Background and Aims Interferon (IFN)‐α, composed of numerous subtypes, plays a crucial role in immune defense. As the most studied subtype, IFN‐α2 has been used for treating chronic hepatitis B virus (HBV) infection, with advantages of finite treatment duration and sustained virologic response, but its efficacy remains relatively low. This study aimed to screen for IFN‐α subtypes with the highest anti‐HBV potency and to characterize mechanisms of IFN‐α–mediated HBV restriction. Approach and Results Using cell culture–based HBV infection systems and a human‐liver chimeric mouse model, IFN‐α subtype–mediated antiviral response and signaling activation were comprehensively analyzed. IFN‐α14 was identified as the most effective subtype in suppression of HBV covalently closed circular DNA transcription and HBV e antigen/HBV surface antigen production, with median inhibitory concentration values approximately 100‐fold lower than those of the conventional IFN‐α2. IFN‐α14 alone elicited IFN‐α and IFN‐γ signaling crosstalk in a manner similar to the combined use of IFN‐α2 and IFN‐γ, inducing multiple potent antiviral effectors, which synergistically restricted HBV replication. Guanylate binding protein 5, one of the most differentially expressed genes between IFN‐α14–treated and IFN‐α2–treated liver cells, was identified as an HBV restriction factor. A strong IFN‐α–IFN‐α receptor subunit 1 interaction determines the anti‐HBV activity of IFN‐α. The in vivo anti‐HBV activity of IFN‐α14 and treatment‐related transcriptional patterns were further confirmed, and few adverse effects were observed. Conclusions A concerted IFN‐α and IFN‐γ response in liver, which could be efficiently elicited by IFN‐α subtype 14, is associated with potent HBV suppression. These data deepen the understanding of the divergent activities of IFN‐α subtypes and the mechanism underlying the synergism between IFN‐α and IFN‐γ signaling, with implications for improved IFN therapy and HBV curative strategies.

Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.

Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia but induce hepatitis B surface antigen (HBsAg) loss in very few patients; also, these therapies do not greatly affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, tazarotene exhibited the most potent anti-HBV effect, with a half-maximal inhibitory concentration (IC) for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected differentiated HepaRG (dHepaRG) models, but not in HepG2.215 cells, and HBV genotypes A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA and RNAs and the activation of HBV promoters. Moreover, RNA sequence analysis showed that tazarotene did not induce an interferon response but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by a specific antagonist significantly attenuated the anti-HBV activity of tazarotene, suggesting that tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of tazarotene and entecavir on HBV DNA levels was observed. Therefore, RAR agonists as represented by tazarotene were identified as potential novel anti-HBV agents.

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Global temporal quantitative proteomic and transcriptomic analysis using long-term hepatitis B virus (HBV)-infected primary human hepatocytes uncovered extensive remodeling of the host proteome and transcriptome and revealed cytopathic effects of long-term viral replication. Metabolic-, complement-, cytoskeleton-, mitochondrial-, and oxidation-related pathways were modulated at transcriptional or posttranscriptional levels, which could be partially rescued by early, rather than late, NA therapy and could be relieved by blocking viral antigens with RNAi.

A zirconium hybrid polyhedral oligomeric silsesquioxane derivative (Zr-POSS-bisDOPO) is synthesized by the corner-capping and Kabachnik-Fields reactions. It is characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR), and then used as a flame retardant in diglycidyl ether of bisphenol A (DGEBA) to endow epoxy resin (EP) with flame retardancy. The flame retardancy, thermal stability, and mechanical properties of the cured EP/Zr-POSS-bisDOPO composites are investigated. The results show that when Zr-POSS-bisDOPO is added by 5-7 wt%, the EP/Zr-POSS-bisDOPO composites pass the UL-94 V-0 rating test. In addition, they have a better flame-retardant effect than pure EP. The combination of Zr atom embedded in the Si-O cubic cage and the two phosphaphenanthrene substituent groups in one corner of cubic cage is expected to realize the Zr/Si/P ternary intramolecular hybrid synergistic effect and achieve the possibility of dispersing metal-POSS cages at a sub-micrometer-scale level into polymer matrix. It also proves that Zr-POSS-bisDOPO produces phosphorus-containing free radicals and terminates the chain reactions in gas phase. Meanwhile the Si-O-Si and Zr-O units are retained in the solid phase, which promote the char formation and enhance the flame retardancy. This kind of Zr-doped POSS will be helpful for developing the new metal-POSS hybrid flame-retardant and polymer composites.

A new polyhedral oligomeric silsesquioxane (POSS) derivate bearing phenylboronic acid group and 6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide (DOPO) unit was synthesized and applied in flame retardant epoxy resin (EP). Compared to pure EP, EP/POSS-DOPO-(phenylboronic acid) composites had good transparency and better thermal stability. Micro-scale combustion calorimetry results showed that the addition of POSS-DOPO-(phenylboronic acid) hybrid could greatly reduce the PHRR and THR of EP/POSS-DOPO-(phenylboronic acid) composite. Simultaneously, the UL-94 of EP composite with 7% POSS-DOPO-(phenylboronic acid) achieved V-0 grade and the LOI value increased from 19.4% (neat EP) to 28.6%. Raman spectra results suggested that POSS-DOPO-(phenylboronic acid) hybrid enhanced the formation of residual char with graphitic structure during combustion. Besides, SEM characterization showed that the char of EP/POSS-DOPO-(phenylboronic acid) composite was much more continuous and compact in comparison with that of control samples. Moreover, the mechanical and dielectric properties of EP/POSS-DOPO-(phenylboronic acid) composites have been greatly improved for a better application. K E Y W O R D S epoxy resin, flame retardant, hybrid, phenylboronic acid, polyhedral oligomeric silsesquioxane | INTRODUCTIONEpoxy resin (EP) is a kind of thermosetting polymer with diverse functions, which has been widely used in many fields such as coatings, adhesives, and electronic packaging materials due to its good chemical corrosion resistance, low dielectric properties, and excellent mechanical strength. 1,2 However, the flammability of epoxy resin limits its further application. Therefore, appropriate approaches and flame retardants must be adopted to reduce the flammability of epoxy resin.

We address a genetic algorithm (GAs) to achieve optimization design for diffractive optical elements (DOE's) for the laser beam shaping. A laser beam shaping system is investigated using genetic algorithm, in which an incident Gaussian profile laser beam is converted into a zero-order Bessel beam.This algorithm exploits the global nature of the genetic algorithms. High-quality DOE's can be achieved by use of the optimization procedure we proposed.