Background & Aims As important virological markers, serum HBsAg and HBV DNA levels show large fluctuations among chronic hepatitis B (CHB) patients. The aim of this study was to reveal the potential impact and mechanisms of amino acid (AA) substitutions in small hepatitis B surface proteins (SHBs) on serum HBsAg and HBV DNA levels. Methods Serum samples from 230 untreated chronic hepatitis B patients with genotype C HBV were analyzed in terms of HBV DNA levels, serological markers of HBV infection and SHBs sequences. In vitro functional analysis of the identified SHBs mutants was performed. Results Among 230 SHBs sequences, there were 39 (16.96%) sequences with no mutation detected (wild-type, WT) and 191 (83.04%) with single or multiple mutations. SHBs consist of 226 AAs, of which 104 (46.02%) had mutations in our study. Some mutations (e.g. sE2G, sL21R, sG24K, sT47A/K, sC69stop (sC69*), sL95W, sL98V, and sG145R) negatively correlated with serum HBsAg levels. HBsAg and HBV DNA levels from this group of patients had a positive correlation (r = 0.61, p < 0.001). In vitro analysis showed that these mutations reduced extracellular HBsAg and HBV DNA levels by restricting virion secretion and antibody binding capacity. Virion secretion could be rescued for sE2G, sC69*, and sG145R by co-expression of WT HBsAg. Conclusion The serum HBsAg levels were lower in untreated CHB patients with novel SHBs mutations outside the major antigenic region than those without mutations. Underlying mechanisms include impairment of virion secretion and lower binding affinity to antibodies used for HBsAg measurements.
Background As an important anti-HBV drug, pegylated interferon α (PegIFNα) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses. Methods We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFNα-2a or PegIFNα-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72. Results HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value < 0.05). HBV RNA ≤ 1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%). Conclusion HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.
Little is known about the discrepancy of the potential antiviral resistance mutation profiles within the hepatitis B virus (HBV) reverse transcriptase (RT) between nucleos(t)ide analogue (NA)-untreated and -treated patients with chronic hepatitis B. Full-length HBV RT sequences from 59 NA-treated and 105 NA-untreated Chinese patients were amplified and sequenced. Forty-two potential NA resistance (NAr) mutation sites were screened within these 164 RT sequences. The NAr mutation prevalence and frequency in the NA-treated group were significantly higher than those in the NA-untreated one (P < 0.001, respectively). The classical primary drug resistance and secondary/compensatory mutations were only detected at seven sites (rtL80, rtI169, rtL180, rtA181, rtT184, rtM204, and rtN236) in NA-treated patients. The non-classical putative NAr and pre-treatment mutations were observed at 22 sites (rtT38, rtN/S53, rtL82, rtL/I91, rtN/Y124, rtH126, rtT128, rtN/D134, rtN139, rtR153, rtV191, rtV207, rtS213, rtV214, rtE218, rtY/F221, rtV/I224, rtL229, rtI233, rtN/H238, rtR242, and rtS/C256) in both groups. Substitutions at seven non-classical mutation sites were of interest due to either detection only in patients with virologic breakthrough (rtL82 and rtV214), or potential ties with HBV genotypes (rtV191 and rtL229), or coexistence with rtM204I/V (rtL229), or increased mutation trends after NA-treatment (rtT128, rtV207, and rtN/H238). In conclusion, NA treatment not only constitutes a major selection factor for the primary and secondary/compensatory NAr mutations but also drives the changes of some of the putative NAr mutation sites, most of which are the genotype-independent RT sites (rtL82, rtT128, rtV191, rtV207, rtV214, rtL229, and rtN/H238). Their antiviral resistance potential calls for further investigations.
A microelectromechanical systems acceleration latching switch with cylindrical contacts and an easy-latching/difficult-releasing (ELDR) latching mechanism is presented in this paper. The cylindrical contacts can make the switch immune to fabrication imperfections and off-axis shocks and can decrease the contact resistance as well. The ELDR latching mechanism can latch the switch reliably. Moreover, all the contacts and their support beams are separated from the proof mass so as to prevent the contacts from opening due to the impact resulting from the rebound or vibration of the proof mass once the switch is latched. The switch has been fabricated by a two-mask silicon-on-glass process and tested. The measured latching shock is over 4600 g and the response time is less than 0.2 ms. The total on-resistance is less than 3 while the insulation resistance is more than 100 G and the maximum allowable current is up to 130 mA.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.