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Hepatitis B virus (HBV) exploits the endosomal sorting complexes required for transport (ESCRT)/multivesicular body (MVB) pathway for virion budding. In addition to enveloped virions, HBV-replicating cells nonlytically release non-enveloped (naked) capsids independent of the integral ESCRT machinery, but the exact secretory mechanism remains elusive. Here, we provide more detailed information about the existence and characteristics of naked capsid, as well as the viral and host regulations of naked capsid egress. HBV capsid/core protein has two highly conserved Lysine residues (K7/K96) that potentially undergo various types of posttranslational modifications for subsequent biological events. Mutagenesis study revealed that the K96 residue is critical for naked capsid egress, and the intracellular egress-competent capsids are associated with ubiquitinated host proteins. Consistent with a previous report, the ESCRT-III-binding protein Alix and its Bro1 domain are required for naked capsid secretion through binding to intracellular capsid, and we further found that the ubiquitinated Alix binds to wild type capsid but not K96R mutant. Moreover, screening of NEDD4 E3 ubiquitin ligase family members revealed that AIP4 stimulates the release of naked capsid, which relies on AIP4 protein integrity and E3 ligase activity. We further demonstrated that AIP4 interacts with Alix and promotes its ubiquitination, and AIP4 is essential for Alix-mediated naked capsid secretion. However, the Bro1 domain of Alix is non-ubiquitinated, indicating that Alix ubiquitination is not absolutely required for AIP4-induced naked capsid secretion. Taken together, our study sheds new light on the mechanism of HBV naked capsid egress in viral life cycle.

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Arsenic (As) mobilization in paddy fields poses significant health risks, necessitating a thorough understanding of the controlling factors and mechanisms to safeguard human health. We conducted a comprehensive investigation of the soil-porewater-rice system throughout the rice life cycle, focusing on monitoring arsenic distribution and porewater characteristics in typical paddy field plots. Soil pH ranged from 4.79 to 7.98, while porewater pH was weakly alkaline, varying from 7.2 to 7.47. Total arsenic content in paddy soils ranged from 6.8 to 17.2 mg/kg, with arsenic concentrations in porewater during rice growth ranging from 2.97 to 14.85 µg/L. Specifically, arsenite concentrations in porewater ranged from 0.48 to 7.91 µg/L, and arsenate concentrations ranged from 0.73 to 5.83 µg/L. Through principal component analysis (PCA) and analysis of redox factors, we identified that arsenic concentration in porewater is predominantly influenced by the interplay of reduction and desorption processes, contributing 43.5 % collectively. Specifically, the reductive dissolution of iron oxides associated with organic carbon accounted for 23.3 % of arsenic concentration dynamics in porewater. Additionally, arsenic release from the soil followed a sequence starting with nitrate reduction, followed by ferric ion reduction, and subsequently sulfate reduction. Our findings provide valuable insights into the mechanisms governing arsenic mobilization within the paddy soil-porewater-rice system. These insights could inform strategies for irrigation management aimed at mitigating arsenic toxicity and associated health risks.

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This study analyzed ancient DNA from the remains of horses unearthed from the Shihuyao tombs. These were found to date from the Han and Tang Dynasties in Xinjiang (approximately 2200 to 1100 years ago). Two high-quality mitochondrial genomes were acquired and analyzed using next-generation sequencing. The genomes were split into two maternal haplogroups, B and D, according to a study that included ancient and contemporary samples from Eurasia. A close genetic affinity was observed between the horse of the Tang Dynasty and Akhal-Teke horses according to the primitive horse haplotype G1. Historical evidence suggests that the ancient Silk Road had a vital role in their dissemination. Additionally, the matrilineal history of the Akhal-Teke horse was accessed and suggested that the early domestication of the breed was for military purposes.

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Iron/chromium hydroxide coprecipitation controls the fate and transport of toxic chromium (Cr) in many natural and engineered systems. Organic coatings on soil and engineered surfaces are ubiquitous; however, mechanistic controls of these organic coatings over Fe/Cr hydroxide coprecipitation are poorly understood. Here, Fe/Cr hydroxide coprecipitation was conducted on model organic coatings of humic acid (HA), sodium alginate (SA), and bovine serum albumin (BSA). The organics bonded with SiO2 through ligand exchange with carboxyl (-COOH), and the adsorbed amounts and pKa values of -COOH controlled surface charges of coatings. The adsorbed organic films also had different complexation capacities with Fe/Cr ions and Fe/Cr hydroxide particles, resulting in significant differences in both the amount (on HA > SA(-COOH) ≫ BSA(-NH2)) and composition (Cr/Fe molar ratio: on BSA(-NH2) ≫ HA > SA(-COOH)) of heterogeneous precipitates. Negatively charged -COOH attracted more Fe ions and oligomers of hydrolyzed Fe/Cr species and subsequently promoted heterogeneous precipitation of Fe/Cr hydroxide nanoparticles. Organic coatings containing -NH2 were positively charged at acidic pH because of the high pKa value of the functional group, limiting cation adsorption and formation of coprecipitates. Meanwhile, the higher local pH near the -NH2 coatings promoted the formation of Cr(OH)3. This study advances fundamental understanding of heterogeneous Fe/Cr hydroxide coprecipitation on organics, which is essential for successful Cr remediation and removal in both natural and engineered settings, as well as the synthesis of Cr-doped iron (oxy)hydroxides for material applications.

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Cadmium (Cd) and arsenic (As) co-contamination is widespread and threatens human health, therefore it is important to investigate the bioavailability of Cd and As co-exposure. Currently, the interactions of Cd and As by in vitro assays are unknown. In this work, we studied the concurrent Cd-As release behaviors and interactions with in vitro simulated gastric bio-fluid assays. The studies demonstrated that As bioaccessibility (2.04 to 0.18 ± 0.03%) decreased with Cd addition compared to the As(V) single system, while Cd bioaccessibility (11.02 to 39.08 ± 1.91%) increased with As addition compared to the Cd single system. Release of Cd and As is coupled to proton-promoted and reductive dissolution of ferrihydrite. The As(V) is released and reduced to As(Ⅲ) by pepsin. Pepsin formed soluble complexes with Cd and As. X-ray photoelectron spectroscopy showed that Cd and As formed Fe-As-Cd ternary complexes on ferrihydrite surfaces. The coordination intensity of As-O-Cd is lower than that of As-O-Fe, resulting in more Cd release from Fe-As-Cd ternary complexes. Our study deepens the understanding of health risks from Cd and As interactions during environmental co-exposure of multiple metal(loid)s.

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Bone disease is a common complication following liver transplantation, often overlooked in clinical practice. Clinical diagnosis of post-liver transplantation bone disease is challenging, and there have been few case report in the literature. This case report presents a patient who underwent two liver transplant surgeries, exhibited good daily activity, and did not display typical clinical symptoms such as fatigue, bone pain, or spinal deformities associated with prolonged sitting or standing. However, within the fifth year after the second liver transplant, the patient experienced two consecutive fractures. In March 2023, the patient underwent the first bone density test, which revealed osteoporosis. This case highlights the fact that severe fractures after liver transplantation may not necessarily be accompanied by typical symptoms of bone disease. Without timely examination and early prevention, serious consequences may arise. Therefore, this condition requires attention, proactive prevention, early detection, and timely treatment. Additionally, a retrospective analysis of the patient's previous laboratory data revealed persistent abnormalities in serum markers such as hypocalcemia and elevated alkaline phosphatase levels after liver transplantation, emphasizing the importance of monitoring these serum markers.

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Inadvertent oral ingestion is an important exposure pathway of arsenic (As) containing soil and dust. Previous researches evidenced health risk of bioaccessible As from soil and dust, but it is unclear about As mobilization mechanisms in health implications from As exposure. In this study, we investigated As release behaviors and the solid-liquid interface reactions toward As(V)-containing iron minerals in simulated gastrointestinal bio-fluids. The maximum As release amount was 0.57 mg/L from As-containing goethite and 0.82 mg/L from As-containing hematite at 9 h, and the As bioaccessibility was 10.8% and 21.6%, respectively. The higher exposure risk from hematite-sorbed As in gastrointestinal fluid was found even though goethite initially contained more arsenate than hematite. Mechanism analysis revealed that As release was mainly coupled with acid dissolution and reductive dissolution of iron minerals. Proteases enhanced As mobilization and thus increased As bioaccessibility. The As(V) released and simultaneously transformed to high toxic As(III) by gastric pepsin, while As(V) reduction in intestine was triggered by pancreatin and freshly formed Fe(II) in gastric digests. CaCl2 reduced As bioaccessibility, indicating that calcium-rich food or drugs may be effective dietary strategies to reduce As toxicity. The results deepened our understanding of the As release mechanisms associated with iron minerals in the simulated gastrointestinal tract and supplied a dietary strategy to alleviate the health risk of incidental As intake.

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OBJECTIVE: The treatment of posterolateral tibial plateau fractures is difficult, and providing sufficient exposure and effective fixation is a challenge. There is great controversy regarding the surgical approach for posterolateral tibial plateau fractures. The purpose of the study was to investigate the clinical effects of open reduction and internal fixation using the Frosch approach for the treatment of posterolateral tibial plateau fractures combined with lateral tibial plateau fractures. METHODS: Data from 19 patients with posterolateral tibial plateau fractures combined with lateral tibial plateau fractures treated from May 2018 to January 2022 were retrospectively analyzed. There were nine men and 10 women, ranging in age from 22 to 62 years, with an average age of 45.6 years. All patients were treated using the Frosch approach. Under direct vision, the posterolateral and lateral fractures were reduced, and full bone grafting was performed. We reshaped the oblique "T" shaped plate for the distal radius and placed it on the posterolateral tibial plateau to fix the posterolateral fractures. The lateral inverted "L" shaped locking plate was placed on the lateral tibial plateau to fix the lateral tibial plateau fractures. Within 2 weeks after the operation, the patients were instructed to perform knee joint function exercises within 90°. At the last follow-up, the Rasmussen radiological criteria were used to evaluate the effectiveness of fracture reduction and fixation. And the knee joint function was evaluated using Rasmussen functional score. RESULTS: The operation time ranged from 100 to 180 min, with an average of 134.2 min; intraoperative blood loss ranged from 20 to 150 mL, with an average of 66.8 mL. The follow-up duration ranged from 14 to 58 months, with an average of 36.2 months. There were no complications, such as vascular or nerve injury or incision infection. Fracture healing was achieved in all patients, and the healing time ranged from 10 to 14 weeks, with an average of 11.2 weeks. During the follow-up period, there was no loosening or breakage of the internal fixation, varus or valgus deformity of the knee joint, re-collapse of the articular surface, or instability of the knee joint. At the last follow-up, the effectiveness of fracture reduction and fixation was excellent in 13 patients and good in six patients. And the knee joint function was excellent in 17 patients and good in two patients. CONCLUSION: The Frosch approach for open reduction and internal fixation in the treatment of posterolateral tibial plateau fractures combined with lateral tibial plateau fractures has a definite clinical benefit and is worthy of promotion and application.

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Cattle are one of the six livestock species that have occupied an important place in Chinese history. Previous ancient DNA studies have indicated that Chinese taurine cattle (Bos taurus taurus) are exotic, but the exact route and diffusion by which they were introduced to China is unknown. In this study, we extracted the mitochondrial genomes of 34 cases of ancient taurine cattle (from the late Neolithic to Qin and Han dynasties) excavated from sites in northern China and the eastern Eurasian steppe, and successfully obtained 14 mitochondrial genome sequences. The results of ancient DNA analysis reveal that with cultural exchange and trade, there was close genetic exchange between domestic taurine cattle in different regions. The haplotypes shared by domestic cattle have genetic continuity, reflecting the strong cultural influence of the large capital city sites such as Taosi, Shimao and Erlitou on the surrounding areas. This study suggests that ancient northern Chinese taurine cattle may have accompanied the westward transmission of agricultural or painted pottery culture and thus had a maternal genetic contribution to modern Tibetan cattle.

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The simultaneous precipitation of (Fe, Cr)(OH)3 nanoparticles in solution (homogeneous) and on soil surfaces (heterogeneous), which controls Cr transport in soil and aquatic systems, was quantified for the first time in the presence of model surfaces, i.e., bare and natural organic matter (NOM)-coated SiO2 and Al2O3. Various characterization techniques were combined to explore the surface-ion-precipitate interactions and the controlling mechanisms. (Fe, Cr)(OH)3 accumulation on negatively charged SiO2 was mainly governed by electrostatic interactions between hydrolyzed ion species or homogeneous (Fe, Cr)(OH)3 and surfaces. The elevated pH through protonation of Al2O3 surface hydroxyls resulted in higher Cr/Fe ratios in both homogeneous and heterogeneous coprecipitates. Due to ignorable NOM adsorption onto SiO2, the amounts of (Fe, Cr)(OH)3 precipitates on bare/NOM-SiO2 were similar; contrarily, attributed to favored NOM adsorption onto Al2O3 and consequently carboxyl association with metal ions or (Fe, Cr)(OH)3 nanoparticles, remarkably more heterogeneous precipitates harvested on NOM-Al2O3 than bare-Al2O3. With the same solution supersaturation, the total amounts of homogeneous and heterogeneous precipitates were similar irrespective of the substrate type. With lower pH, decreased electrostatic forces between substrates and precipitates shifted (Fe, Cr)(OH)3 distribution from heterogeneous to homogeneous phases. The quantitative knowledge of (Fe, Cr)(OH)3 distribution and the controlling mechanisms can assist in better Cr sequestration in natural and engineered settings.

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OBJECTIVE: To evaluate the biomechanical effects of different miniplates on restorative laminoplasty. METHODS: Assembled restorative laminoplasty models were developed based on 3D printed L4 lamina. Based on different internal fixations, the research was divided into H-shaped miniplates (HSMs) group, two-hole miniplates (THMs) group, and L-shaped miniplates (LSMs) group. The static and dynamic compression tests were analyzed to investigate the biomechanical effects of different internal fixations in restorative laminoplasty, until the failure and fracture of miniplates, or the collapse of miniplates. The static compression tests adopted the speed control mode, and the dynamic fatigue compression tests adopted the load control mode. RESULTS: The "door close" and the collapse of lamina occurred in THMs group and LSMs group, and plate break occurred in LSMs group. However, these phenomenon was absent in HSMs group, and only plate crack around a screw and looseness of a screw tail cap were found in HSMs group. The sustainable yield load of HSMs group was greater than that of THMs group and LSMs group (P < 0.05). No significant difference in yielding-displacement was found between HSMs group and LSMs group (P > 0.05), while both were much less than that of THMs (P < 0.05). Moreover, the compressive stiffness and the axial displacement under the same mechanical load were arranged as follows: HSMs group > LSMs group > THMs group (P < 0.05). The results of dynamic compression test revealed that the peak load of HSMs group could reached 873 N and was 95% of the average yield load of the static compression, and was better than that in THMs group and LSMs group (P < 0.05). Besides, according to the fatigue life-peak load diagram, the ultimate load of HSMs group was more than twice that of THMs group or LSMs group. CONCLUSIONS: The mechanical strength of H-shaped miniplates was superior to two-hole miniplates and L-shaped miniplates in maintaining spinal canal enlargement and spinal stability, and was more excellent in fatigue stability and ultimate load.

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Purpose: To evaluate the clinical outcomes for arthroscopic treatment of acute posterior cruciate ligament (PCL) avulsion fractures with adjustable-loop cortical button fixation device. Methods: Patients with PCL tibial avulsion fractures treated with an adjustable-loop cortical button fixation device between October 2019 and October 2020 were retrospectively identified. Patients with type 1 were treated using plaster fixation as a conservative treatment, whereas patients with type 2 and 3 with displacement were treated using an arthroscopic adjustable-loop cortical button. Operating time, incision recovery, complications, and postoperative fracture healing time were monitored. All patient follow-up was done at 12 months' postoperatively. Lysholm Knee Score and the International Knee Documentation Committee score were used to assess knee function. Results: A total of 30 patients were included in the study (20 male/10 female; mean age 45.5 years, range 35-68 years). The mean operative time was 67.5 minutes (range: 50-90 minutes). The postoperative incision healed at stage A without complications, such as medically induced vascular nerve injury, intra-articular hematoma, or infection. All 30 patients were tracked postoperatively for 12 to 14 months, with a mean follow-up period of 12.6 months. The Lysholm knee function score was 45.93 ± 6.15 before surgery and 87.10 ± 3.71 at 12 months after surgery, and the International Knee Documentation Committee score was 19.27 ± 4.40 before surgery and 95.47 ± 1.87 at 12 months after surgery, with a statistically significant difference. Conclusions: The treatment of PCL avulsion fractures with arthroscopic adjustable-loop cortical button fixation is easy to perform and shows good clinical results in our study. Level of Evidence: IV, therapeutic case series.

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As miniature fibre-optic platforms, micro/nanofibres (MNFs) taper-drawn from silica fibres have been widely studied for applications from optical sensing, nonlinear optics to optomechanics and atom optics. While continuous-wave (CW) optical waveguiding is frequently adopted, so far almost all MNFs are operated in low-power region (e.g., <0.1 W). Here, we demonstrate high-power low-loss CW optical waveguiding in MNFs around 1550-nm wavelength. We show that a pristine MNF, even with a diameter down to 410 nm, can waveguide an optical power higher than 10 W, which is about 30 times higher than demonstrated previously. Also, we predict an optical damage threshold of 70 W. In high-power CW waveguiding MNFs, we demonstrate high-speed optomechanical driving of microparticles in air, and second harmonic generation efficiency higher than those pumped by short pulses. Our results may pave a way towards high-power MNF optics, for both scientific research and technological applications.

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HBV cccDNA is the persistent form of viral genome, which exists in host cell nucleus as an episomal minichromosome decorated with histone and non-histone proteins. cccDNA is the authentic viral transcription template and resistant to current antivirals. Growing evidence shows that the transcriptional activity of cccDNA minichromosome undergoes epigenetic regulations, suggesting a new perspective for anti-cccDNA drug development through targeting histone modifications. In this study, we screened an epigenetic compound library in the cccDNA reporter cell line HepBHAe82, which produces the HA-tagged HBeAg in a cccDNA-dependent manner. Among the obtained hits, a bromodomain-containing protein 4 (BRD4) inhibitor MS436 exhibited marked inhibition of cccDNA transcription in both HBV stable cell line HepAD38 and HepG2-NTCP or primary human hepatocyte infection system under noncytotoxic concentrations. Chromatin immunoprecipitation (ChIP) assay demonstrated that MS436 dramatically reduced the enrichment of H3K27ac, an activating histone modification pattern, on cccDNA minichromosome. RNAseq differential analysis showed that MS436 does not drastically change host transcriptome or induce any known anti-HBV factors/pathways, indicating a direct antiviral effect of MS436 on cccDNA minichromosome. Interestingly, the MS436-mediated inhibition of cccDNA transcription is accompanied by cccDNA destabilization in HBV infection and a recombinant cccDNA system, indicating that BRD4 activity may also play a role in cccDNA maintenance. Furthermore, depletion of BRD4 by siRNA knockdown or PROTAC degrader resulted in cccDNA inhibition in HBV-infected HepG2-NTCP cells, further validating BRD4 as an antiviral target. Taken together, our study has demonstrated the practicability of HepBHAe82-based anti-HBV drug screening system and provided a proof-of-concept for targeting HBV cccDNA with epigenetic compounds.

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HBV cure rates remain low despite prolonged nucleos(t)ide (NrtI) therapy, likely due to persistent residual viral replication and an inability to eliminate covalently closed circular DNA (cccDNA). Therapies with novel mechanisms of action against hepatitis B virus (HBV) are being explored with the goal of achieving sustained off-treatment response and a functional cure without requiring lifelong therapy. Recent studies have indicated that serum HBV DNA levels (a biomarker for viral replication) combined with serum pregenomic RNA (pgRNA) levels (a surrogate for intrahepatic cccDNA transcriptional activity), may provide a better prediction for the risk of liver-related complications. Current HBV DNA assays, such as the COBAS AmpliPrep/COBAS TaqMan HBV test v2.0, quantitate HBV DNA down to 20 IU/mL, but are not able to monitor loss of residual virus in patients on NrtI therapy. There are no commercially available assays approved to detect serum/plasma HBV pgRNA levels. We have developed a multi-assay panel of highly sensitive nucleic acid assays designed to monitor levels of HBV DNA, pgRNA and total nucleic acids (TNA, composite DNA + pgRNA) in clinical specimens and to monitor changes during treatment with new antiviral combination regimens.

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The HBV core protein plays an integral role in multiple steps of the HBV lifecycle. Consequently, HBV core inhibitors interrupt multiple steps of the replication cycle, including blocking pgRNA encapsidation and prematurely disassembling existing nucleocapsids, thereby preventing them from transporting relaxed circular (rcDNA) to the nucleus for conversion to covalently closed circular DNA (cccDNA). ABI-H2158 is an HBV core inhibitor that advanced into Phase 2 clinical trials for the treatment of chronic hepatitis B virus infection (cHBV) but was discontinued due to hepatotoxicity. Here, the potency, selectivity, and mechanisms of action of ABI-H2158 were evaluated using a variety of cell-based assays. Antiviral activity was measured by quantifying intracellular or secreted HBV DNA, RNA, and antigens. ABI-H2158 inhibited HBV replication by blocking pgRNA encapsidation in induced HepAD38 cells (EC50 = 22 nM) and had similar potency in HBV-infected HepG2-NTCP cells (EC50 = 27 nM) and primary human hepatocytes (PHH) (EC50 = 41 nM). ABI-H2158 is a pan-genotypic HBV inhibitor, with EC50s ranging from 7.1 to 22 nM across HBV genotypes A-E. ABI-H2158 also potently blocked the formation of cccDNA in de novo HBV infections with EC50s of ∼200 nM in HepG2-NTCP and PHH assays. These results indicate ABI-H2158 has dual mechanisms of action, inhibiting both early and late steps of the HBV replication cycle.

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Background: Bladder urothelial carcinoma (BLCA) is a common malignant tumor with the greatest recurrence rate of any solid tumor. Hypoxia is crucial in the growth and immune escape of malignant tumors. To predict clinical outcomes and immunological microenvironment of patients with BLCA, a hypoxia-related long non-coding RNA (HRlncRNA) signature was established. Methods: The Cancer Genome Atlas (TCGA) provided us with the differentially expressed profile of HRlncRNAs as well as clinical data from patients with BLCA, and we used weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with malignancies. Results: Finally, Cox analysis revealed that HRlncRNAs, which comprised 13 lncRNAs, were implicated in the predictive signature. The training, testing, and overall cohorts of BLCA patients were divided into the low-risk group and high-risk group based on the median of the risk score. The Kaplan-Meier curves revealed that BLCA patients with a high-risk score had a poor prognosis, and the difference between subgroups was statistically significant. The receiver operating characteristic curves revealed that this signature outperformed other strategies in terms of predicting ability. Multivariate analysis revealed that the risk score was an independent prognostic index for overall survival (HR = 1.411; 1.259-1.582; p < 0.001). Then, a nomogram with clinicopathological features and risk score was established. This signature could effectively enhance the capacity to predict survival, according to the calibration plots, stratification, and clinical analysis. The majority of Kyoto Encyclopedia of Genes and Genomes (KEGG) were WNT, MAPK, and ERBB signaling pathways. Two groups had different immune cell subtypes, immune checkpoints, immunotherapy response, and anti-tumor drug sensitivity, which might result in differing survival outcomes. We then validated the differential expression of signature-related genes between tumor and normal tissues using TCGA paired data. Conclusion: This prognostic signature based on 13 HRlncRNAs may become a novel and potential prognostic biomarker, providing more accurate clinical decision-making and effective treatment for BLCA patients.

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Irrigation activities can cause strong geochemical and hydrological fluctuations in the unsaturated zone, and affect arsenic (As) migration and transformation. The As geochemical cycle in the unsaturated zone is coupled with that of iron minerals through sorption-desorption, coprecipitation and redox processes. Dynamic batch experiments and wetting-drying cycling column experiments were conducted to evaluate As mobilization behaviors under the effects of exogenous substances, redox condition and intermittent flow. Our results show that As release under exogenous substances carried by irrigation (e.g., phosphate, carbonate, fulvic acid, humic acid, etc.) followed three trends with the types of exogenous inputs. Inorganic anions and organic matter resulted in opposite trends of arsenate release in different redox conditions. In anoxic environments, As(V) release was favored by the addition of phosphate and carbonate, while in oxic environments, the mobilization of As(V) was promoted by the addition of fulvic acid (FA). Further, intermittent irrigation promoted the reductive dissolution of Fe oxides and the mobilization of As. The addition of humic acid (HA) resulted in the mobilization of arsenate as As-Fe-HA ternary complexes. The mechanism of arsenic mobilization under irrigation has importance for prevention of arsenic exposure through soil to food chain transfer in typical high arsenic farmland.

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Background: This study aimed to assess the efficacy of mirabegron (50 mg daily) as a medical expulsive therapy for ureteral stones in adults. Materials and Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science from inception to July 2021 to collect the clinical trials. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies by using the Cochrane risk of bias tool. Review Manager 5.3 software was used for the meta-analysis. Results: A total of four studies were included, involving 398 patients: 197 patients in mirabegron group and 201 patients in control group. The meta-analysis showed that the stone expulsion rate was higher in the mirabegron group than in the control group (OR: 2.12; 95% CI: 1.33 to 3.40; p=0.002). Subgroup analysis identified that the stone expulsion rate of patients with stone size <5/6 mm was significantly higher than that of patients with stone size ≥5/6 mm (OR: 0.31; 95% CI: 0.13 to 0.72; p=0.006). But no significant difference was identified between the mirabegron group and the control group for the stone expulsion interval (MD: -1.16, 95% CI: -3.56 to 1.24; p=0.35). In terms of pain episodes, the mirabegron group was significantly lower than that of the control group (MD: -0.34, 95% CI: -0.50 to 0.19; p < 0.0001). Conclusions: The medical expulsive therapy with mirabegron had a significant effect in improving the stone expulsion rate for patients with ureteral stones, especially in those whose stone size <5/6 mm. Mirabegron had no effect on the stone expulsion interval but did decrease the pain episodes.

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Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), serving as the viral persistence form and transcription template of HBV infection, hijacks host histone and non-histone proteins to form a minichromosome and utilizes posttranslational modifications (PTMs) "histone code" for its transcriptional regulation. HBV X protein (HBx) is known as a cccDNA transcription activator. In this study we established a dual system of the inducible reporter cell lines modelling infection with wildtype (wt) and HBx-null HBV, both secreting HA-tagged HBeAg as a semi-quantitative marker for cccDNA transcription. The cccDNA-bound histone PTM profiling of wt and HBx-null systems, using chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR), confirmed that HBx is essential for maintenance of cccDNA at transcriptionally active state, characterized by active histone PTM markers. Differential proteomics analysis of cccDNA minichromosome established in wt and HBx-null HBV cell lines revealed group-specific hits. One of the hits in HBx-deficient condition was a non-histone host DNA-binding protein high mobility group box 1 (HMGB1). Its elevated association to HBx-null cccDNA was validated by ChIP-qPCR assay in both the HBV stable cell lines and infection systems in vitro. Furthermore, experimental downregulation of HMGB1 in HBx-null HBV inducible and infection models resulted in transcriptional re-activation of the cccDNA minichromosome, accompanied by a switch of the cccDNA-associated histones to euchromatic state with activating histone PTMs landscape and subsequent upregulation of cccDNA transcription. Mechanistically, HBx interacts with HMGB1 and prevents its binding to cccDNA without affecting the steady state level of HMGB1. Taken together, our results suggest that HMGB1 is a novel host restriction factor of HBV cccDNA with epigenetic silencing mechanism, which can be counteracted by viral transcription activator HBx.

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