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Abstract Background Hepatitis B virus (HBV) infection is a persistent global public health problem, and curing for chronic hepatitis B (CHB) through the application of existing antiviral drugs is beset by numerous challenges. The viral protein HBx is a critical regulatory factor in the life cycle of HBV. Targeting HBx is a promising possibility for the development of novel therapeutic strategies. Methods The Nano-Glo® HiBiT Lysis Detection System was used to screen the herbal monomer compound library for compounds that inhibit HBx expression. Western blotting was used to examine proteins expression. Southern blotting or Northern blotting were used to detect HBV DNA or HBV RNA. ELISA was performed to detect the HBsAg level. The effect of asiatic acid on HBV in vivo was investigated by using recombinant cccDNA mouse model. Results Asiatic acid, an extract of Centella asiatica, significantly reduced the HBx level. Mechanistic studies demonstrated that asiatic acid may promote the degradation of HBx in an autophagy pathway-dependent manner. Subsequently, asiatic acid was found to reduce the amount of HBx bound to covalently closed circular DNA (cccDNA) microchromosomes, and repressive chromatin modifications then occurred, ultimately inhibiting cccDNA transcriptional activity. Moreover, in HBV-infected cells and a mouse model of persistent HBV infection, asiatic acid exhibited potent anti-HBV activity, as evidenced by decreased levels of HBV RNAs, HBV DNA and HBsAg. Conclusions Asiatic acid was identified as a compound that targets HBx, revealing its potential for application as an anti-HBV agent.

Abstract Phenotypes play a fundamental role in medical genetics, serving as external manifestations of underlying genotypes. Deep phenotyping, a cornerstone of precision medicine, involves precise multi-system phenotype assessments, facilitating disease subtyping and genetic understanding. Despite their significance, the field lacks standardized protocols for accurate phenotype evaluation, hindering clinical comprehension and research comparability. We present a comprehensive workflow of deep phenotyping for rare bone diseases from the Genetics Clinic of Skeletal Deformity at Peking Union Medical College Hospital. Our workflow integrates referral, informed consent, and detailed phenotype evaluation through HPO standards, capturing nuanced phenotypic characteristics using clinical examinations, questionnaires, and multimedia documentation. Genetic testing and counseling follow, based on deep phenotyping results, ensuring personalized interventions. Multidisciplinary team consultations facilitate comprehensive patient care and clinical guideline development. Regular follow-up visits emphasize dynamic phenotype reassessment, ensuring treatment strategies remain responsive to evolving patient needs. In conclusion, this study highlights the importance of deep phenotyping in rare bone diseases, offering a standardized framework for phenotype evaluation, genetic analysis, and multidisciplinary intervention. By enhancing clinical care and research outcomes, this approach contributes to the advancement of precision medicine in the field of medical genetics.

Abstract The HBV core protein (HBc) is an important viral protein of HBV that plays an indispensable role in the lifecycle of HBV, including capsid assembly and transport, reverse transcription and virus release. In recent years, evidence has shown that HBc may be involved in the malignant progression of HCC. Thus, HBc is an attractive target for antiviral agents and provides a new strategy for the treatment of HBV-related HCC. Here, we identified a novel anti‐HBc compound—colchicine, an alkaloid compound—that promoted selective autophagic degradation of HBc through the AMPK/mTOR/ULK1 signalling pathway. We further confirmed that colchicine promoted the selective autophagy of HBc by enhancing the binding of HBc to the autophagy receptor p62. Finally, we evaluated the effects of colchicine on HBV replication and HBc-mediated HCC metastasis in vitro and in vivo. Our research indicated that the inhibitory effects of colchicine on HBV and HBV-related HCC depend on the selective autophagic degradation of HBc. Thus, colchicine is not only a promising therapeutic strategy for chronic hepatitis B but also a new treatment for HBV-related HCC.

Abstract Background β-Arbutin, a hydroquinone glucoside found in pears, bearberry leaves, and various plants, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. β-Arbutin has wide applications in the pharmaceutical and cosmetic industries. However, the limited availability of high-performance strains limits the biobased production of β-arbutin. Results This study established the β-arbutin biosynthetic pathway in C. glutamicum ATCC13032 by introducing codon-optimized ubiC, MNX1, and AS. Additionally, the production titer of β-arbutin was increased by further inactivation of csm and trpE to impede the competitive metabolic pathway. Further modification of the upstream metabolic pathway and supplementation of UDP-glucose resulted in the final engineered strain, C. glutamicum AR11, which achieved a β-arbutin production titer of 7.94 g/L in the optimized fermentation medium. Conclusions This study represents the first successful instance of de novo β-arbutin production in C. glutamicum, offering a chassis cell for β-arbutin biosynthesis.

Abstract This paper proposes an estimation approach following the constructive identification strategy of Athey and Haile, and Gentry and Li with adaption in the context of ascending auctions with selective entry. Our estimators are shown to be consistent in a large sample and to perform well in a finite sample by a simulation study. We apply our estimation approach to the Alibaba online judicial auctions of used cars to recover the bounds of conditional value distribution and the entry cost. The bounds estimates of both conditional value distribution and entry cost are quite tight (resp., relatively wide) for middle‐valued (resp., low‐valued or high‐valued) signal, and the cumulative distribution functions of conditional value distribution given signal comply with the law of ordered dominance. Finally, our counterfactual analysis indicates that (i) the ascending auction yields a higher revenue than the first‐price sealed bid auction, and (ii) the revenue can be improved significantly when the entry cost is cut by half.

BackgroundRecent findings highlight the significant impact of intestinal fungi on the complex makeup of the gut microbiota and human health, challenging past oversights. However, a lack of thorough systematic and quantitative analyses remains. This study aims to address this gap by thoroughly examining the current research on gut fungi. Through analyzing developments and unique features in this area, our goal is to foster a deeper understanding and identify future research pathways.MethodsWe performed an extensive bibliometric analysis on documents from 2000 to 2023, sourced from the Web of Science Core Collection (WoSCC). Utilizing advanced visualization tools such as VOSviewer, CiteSpace, and Bibliometrix R, we meticulously examined and illustrated the data in scientific landscapes and networks.ResultsA total of 1434 papers were analyzed, revealing a substantial increase in publication volume over the past two decades, particularly in 2020. Contributions came from 67 countries, 2178 institutions, and 8,479 authors. China led in publication output with 468 articles, followed by the University of California with 84 articles, and ZHANG F as the most prolific author with 17 articles. Emerging research areas such as “Fungal-Bacteria Interactions,” “Gut Fungus and Gut-Brain Axis,” and “Gut Fungus and Immunity” are expected to attract growing interest in the future.ConclusionThis extensive bibliometric analysis offers a current overview of scholarly efforts concerning intestinal fungi, highlighting the predominant landscape in this field. These insights can assist scholars in identifying appropriate publication avenues, forming collaborative relationships, and enhancing understanding of key themes and emerging areas, thereby stimulating future research endeavors.

IntroductionIn the search for sustainable development, urban eco-development is becoming a core agenda for all countries. China’s low-carbon city pilot (LCCP) policy is an important initiative to promote urban low-carbon governance. And exploring the direction of LCCP policy is an important step towards sustainable urban development.MethodsSuper-SBM is employed to calculate urban ecological efficiency using panel data from 254 prefecture-level cities between 2007 and 2020. The methods of kernel density estimation and spatial Markov chains are applied to the spatial analysis of urban ecological efficiency. The spatial analyses examine the spatiotemporal patterns and dynamic evolving trends of urban ecological efficiency. Additionally, the multiperiod difference-in-differences method is used to assess the impact of the LCCP policy on urban ecological efficiency. On this basis, we apply the method of mechanism analysis to discuss the influence mechanism.ResultsThe results indicate that urban ecological efficiency gradually forms a continuous spatial clustering pattern, although there is a widening tendency in the absolute differences. In the subsequent transfer process, the spatial factor plays a highly significant role. Benchmark regressions and auxiliary robustness tests demonstrate that the LCCP policy is effective in improving urban ecological efficiency. Further analysis shows that the effect of LCCP policies on ecological efficiency can be transmitted by promoting green technology innovation as well as facilitating a low-carbon transition in the energy mix. The above findings indicate the presence of the "Green Innovation Effect" and the "Decoupling Effect".DiscussionThese discoveries enhance the theoretical framework of urban ecology and offer valuable insights for other regions seeking to implement low-carbon urban governance.

Abstract Background The Ehlers-Danlos syndromes (EDS) are a group of rare hereditary connective tissue disorders. EDS is clinically and genetically heterogeneous and usually involves multiple systems. There are 14 subtypes of EDS with hallmark features including joint hypermobility, skin hyperextensibility, and tissue fragility. The clinical manifestations and their severity differ among the subtypes, encompassing recurrent joint dislocations, scoliosis, arterial aneurysm and dissection, and organ rupture. Challenges in diagnosis and management arise from the complexity of the disease, which is further complicated by its rarity. The development of clinical guidelines and implementation of coordinated multi-disciplinary team (MDT) approaches have emerged as global priorities. Main body Chinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes was therefore established. Healthcare professionals were recruited from 25 top hospitals across China. The experts are specialized in 24 fields, including genetics, vascular surgery, dermatology, and orthopedics, as well as nursing care, rehabilitation, psychology, and nutrition. Based on GRADE methodology, the Guidelines were written by the Group supervised by methodologists, following a systemic review of all 4453 articles in PubMed published before August 9, 2023, using the search term “Ehlers Danlos”. A coordinated MDT approach for the diagnosis and management of EDS is highly recommended by the Group, along with 29 specific recommendations addressing key clinical questions. In addition to the treatment plan, the Guidelines also emphasize integrating support from nursing care, rehabilitation, psychology, and nutrition. This integration not only facilitates recovery in hospital settings, but most importantly, the transition from an illness-defined life to a more “normalized” life. Conclusion The first guidelines on EDS will shorten the diagnostic odyssey and solve the unmet medical needs of the patients. This article is a synopsis of the full guidelines.

The WNT/β-catenin signaling pathway plays crucial roles in tumorigenesis and relapse, metastasis, drug resistance, and tumor stemness maintenance. In most tumors, the WNT/β-catenin signaling pathway is often aberrantly activated. The therapeutic usefulness of inhibition of WNT/β-catenin signaling has been reported to improve the efficiency of different cancer treatments and this inhibition of signaling has been carried out using different methods including pharmacological agents, short interfering RNA (siRNA), and antibodies. Here, we review the WNT-inhibitory effects of some FDA-approved drugs and natural products in cancer treatment and focus on recent progress of the WNT signaling inhibitors in improving the efficiency of chemotherapy, immunotherapy, gene therapy, and physical therapy. We also classified these FDA-approved drugs and natural products according to their structure and physicochemical properties, and introduced briefly their potential mechanisms of inhibiting the WNT signaling pathway. The review provides a comprehensive understanding of inhibitors of WNT/β-catenin pathway in various cancer therapeutics. This will benefit novel WNT inhibitor development and optimal clinical use of WNT signaling-related drugs in synergistic cancer therapy.

Abstract Background Progressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study. Methods HepG2-Na+/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148’s impact on HBV in vivo was investigated using an established rcccDNA mouse model. Results ZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRα) expression by binding to the RXRα promoter sequence. RXRα binding site mutation or RXRα overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model. Conclusions ZNF148 inhibited HBV replication by downregulating RXRα transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies.

In non-invasive blood glucose measurement, the sensitivity of glucose-induced optical signals within human tissue is a crucial reference point. This study evaluates the sensitivity of glucose-induced diffuse reflectance in the 1000–1700 nm range. A key factor in understanding this sensitivity is the rate at which the scattering coefficient changes due to glucose, as it is significantly higher than in non-living media and predominantly influences the diffuse light signal level when blood glucose levels change. The study measured and calculated the changes in the scattering coefficient at 1314 nm, a wavelength chosen for its minimal interference from glucose absorption and other bodily constituents. Based on the Mie scattering theory and the results at 1314 nm, the changes in the scattering coefficient within the 1000–1700 nm range were estimated. Subsequently, the sensitivity of the glucose signal across this range was determined through Monte Carlo (MC) simulations. The findings from 25 human trials indicate that the measured sensitivities at five other typical wavelengths within this band generally align with the sensitivities calculated using the aforementioned method. This research can guide the identification of blood glucose signals and the selection of wavelengths for non-invasive blood glucose measurements.

The design and development of highly efficient electrocatalysts for oxygen evolution reaction (OER) are critical for renewable energy generation. Ni‐based electrocatalysts are widely used in the water electrolysis process. In this work, heterostructure consisting of selenides and layered double hydroxides (LDH) named (Co, Ni)Se4@NiFe‐LDH, are prepared by an LDH‐based strategy, in which the electronic structure of Ni active sites is regulated by interfacial electron interaction. The (Co, Ni)Se4@NiFe‐LDH shows an optimized charge distribution of Ni sites and excellent catalytic activity. The effective charge modulation results in lowering the energy barrier of OOH* intermediate formation and adequate adsorption strength of the intermediates on Ni‐active sites, which improves the kinetics of OER. Specifically, the (Co, Ni)Se4@NiFe‐LDH only requires an overpotential of 237 mV to reach the current density of 10 mA cm−2 under alkaline conditions. The results of this work demonstrate that reasonable engineering of heterostructure is an effective strategy to improve the intrinsic property of OER electrocatalysts for water splitting.

The Haiyang-2D (HY2D) satellite is the fourth ocean dynamics environment monitoring satellite launched by China. The satellite operates on a re-entry frozen orbit, which necessitates orbital maneuvers to maintain its designated path once the satellite’s sub-satellite point deviates beyond a certain threshold. However, the execution of orbit maneuvers presents a significant challenge to the field of Precise Orbit Determination (POD). The thesis selects the on-board GPS data of HY2D satellite in December 2023 and five maneuvering days of that year. Employing a multifaceted approach that includes the assessment of observational data quality, orbit overlap, external orbit validation, and SLR (Satellite Laser Ranging) verification, the research delves into precise orbit determination during both maneuver and non-maneuver periods. The results indicate that: (1) The average number of satellites tracked by the receiver is 6.4; (2) During the non-maneuver periods, the average RMS (Root Mean Square) value of the radial difference in the 6-h overlapping arc segment is 0.66 cm, and the three-dimensional position difference is about 1.16 cm; (3) When compared with the precision science orbits (PSO) provided by CNES (Centre National d’Études Spatiales), the average values of the RMS values of the differences in the radial (R), transverse (T), and normal (N) directions during the non-maneuver and maneuver periods are respectively 1.32 cm, 2.31 cm, 1.92 cm and 3.04 cm, 8.78 cm, 2.72 cm. (4) The SLR verification of the orbit revealed a residual RMS of 2.24 cm. This suggests that by incorporating the modeling of maneuver forces during the maneuver periods, the impact of orbital maneuvers on orbit determination can be mitigated.

Popular music is valuable in music teacher education because it can allow the considering of divergent and unique perspectives. However, viewing popular music making as a static process can constrain its values. Drawing on the work of Roland Barthes (1977), the purpose of this philosophical inquiry is to examine the limitations of current ways of interpreting popular music and to reimagine popular music interpretation in general music teacher education. After providing an overview of Barthes's (1977) three levels of meaning--the information level of meaning, the symbolic level of meaning, and the third meaning--I problematize popular music interpretation at the first two levels because it reassures individuals' current ways of being, reinforcing "what is." In response to the closed ways of interpreting popular music that confine how popular music can be valued and engaged, I propose interpreting popular music through the third meaning during which individuals no longer passively receive "what is," but actively explore "what might be" as well as whom they "might connect with" and "become." Additionally, I offer practical applications on how one can relate, express, connect, and become through the third meaning in the context of general music teacher education.

Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte--derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis. [ABSTRACT FROM AUTHOR]

N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss in ccRCC affects m6A patterns. In this study, we demonstrate that VHL binds and promotes METTL3/METTL14 complex formation while VHL depletion suppresses m6A modification, which is distinctive from its canonical E3 ligase role. m6A RNA immunoprecipitation sequencing (RIP-Seq) coupled with RNA-Seq allows us to identify a selection of genes whose expression may be regulated by VHL-m6A signaling. Specifically, PIK3R3 is identified to be a critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while its overexpression leads to decreased tumorigenesis. Mechanistically, the VHL-m6A-regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a mechanism by which VHL regulates m6A through modulation of METTL3/METTL14 complex formation, thereby promoting PIK3R3 mRNA stability and protein levels that are critical for regulating ccRCC tumorigenesis. [ABSTRACT FROM AUTHOR]