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Background & Aims: The expression of HBsAg from integrated HBV DNA limits the achievement of functional cure for chronic hepatitis B. Thus, characterising the unique expression and secretion of HBsAg derived from integrated HBV DNA is of clinical significance. Methods: A total of 563 treatment-naive patients and 62 functionally cured patients were enrolled, and HBsAg and HBcAg immunohistochemistry of their liver biopsy tissues was conducted followed by semi-quantitative analysis. Then, based on stratified analysis of HBeAg-positive and -negative patients, long-read RNA sequencing analysis, as well as an in vitro HBV integration model, we explored the HBsAg secretion characteristics of integrated HBV DNA and underlying mechanisms. Results: In contrast to the significantly lower serum HBsAg levels, no significant decrease of intrahepatic HBsAg protein was observed in HBeAg-negative patients, as compared with HBeAg-positive patients. The results of long-read RNA sequencing of liver tissues from patients with chronic HBV infection and in vitro studies using integrated HBV DNA mimicking dslDNA plasmid revealed that, the lower HBsAg secretion efficiency seen in HBeAg-negative patients might be attributed to an increased proportion of preS1 mRNA derived from integrated HBV DNA instead of covalently closed circular DNA. The latter resulted in an increased L-HBsAg proportion and impaired HBsAg secretion. Enhancer 1 (EnhI) in integrated HBV DNA could retarget preS1 (SP1) and preS2 (SP2) promoters to disrupt their transcriptional activity balance. Conclusions: The secretion of HBsAg originating from integrated HBV DNA was impaired. Mechanistically, functional deficiency of core promoter leads to retargeting of EnhI and thus uneven activation of the SP1 over the SP2 promoter, resulting in an increase in the proportion of L-HBsAg. Impact and implications: Integrated hepatitis B virus (HBV) DNA can serve as an important reservoir for HBV surface antigen (HBsAg) expression, and this limits the achievement of a functional cure. This study revealed that secretion efficiency is lower for HBsAg derived from integrated HBV DNA than HBsAg derived from covalently closed circular DNA, as determined by the unique sequence features of integrated HBV DNA. This study can broaden our understanding of the role of HBV integration and shed new light on antiviral strategies to facilitate a functional cure. We believe our results are of great general interest to a broad audience, including patients and patient organisations, the medical community, academia, the life science industry and the public.

Mulberry is a common crop rich in flavonoids, and its leaves (ML), fruits (M), and branches (Ramulus Mori, RM) have medicinal value. In the present study, a total of 118 flavonoid metabolites (47 flavone, 23 flavonol, 16 flavonoid, 8 anthocyanins, 8 isoflavone, 14 flavanone, and 2 proanthocyanidins) and 12 polyphenols were identified by ultra-performance liquid chromatography–electrospray ionization-tandem mass spectrometry. The most abundant in ML were 8-C-hexosyl-hesperetin O-hexoside and astragalin, the most abundant in M were 8-C-hexosyl-hesperetin O-hexoside and naringenin, and the most abundant in RM were cyanidin 3-O-galactoside and gallocatechin–gallocatechin. The total flavonoid compositions of ML and RM were essentially the same, but the contents of flavonoid metabolite in more than half of them were higher than those in M. Compared with ML, the contents of flavone and flavonoid in RM and M were generally down-regulated. Each tissue part had a unique flavonoid, which could be used as a marker to distinguish different tissue parts. In this study, the differences between flavonoid metabolite among RM, ML, and M were studied, which provided a theoretical basis for making full use of mulberry resources.

The integration of HBV DNA is one of the carcinogenic mechanisms of HBV. The clearance of HBV integration in hepatocyte is of great significance to cure chronic HBV infection and thereby prevent the occurrence of HBV-related hepatocellular carcinoma (HCC). However, the low throughput of traditional methods, such as Alu-PCR, results in low detecting sensitivity of HBV integration. Although the second-generation sequencing can obtain a large amount of sequencing data, but the sequencing fragments are extremely short, so it cannot fully explore the characteristics of HBV integration. In this study, we used the third-generation sequencing technology owning advantages both in sequencing length and in sequencing depth to analyze the HBV integration characteristics in PLC/PRF/5 cells comprehensively. A total of 4,142,311 cleaning reads was obtained, with an average length of 18,775.6 bp, of which 84 reads were fusion fragments of the HBV DNA and human genome. These 84 fragments located in seven chromosomes, including chr3, chr4, chr8, chr12, chr13, chr16, and chr17. We observed lots of DNA rearrangement both in the human genome and in HBV DNA fragments surrounding the HBV integration site, indicating the genome instability causing by HBV integration. By analyzing HBV integrated fragments of PLC/PRF/5 cells that can potentially express HBsAg, we selected three combinations of sgRNAs targeting the integrated fragments to knock them out with CRISPR/Cas9 system. We found that the sgRNA combinations could significantly decrease the level of HBsAg in the supernatant of PLC/PRF/5 cells, while accelerated cell proliferation. This study proved the effectiveness of third-generation sequencing to detect HBV integration, and provide a potential strategy to reach HBsAg clearance for chronic HBV infection patients, but the knock-out of HBV integration from human genome by CRISPR/Cas9 system may have a potential of carcinogenic risk.

In February 2019, following the annual taxon ratification vote, the order Bunyavirales was amended by creation of two new families, four new subfamilies, 11 new genera and 77 new species, merging of two species, and deletion of one species. This article presents the updated taxonomy of the order Bunyavirales now accepted by the International Committee on Taxonomy of Viruses (ICTV).

Background: Osteoporotic vertebral fractures and their complications pose increasing risks to the elderly. The purpose of this study was to evaluate the clinical efficacy of unilateral percutaneous vertebroplasty in patients with osteoporotic vertebral compression fractures (OVCF) by assessing postoperative cement distribution. Objective: This study aimed to investigate the impact of cement distribution on the efficacy of vertebral compression fracture repair to provide effective preventive and therapeutic measures, prevent postoperative vertebral re-fracture, and improve surgical outcomes. Methods: A total of 170 patients who underwent unilateral percutaneous vertebroplasty at our hospital from January 2020 to December 2022 were selected. Based on the postoperative X-ray cement distribution morphology, they were divided into the good distribution group (n = 87) and the poor dispersion group (n = 83). The basic information of patients, surgery-related indicators including operation time, total hospitalization costs, postoperative hospitalization time, cement injection volume, visual analog scale (VAS) for back pain, Oswestry Disability Index (ODI) for back pain, vertebral height restoration rate, local kyphotic angle of the vertebra, and incidence of re-fracture of injured and adjacent vertebrae were compared between the two groups, and the follow-up results of all patients were recorded. Results: There were no significant differences in age, gender, body mass index, fracture days, menopausal age of female patients, bone density T value, medical history, smoking history, alcohol history, and surgical segments between the two groups (P > 0.05). The VAS scores for back pain at 1 month and 1 year postoperatively were significantly lower in the good distribution group than in the poor dispersion group, with statistical significance (P < 0.05). The good distribution group had a significantly lower incidence of re-fracture of injured vertebrae and overall fracture incidence than the poor dispersion group (P < 0.05). There were no statistically significant differences in operation time, cement dosage, cement leakage, postoperative hospitalization time, adjacent vertebral fractures, postoperative vertebral height restoration rate, VAS scores for back pain at preoperative and 1 week postoperative, and ODI at preoperative, 1 week, 1 month, and 1 year postoperative between the two groups (P > 0.05). Conclusion: Compared with the poor dispersion group, patients in the cement distribution group achieved better short-term clinical efficacy, and long-term prognosis effects are still under observation. Moreover, the cement good distribution group significantly reduced the incidence of re-fracture of injured vertebrae and overall fracture incidence, thereby achieving better surgical outcomes. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IDD) is a degenerative condition associated with impaired mitophagy. MANF has been shown to promote mitophagy in murine kidneys; however, its role in IDD remains unexplored. This study aimed to elucidate the mechanism by which MANF influences IDD development through the regulation of mitophagy. Human nucleus pulposus (NP) cells were exposed to tert-butyl hydroperoxide (TBHP) to establish an oxidative stress-induced cellular model. The expression levels of MANF in NP cells were quantified using quantitative real-time PCR (qPCR) and Western blotting. The impact of MANF on TBHP-induced NP cells was evaluated by assessing cell viability, apoptosis, and the levels of mitophagy-related proteins. The underlying mechanisms were further investigated using RNA-binding protein immunoprecipitation (RIP), dual-luciferase reporter assays, qPCR, and Western blotting. Results indicated that MANF expression was significantly downregulated in both IDD patients and TBHP-induced NP cells. Overexpression of MANF inhibited apoptosis, enhanced cell viability, and promoted mitophagy in TBHP-treated NP cells. MFN2 was identified as a downstream target of MANF, and MANF overexpression upregulated MFN2 expression in NP cells, whereas TBHP markedly suppressed MFN2 expression. Furthermore, knockdown of MFN2 partially reversed the effects of MANF overexpression on apoptosis, cell viability, and mitophagy in TBHP-treated NP cells. Collectively, these findings demonstrate that MANF overexpression enhances mitophagy by upregulating MFN2 expression, thereby mitigating oxidative stress-induced apoptosis in NP cells. These results provide novel insights into the pathogenesis of IDD. [ABSTRACT FROM AUTHOR]

In the papers Carmona and Durrleman [Pricing and hedging spread options in a log-normal model. Technical report: Department of Operations Research and Financial Engineering, Princeton, NJ, Princeton University, 2003] and Bjerksund and Stensland [Closed form spread option valuation. Quant. Finance, 2014, 14(10), 1785–1794], closed-form approximations for spread call option prices were studied under the log-normal models. In this paper, we give an alternative closed-form formula for the price of spread call options under the log-normal models also. Our formula can be seen as a generalization of the closed-form formula presented in Bjerksund and Stensland [Closed form spread option valuation. Quant. Finance, 2014, 14(10), 1785–1794] as their formula can be obtained by selecting special parameter values for our formula. Numerical tests show that our formula performs better for a certain range of model parameters than the closed-form formula presented in Bjerksund and Stensland [Closed form spread option valuation. Quant. Finance, 2014, 14(10), 1785–1794]. [ABSTRACT FROM AUTHOR]

BackgroundA growing number of studies have implicated that gut microbial abundance and metabolite concentration alterations are associated with celiac disease (CD). However, the causal relationship underlying these associations is unclear. Here, we used Mendelian randomization (MR) to reveal the causal effect of gut microbiota and metabolites on CD.MethodsGenome-wide association study (GWAS) summary-level data for gut microbiota, metabolites, and CD were extracted from published GWASs. Causal bacterial taxa and metabolites for CD were determined by two-sample MR analyses. The robustness of the results was assessed with sensitivity analyses. Finally, reverse causality was investigated with a reverse MR analysis.ResultsGenetically, increased genus Bifidobacterium was potentially associated with higher CD risk (odds ratio [OR] = 1.447, 95% confidence interval [CI]: 1.054–1.988, p = 0.022) while phylum Lentisphaerae (OR = 0.798, 95% CI: 0.648–0.983, p = 0.034) and genus Coprobacter (OR = 0.683, 95% CI: 0.531–0.880, p = 0.003) were related to lower CD risk. Moreover, there were suggestive associations between CD and the following seven metabolites: 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 1,6-anhydroglucose, phenylacetylglutamine, tryptophan betaine, 10-undecenoate, and tyrosine. Sensitivity analyses deemed the results reliable without pleiotropy.ConclusionWe investigated the causal relationships between gut microbiota, metabolites, and CD with two-sample MR. Our findings suggest several novel potential therapeutic targets for CD treatment. Further understanding of the underlying mechanism may provide insights into CD pathogenesis.

Celiac disease (CD) is an autoimmune small bowel disease. The pattern of gut microbiota is closely related to dietary habits, genetic background, and geographical factors. There is a lack of research on CD-related gut microbiota in China. This study aimed to use 16S rDNA sequencing and metabolomics to analyze the fecal microbial composition and metabolome characteristics in patients diagnosed with CD in Northwest China, and to screen potential biomarkers that could be used for its diagnosis. A significant difference in the gut microbiota composition was observed between the CD and healthy controls groups. At the genus level, the abundance of Streptococcus, Lactobacillus, Veillonella, and Allisonella communities in the CD group were increased (Q