Search

The intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma‐derived HBV (genotype B and C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT‐PCR (RNA, covalently closed circular DNA [cccDNA], extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon‐stimulated genes [ISG]) to interferon‐α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well‐differentiated ICOs using spinoculation, with time and donor‐dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor‐dependent drug responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon‐α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor‐dependent variation in viral dynamics and cellular responses. These features can be utilized for the development of personalized drug testing platform for antivirals. [ABSTRACT FROM AUTHOR]

Viperin is an interferon‐inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin's broad antiviral activity by demonstrating the protein's ability to synergistically enhance the innate immune dsDNA signaling pathway to limit viral infection. Viperin co‐localized with the key signaling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63‐linked polyubiquitination of TBK1. Subsequent analysis identified viperin's necessity to bind the cytosolic iron‐sulfur assembly component 2A, to prolong its enhancement of the type‐I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signaling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signaling pathway, which results in an enhanced antiviral state. We also provide evidence for viperin's radical SAM enzymatic activity to self‐limit its immunomodulatory functions. These data further define viperin's role as a positive regulator of innate immune signaling, offering a mechanism of viperin's broad antiviral capacity. [ABSTRACT FROM AUTHOR]

Focuses on the diagnosis of patients with familial erythrocytosis associated with low plasma erythropoietin. Detection of mutations in the Epo receptor; Chuvash form of polycythemia; Molecular pathophysiology underlying the Chuvash polycythemia.

Presents information on the Paget's disease of the bone. Function of osteoclasts; Cause of the increased osteoclastic activity found in Paget's disease and myeloma.

Focuses on the efforts to control the sale of handguns in the United States. Availability of handguns and death and injury; Acquisition and use of handguns. INSET: The Pistol-Packers at Remington Arms.