OBJECTIVE To identify the active components of Desmodium styracifolium （Osb.） Merr. extract （DME） against cholestatic liver injury （CLI）， and to verify its target and molecular mechanism， so as to provide scientific evidence for the clinical application of D.styracifolium （Osb.） Merr. and the development of new hepatoprotective agents.METHODS High-performance liquid chromatography was applied to establish fingerprints of 19 batches of DME， followed by similarity evaluation and identification of common peaks. An in vitro CLI model was constructed by lithocholic acid （LCA）-induced injury in HepG2 cells to evaluate the in vitro protective effect of DME against CLI. Spearman correlation analysis， grey relational analysis and partial least-squares regression analysis were adopted to investigate the spectrum-effect relationship of DME against CLI and preliminarily screen the core active components. Molecular docking and surface plasmon resonance technology were used to predict and verify the binding capacity between core active components and farnesoid X receptor （FXR）. qRT-PCR， Western blot and immunofluorescence staining tests were performed to validate the influences of core active components on the expression of molecules related to FXR/bile salt export pump （BSEP） pathway in CLI model cells.RESULTS A total of 12 common peaks were calibrated in the fingerprints of 19 batches of DME， and the similarity values were all above 0.990. Four common peaks were identified， namely peak 6 （schaftoside）， peak 7 （isoorientin）， peak 11 （isoschaftoside） and peak 12 （isovitexin）. DME at 80 μg/mL exerted the optimal protective effect on CLI-model cells， and the cell viability reached （75.66±4.60）% after 24 h of treatment. Spectrum-effect analysis revealed that schaftoside possessed the strongest correlation with the anti-CLI activity of DME and served as the core active component. Target prediction and validation results showed that the binding energy between schaftoside and FXR was －8.1 kcal/mol， and the equilibrium dissociation constant was 27.3 μmol/L. Mechanistic experiments demonstrated that 100 μmol/L schaftoside significantly elevated the expression levels of FXR and BSEP， and mRNA of their encoded genes Nr1h4 ， Abcb11 in CLI-model cells （ P ＜0.05）.CONCLUSIONS Schaftoside may be the core active component of DME against CLI， and its mechanism may be related to the activation of FXR/BSEP pathway.

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

BACKGROUND:Degenerative scoliosis is defined as a condition that occurs in adulthood with a coronal cobb angle of the spine>10° accompanied by sagittal deformity and rotational subluxation,which often produces symptoms of spinal cord and nerve compression,such as lumbar pain,lower limb pain,numbness,weakness,and neurogenic claudication.The finite element method is a mechanical analysis technique for computer modelling,which can be used for spinal mechanics research by building digital models that can realistically restore the human spine model and design modifications. OBJECTIVE:To review the application of finite element method in the etiology and treatment of degenerative scoliosis. METHODS:The literature databases CNKI,PubMed,and Web of Science were searched for articles on the application of finite element method in degenerative scoliosis published before October 2023.Search terms were"finite element analysis,biomechanics,stress analysis,degenerative scoliosis,adult spinal deformity"in Chinese and English.Fifty-four papers were finally included. RESULTS AND CONCLUSION:(1)The biomechanical findings from the degenerative scoliosis model constructed using the finite element method were identical to those from the in vivo experimental studies,which proves that the finite element method has a high practical value in degenerative scoliosis.(2)The study of the etiology and treatment of degenerative scoliosis by the finite element method is conducive to the prevention of the occurrence of the scoliosis,slowing down the progress of the scoliosis,the development of a more appropriate treatment plan,the reduction of complications,and the promotion of the patients'surgical operation.(3)The finite element method has gradually evolved from a single bony structure to the inclusion of soft tissues such as muscle ligaments,and the small sample content is increasingly unable to meet the research needs.(4)The finite element method has much room for exploration in degenerative scoliosis.

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

BACKGROUND: There is little literature describing the artificial intelligence (AI)-aided diagnosis of severe pneumonia (SP) subphenotypes and the association of the subphenotypes with the ventilatory treatment efficacy. The aim of our study is to illustrate whether clinical and biological heterogeneity, such as ventilation and gas-exchange, exists among patients with SP using chest computed tomography (CT)-based AI-aided latent class analysis (LCA). METHODS: This retrospective study included 413 patients hospitalized at Xinhua Hospital diagnosed with SP from June 1, 2015 to May 30, 2020. AI quantification results of chest CT and their combination with additional clinical variables were used to develop LCA models in an SP population. The optimal subphenotypes were determined though evaluating statistical indicators of all the LCA models, and clinical implications of them such as guiding ventilation strategies were further explored by statistical methods. RESULTS: The two-class LCA model based on AI quantification results of chest CT can describe the biological characteristics of the SP population well and hence yielded the two clinical subphenotypes. Patients with subphenotype-1 had milder infections ( P <0.001) than patients with subphenotype-2 and had lower 30-day ( P <0.001) and 90-day ( P <0.001) mortality, and lower in-hospital ( P = 0.001) and 2-year ( P <0.001) mortality. Patients with subphenotype-1 showed a better match between the percentage of non-infected lung volume (used to quantify ventilation) and oxygen saturation (used to reflect gas exchange), compared with patients with subphenotype-2. There were significant differences in the matching degree of lung ventilation and gas exchange between the two subphenotypes ( P <0.001). Compared with patients with subphenotype-2, those with subphenotype-1 showed a relatively better match between CT-based AI metrics of the non-infected region and oxygenation, and their clinical outcomes were effectively improved after receiving invasive ventilation treatment. CONCLUSIONS A two-class LCA model based on AI quantification results of chest CT in the SP population particularly revealed clinical heterogeneity of lung function. Identifying the degree of match between ventilation and gas-exchange may help guide decisions about assisted ventilation.
Humans ; Tomography, X-Ray Computed/methods* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Artificial Intelligence ; Aged ; Pneumonia/diagnosis* ; Latent Class Analysis ; Adult

BACKGROUND:The highest incidence of spinal fracture is in the thoracolumbar segment,and its symptoms are back pain,posterior convexity deformity,activity limitation,or with spinal cord nerve injury causing lower limb pain,numbness,and even paraplegia and other complications.The finite element method is a digital computer modeling technique,which can simulate the physical model and carry out force analysis realistically.OBJECTIVE:To review the application of finite element method in thoracolumbar spine fractures.METHODS:We searched the Chinese and English literature databases PubMed,Web of Science,and CNKI for relevant literature on the application of the finite element analysis method in spinal thoracolumbar fracture published before March 2024.The search terms in Chinese and English were:finite element analysis methods,biomechanical phenomena,stress analysis,thoracolumbar fractures,spinal fractures.Finally,55 papers were included.RESULTS AND CONCLUSION:(1)The exploration of thoracolumbar fractures caused by different etiologies(osteoporotic,traumatic,and pathological)through the finite element method is conducive to a deeper understanding of the biomechanics of various types of thoracolumbar fractures,and to improve the individualized and fine-tuned treatment of thoracolumbar fractures.(2)The finite element analysis of a single sample or a small number of samples has the chance,and a larger number of samples are required for the future finite element analysis to reduce the chance caused by the sample.(3)The rigid structure of bones alone cannot meet the biomechanical working conditions of the integrity of the physical object,and future finite element models need to incorporate all the structures of the physical object(e.g.,soft tissues,such as muscles and ligaments)as far as possible.(4)The finite element method has been used in more studies on osteoporotic and traumatic thoracolumbar spine fractures,which will need to be more in-depth in the future,and less in the field of pathologic thoracolumbar fractures,which has a wider scope for future research.

BACKGROUND:The highest incidence of spinal fracture is in the thoracolumbar segment,and its symptoms are back pain,posterior convexity deformity,activity limitation,or with spinal cord nerve injury causing lower limb pain,numbness,and even paraplegia and other complications.The finite element method is a digital computer modeling technique,which can simulate the physical model and carry out force analysis realistically.OBJECTIVE:To review the application of finite element method in thoracolumbar spine fractures.METHODS:We searched the Chinese and English literature databases PubMed,Web of Science,and CNKI for relevant literature on the application of the finite element analysis method in spinal thoracolumbar fracture published before March 2024.The search terms in Chinese and English were:finite element analysis methods,biomechanical phenomena,stress analysis,thoracolumbar fractures,spinal fractures.Finally,55 papers were included.RESULTS AND CONCLUSION:(1)The exploration of thoracolumbar fractures caused by different etiologies(osteoporotic,traumatic,and pathological)through the finite element method is conducive to a deeper understanding of the biomechanics of various types of thoracolumbar fractures,and to improve the individualized and fine-tuned treatment of thoracolumbar fractures.(2)The finite element analysis of a single sample or a small number of samples has the chance,and a larger number of samples are required for the future finite element analysis to reduce the chance caused by the sample.(3)The rigid structure of bones alone cannot meet the biomechanical working conditions of the integrity of the physical object,and future finite element models need to incorporate all the structures of the physical object(e.g.,soft tissues,such as muscles and ligaments)as far as possible.(4)The finite element method has been used in more studies on osteoporotic and traumatic thoracolumbar spine fractures,which will need to be more in-depth in the future,and less in the field of pathologic thoracolumbar fractures,which has a wider scope for future research.

Using conventional broth microdilution assays,the synthetic phenolic antioxidant 2,6-di-tert-butyl-4-methylphenol(butylated hydroxytoluene,BHT)was screened for synergistic antimi-crobial activity with β-lactam antibiotics.Further validation through checkerboard assays,growth curve analysis,and time-kill curve experiments confirmed the synergistic effect of BHT and β-lac-tams against methicillin-resistant Staphylococcus aureus(MRSA)(FICI≤0.5).To elucidate the underlying mechanism of synergy,this study evaluated changes in membrane permeability and pro-ton transmembrane gradients-key factors in biofilm functionality-along with critical indicators of bacterial energy metabolism,including ATP levels and the NAD+/NADH ratio.The results dem-onstrated that BHT disrupts the proton motive force(PMF),impairs membrane potential,and perturbs bacterial energy homeostasis,thereby significantly enhancing the antibacterial efficacy ofβ-lactams.Furthermore,a murine pneumonia infection model was established to assess the in vivo therapeutic efficacy of BHT combined with amoxicillin.The combination therapy alleviated pulmo-nary tissue damage,reduced bacterial loads in target organs(liver,spleen,and lungs),and decreased systemic inflammatory responses.This study elucidates the synergistic antimicrobial action and mechanistic basis of BHT combined with amoxicillin,offering a novel combinatorial therapeutic strategy to address MRSA resistance.The findings hold significant clinical potential and research value for overcoming antibiotic resistance in MRSA infections.

Objective:To investigate the clinical significance of CD105 and erythropoietin-producing hepatocellular receptor A2 (EPHA2) expressions in breast invasive ductal carcinoma and the effects of the combination of diabetes mellitus on CD105 and EPHA2 expressions.Methods:A retrospective case series study was conducted. A total of 74 patients with breast invasive ductal carcinoma in Affiliated Hospital of Jiangsu University from June 2019 to June 2024 were selected, and paraffin specimens from the patients after surgery were collected. Immunohistochemistry SP method was used to detect the expressions of CD105 and EPHA2 proteins in specimens. CD105 expression was expressed as the number of CD105 labeled microvessels, and EPHA2 expression was expressed as the proportion of EPHA2 positive expression area. The correlation of CD105 and EPHA2 expressions with the clinicopathological characteristics and diabetes mellitus of patients, as well as the relationship between the expressions of CD105 and EPHA2 were analyzed. Cox proportional hazards model was used to make univariate and multivariate analysis of the factors influencing overall survival of patients.Results:All 74 patients were female. The median age was 60 years old, 44 patients (59.46%) had tumor grade ≥ grade 3, 36 patients (48.65%) had tumor diameter ≥ 2 cm, 28 patients (37.84%) had lymph node metastasis, 30 patients (40.54%) had nerve vessel invasion, and 32 patients (43.24%) had diabetes mellitus. There were statistically significant differences in the proportion of patients with different age, tumor diameter, TNM stage, lymph node metastasis or not and nerve vessel invasion or not between diabetes mellitus group and non-diabetes mellitus group (all P < 0.05). The number of CD105 marking the microvessel was (32±9) and (24±8), respectively in diabetes mellitus group and non-diabetes mellitus group, and the difference was statistically significant ( t = 3.63, P < 0.010); the positive expression area proportion of EPHA2 was (19±5)% and (15±4)%, respectively, and the difference was statistically significant ( t = 3.85, P < 0.010). The expression of CD105 was related to the duration of diabetes mellitus, tumor diameter, TNM stage and lymph node metastasis or not (all P < 0.05), and the expression of EPHA2 was related to tumor diameter and TNM stage (all P < 0.05). Pearson correlation analysis showed a positive correlation between CD105 and EPHA2 expression ( r = 0.75, P < 0.001). The differences in overall survival of patients with or without diabetes mellitus and patients with different CD105 and EPHA2 expressions were statistically significant (all P < 0.05). Multivariate analysis showed that CD105 expression ( HR = 1.10, 95% CI: 1.04-1.16, P = 0.001) and EPHA2 expression ( HR = 1.35, 95% CI: 1.10-1.66, P = 0.005) were independent factors influencing the overall survival of patients with breast invasive ductal carcinoma. Conclusions:The expressions of CD105 and EPHA2 are independent prognostic factors in patients with breast invasive ductal carcinoma, and diabetes mellitus can promote the expressions of CD105 and EPHA2, which may increase the risk of poor prognosis.

To identify the bacterial pathogens in a case of goat respiratory disease in Yunnan prov-ince,three Gram-negative,rod-shaped bacteria strains,YN240861,YN240862 and YN240863,were isolated from lung samples of three diseased goats with respiratory disease,and the identifications of the biochemical and the sequence similarity and phylogeny of 16S rDNA gene,and the analyses of the pathogenicity and antimicrobial susceptibility were studied.The results of the bacterial iden-tification indicated that the most biochemical characteristics of the three isolates were identical with those of the Histophilus somni(H.somni)type stain ATCC 43625T and the other reference strains of H.somni.The three strains had the 16S rDNA sequence similarity of 97.7％with H.som-ni type strain ATCC 43625T,and shared the 16S rDNA sequence similatiies of 99.4％-99.9％with the other H.somni reference strains.The three strains formed the same branch with all the H.som-ni reference strains in the 16S rDNA gene sequence phylogenetic tree.Based on these identification results,the three strains were identified as H.somni.The mouse pathogenicity test showed that each of the three strains had the median lethal dose(LD50)≤7.6×10 5 CFU in mice,which indica-ted that the three stains have higher pathogenicity to mice.The results of the antimicrobial suscep-tibility test indicated that the three strains were sensitive to ampicillin of penicillins,cefazolin and ceftriaxone of cephalosporins,chloramphenicol and florfenicol of chloramphenicols,kanamycin and gentamicin of aminoglycosides,and ofloxacin of quinolones.The strain YN240862 was resistant to sulfamethoxazole of sulfonamides.To our knowledge,this is the first isolation of Hi.somni in Chi-na,and confirmed the presence of H.somni infection in goats in China,which provides the basic da-ta for the prevention and treatment of H.somni infection in goats in China.