, all the chemically synthesized PNC samples show negative dielectric permittivity and the permittivity change is related to the instinct metallic state in PANI. In addition, positive magnetoresistance (MR) is observed in all kinds of PNCs and analyzed theoretically from the wave function shrinkage model. © 2012 American Chemical Society

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure–activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of <b>3</b> (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included