ObjectiveTo characterize the quality differences among different germplasm and introduced varieties of Bupleurum scorzonerifolium roots（BSR）， and explore the underlying molecular mechanisms， providing a basis for high-quality production and quality control. MethodsWild BSR from Yulin（YLW） served as the quality reference， we conducted comparative analysis among YLW， locally domesticated wild germplasm in Yulin（YLC3）， Daqing germplasm introduced and cultivated in Yulin（YLDQC3）， and locally cultivated germplasm in Daqing（DQC3）. A combination of traditional pharmacognostic methods and modern multi-omics analyses was employed， including macroscopic traits（appearance， odor）， microscopic features（proportions of cork， phloem， xylem）， cell wall component contents（hemicellulose， cellulose， lignin）， carbohydrate contents（starch， water-soluble polysaccharides）， marker compound contents（ethanol-soluble extracts， total saponins， liposoluble extracts， and saikosaponins A， B₂， C， D）， metabolomics， and transcriptomics， in order to systematically characterize quality differences and investigate molecular mechanisms among these samples. ResultsMacroscopically， Yulin-produced BSR（YLW， YLC3， YLDQC3） exhibited significantly greater weight， length， and upper and middle diameters than Daqing-produced BSR（DQC3）. Odor-wise， YLW and YLC3 had a a fragrance taste， YLDQC3 had a rancid oil odor， and DQC3 had a sweet and fragrant taste. Microscopically， Yulin germplasm（YLW， YLC3） and Daqing germplasm（YLDQC3， DQC3） shared similar structural features， respectively. However， Yulin germplasm showed significantly higher proportions of cork and phloem， as well as stronger xylem vessel staining intensity compared to Daqing germplasm. Regarding various component contents， Yulin germplasm contained significantly higher levels of ethanol-soluble extracts， total saponins， and saikosaponins A， B₂， C， D， while Daqing germplasm had significantly higher levels of hemicellulose， starch， and liposoluble extracts. After introduction to Yulin， the Daqing germplasm（YLDQC3） showed increased starch， water-soluble polysaccharides and liposoluble extracts contents， decreased cell wall component content， but no significant difference in other component contents. Metabolomics revealed that saponins and terpenes accumulated significantly in Yulin germplasm， while alcohols and aldehydes accumulated predominantly in Daqing germplasm. Transcriptomics indicated similar gene expression patterns within the same germplasm but specificity between different germplasms. Integrative metabolomic-transcriptomic analysis identified 145 potential key genes associated with the saikosaponin biosynthesis pathway， including one acetyl-coenzyme A（CoA） acetyltransferase gene（ACAT）， one 3-hydroxy-3-methylglutaryl-coenzyme A synthase gene（HMGS）， two hydroxymethylglutaryl-CoA（HMG-CoA） reductase genes（HMG）， one phosphomevalonate kinase gene（PMK）， one 1-deoxy-D-xylose-5-phosphate synthase gene（CLA）， one hydroxymethylbuten-1-aldol synthase gene（HDR）， two farnesyl pyrophosphate synthase genes（FPPS）， one squalene synthase gene（SQS）， one β-amyrin synthase gene（BAS）， 102 cytochrome P450（CYP450） gene family members， and 32 uridine diphosphate-glucuronosyltransferase（UGT） gene family members. ConclusionAmong the three cultivated types， YLC3 most closely resembles YLW in appearance， microscopic features， contents of major bioactive constituents， metabolomic and transcriptomic profiles. Yulin germplasm exhibits superior saponin synthesis capability compared to Daqing germplasm， and Yulin region is more suitable for the growth of B. scorzonerifolium. Based on these findings， it is recommended that artificial cultivation in northern Shaanxi and similar regions utilize the local Yulin germplasm source cultivated for at least three years.

Aquatic organisms can secrete biomacromolecules through specialized organs, tissues, or structures, enabling adhesion to underwater material surfaces and leading to severe biofouling issues. This phenomenon adversely impacts aquatic ecosystem health and human activities. Biofouling has emerged as an emerging global environmental challenge. Adhesion serves as the foundation of biofouling, representing a critical step toward a comprehensive understanding of the adhesion mechanisms of aquatic organisms. Biomacromolecules, including proteins, lipids, and carbohydrates, are the primary functional components in the adhesive substances of aquatic fouling organisms. Research indicates that these biomacromolecules exhibit diversity in types and characteristics across different aquatic organisms, yet their adhesion mechanisms show unifying features. Despite significant progress, there remains a lack of comprehensive reviews on the adhesion mechanisms mediated by biomacromolecules in aquatic fouling organisms, particularly on the roles of lipids and carbohydrates. Through a comprehensive analysis of existing literature, this review systematically summarizes the mechanistic roles of three classes of macromolecules in aquatic biofouling adhesion processes. Proteins demonstrate central functionality in interfacial adhesion and cohesion through specialized functional amino acids, conserved structural domains, and post-translational modifications. Lipids enhance structural stability via hydrophobic barrier formation and antioxidative protection mechanisms. Carbohydrates contribute to adhesion persistence through cohesive reinforcement and enzymatic resistance of adhesive matrices. Building upon these mechanisms, this review proposes four prospective research directions: optimization of protein-mediated adhesion functionality, elucidation of lipid participation in adhesion dynamics, systematic characterization of carbohydrate adhesion modalities, and investigation of macromolecular synergy in composite adhesive systems. The synthesized knowledge provides critical insights into underwater adhesion mechanisms of aquatic fouling organisms and establishes a theoretical foundation for developing mechanism-driven antifouling strategies. This work advances fundamental understanding of bioadhesion phenomena while offering practical guidance for next-generation antifouling technology development.

OBJECTIVES: To investigate the clinical features of children with STAT gene mutations, and to explore corresponding immunotherapy strategies. METHODS: A retrospective analysis was performed for the clinical data of 10 children with STAT gene mutations who were admitted to the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University, from October 2015 to October 2024. Exploratory immunotherapy was implemented in some refractory cases, and the changes in symptoms, imaging manifestations, and cytokine levels were assessed after treatment. RESULTS: For the 10 children, the main clinical manifestations were recurrent rash since birth (7/10), cough (8/10), wheezing (5/10), expectoration (4/10), and purulent nasal discharge (4/10). Genotyping results showed that there was one child with heterozygous loss-of-function (LOF) mutation in the STAT1 gene, four children with heterozygous LOF mutation in the STAT3 gene, and five children with heterozygous gain-of-function (GOF) mutation in the STAT3 gene. Two children with LOF mutation in the STAT3 gene showed decreased interleukin-6 levels and improved clinical symptoms and imaging findings after omalizumab treatment. Three children with GOF mutation in the STAT3 gene achieved effective disease control after treatment with methylprednisolone (0.5 mg/kg per day). Two children with GOF mutation in the STAT3 gene received treatment with JAK inhibitor and then showed some improvement in symptoms. CONCLUSIONS STAT gene mutation screening should be considered for children with recurrent rash and purulent respiratory tract infections. Targeted immunotherapy may improve prognosis in patients with no response to conventional treatment.
Humans ; Male ; Immunotherapy ; Female ; Child, Preschool ; Child ; Gain of Function Mutation ; Retrospective Studies ; Infant ; Loss of Function Mutation ; STAT Transcription Factors/genetics*

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Objective To evaluate the effects of high-fat diet on the pharmacokinetics of metronidazole in Chinese healthy adult subjects.Methods This program is designed according to a single-center,randomized,open,single-dose trial.Forty-seven healthy subjects were assigned to receive single dose of metronidazole tablets 200 mg in either fasting and high-fat diet state,and blood samples were taken at different time points,respectively.The concentrations of metronidazole in plasma were determined by high performance liquid chromatography-mass spectromentry.Results The main pharmacokinetic parameters of metronidazole in fasting state and high-fat diet state were as follows:Cmax were(4 799.13±1 195.32)and(4 044.17±773.98)ng·mL-1;tmax were 1.00 and 2.25 h;t1/2 were(9.11±1.73)and(9.37±1.79)h;AUC0_t were(5.59±1.19)x 104 and(5.51±1.18)x 104 ng·mL-1·h;AUC0_∞ were(5.79±1.33)x 104 and(5.74±1.32)× 104 ng·mL-1·h.Compared to the fasting state,the tmaxof the drug taken after a high fat diet was delayed by 1.25 h(P＜0.01),Cmax,AUC0_t,AUC0-∞ were less or decreased in different degrees,but the effects were small(all P＞0.05).Conclusion High-fat diet has little effects on the pharmacokinetic parameters of metronidazole,which does not significantly change the degree of drug absorption,but can significantly delay the time to peak.

Based on the pathogenesis of “tendon off-position and joint subluxation”， combined with modern ana-tomy and biomechanics， the characteristic manifestations of “tendon off-position” and “joint subluxation” of the knee and the intrinsic connection between them are clarified. Through sorting out the relationship between “tendon off-position and joint subluxation” and knee osteoarthritis （KOA） in modern research， it is believed that “tendon off-position and joint subluxation” is the key mechanism for the occurrence and development of KOA， and accordingly， it is proposed to take the diet as the guide， use bone manipulation for external diagnosis and treatment， use traditional Chinese medicine decoction for internal treatment， and use Daoyin exercise throughout the whole process as the strategy for KOA's comprehensive traditional Chinese medicine treatment to improve the clinical effectiveness.

BACKGROUND:"Tendon off-position"is a disease name included in the International Classification of Diseases 11th Revision,and also a clinical indication of manipulation,acupuncture and other treatments.However,its specific mechanism is still unclear.It is urgent to establish an animal model that can reflect the clinical and pathological characteristics of"tendon off-position,"so as to further study the mechanism of effective clinical treatments. OBJECTIVE:To establish an animal model of"tendon off-position"in rats based on isometric contraction of skeletal muscles,and to explore the changes of skeletal muscle function and morphological phenotype after"tendon off-position." METHODS:Sixty rats were randomly divided into control group,static-loading group and extra loading group,with twenty rats in each group.Rats in the control group were kept normally without treatment.In the latter two groups,the rats were fixed by the self-made static-loading modeling device and a static-loading(the body mass of each rats was applied as the static-loading)was applied to cause sustained isometric contraction of the upper limb muscles.Then,animal models of"tendon off-position"were successfully established.In the extra loading group,50%of the body mass was added to the ankle joint after modeling.The skeletal muscle samples were harvested at 2 and 4 weeks after modeling.The changes of limb grip strength,wet mass of skeletal muscle,and serum levels of creatine kinase-muscle and lactate dehydrogenase A were measured,and the changes of skeletal muscle histomorphology and ultrastructure were observed. RESULTS AND CONCLUSION:At 2 weeks after modeling,the rats in the static-loading group and extra loading group showed significantly decreased grip strength and wet muscle mass,significantly increased serum levels of creatine kinase-muscle and lactate dehydrogenase A,and abnormal muscle fiber morphology and structure accompanied by a large number of deposited collagen fibers.Electron microscopy results showed that the structure of myofibrils was disordered,the Z-line was distorted,and the light and dark boundaries were blurred.At 4 weeks after modeling,the grip strength of the model rats was increased compared with that at 2 weeks,the serum creatine kinase-muscle and lactate dehydrogenase A levels were decreased,and the changes of muscle fiber morphology and ultrastructure were recovered to varying degrees.It is suggested that the rat skeletal muscle injury model based on continuous isometric contraction of skeletal muscle can well reflect the pathological characteristics of"tendon off-position"at 2 weeks,and can be used to study the mechanism of acupuncture and manipulation in the treatment of"tendon off-position."