Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from ¹³C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Objective·To evaluate the changes in cognitive function in overweight and obese adolescents,and explore the association between cognitive function and fibroblast growth factor 21(FGF21).Methods·A total of 175 adolescents from a senior high school in Shanghai were divided into normal weight group(n=50),overweight group(n=50)and obese group(n=75)based on their body mass index(BMI).General information,anthropometric data and laboratory testing indicators of the adolescents were collected and compared.The cognitive function of the three groups of adolescents was assessed by using the accuracy(ACC)and reaction time of Flanker task and n-back task.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum FGF21 level of the three groups of adolescents.Partial correlation analysis and multiple linear regression model were used to evaluate the correlation between cognitive task performance and anthropometric data and laboratory testing indicators.Results·Compared with the normal weight group,systolic blood pressure,diastolic blood pressure,and the levels of fasting plasma glucose,glycosylated hemoglobin and triacylglycerol in the obese group were higher(all P<0.05).Under congruent or incongruent stimulus conditions in the Flanker task,there was no significant difference in ACC between any two groups;compared with the normal weight and overweight groups,the reaction time of the adolescents in the obese group was prolonged(all P<0.05).In the n-back task,there were no significant differences in ACC between any two groups,while the obese group had longer reaction time in the 1-back and 2-back tasks compared to the normal weight and overweight groups(all P<0.05).Compared with the normal weight group,serum FGF21 levels of the adolescents in the obese group were higher(P=0.000).Partial correlation analysis showed that the reaction time of the adolescents in Flanker and n-back tasks was correlated with their BMI,body fat mass,waist circumference,waist-to-hip ratio and FGF21 level(all P<0.05).Multiple linear regression analysis further confirmed that BMI was associated with prolonged reaction time in cognitive-related behavioral tasks in the adolescents(all P<0.05),and FGF21 level was associated with ACC in the 2-back task(P=0.000)and reaction time in the incongruent stimulus condition(P=0.048).Conclusion·Overweight and obese adolescents have cognitive impairments,and BMI and serum FGF21 levels are associated with changes in their cognitive function.

Objective To analyze the infectious indicators,HBV s gene mutations and changes in bioinformatics char-acteristics of HBV DNA+/HBsAg-blood donor.Methods A sample of HBV DNA+/HBsAg-was screened by PCR meth-od,and HBsAg/HBsAb/HBeAg/HBeAb/HBcAb of HBV in the sample were detected by ELISA and chemiluminescence methods.The mutation of the HBVs gene fragment in the sample was sequenced and analyzed,and the bioinformatics analy-sis was performed using analysis software.Results The sample showed HBV DNA+,HBsAg-,HBsAb+,HBeAg+,HBe-Ab-and HBcAb+,with an amino acid unit point mutation(P151L)occurred in the HBV s gene,and the spatial structure changed.Conclusion The spatial structural changes in the gene sequence of HBVs may be the reason for the appearance of serological HBsAg-/HBsAb+/HBV DNA+in the test results.

Objective:To investigate the influencing factors of pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC), and to compare the clinical prognosis of ESCC patients with and without pCR after NCRT (40 Gy/ 20F).Methods:Among patients enrolled in a prospective clinical study, 87 ESCC patients treated with NCRT followed by surgery in Tianjin Medical University Cancer Institute & Hospital between June 2015 and October 2019 were selected. They were divided into the pCR ( n=35) and non-pCR groups ( n=52). Clinicopathological characteristics were retrospectively analyzed and subsequent follow-up was performed. Clinical prognosis and influencing factors were compared between two groups by using Kaplan-Meier and Cox regression analyses. Results:After NCRT, 40% of the ESCC patients could achieve pCR. Univariate analysis showed that patients in the pCR group had a disease-free survival (DFS) of 39.3 months and an overall survival (OS) of 64.0 months. In comparison, patients in the non-pCR group had a DFS of only 14.1 months and an OS of only 25.2 months. The differences were statistically significant (DFS: P<0.01, OS: P<0.05). Multivariate analysis revealed that whether pCR or not after NCRT, age, number of primary lesions, evaluation results after NCRT and postoperative pathological outcomes were important prognostic factors. The differences were statistically significant between two groups (all P<0.05). Conclusion:pCR after NCRT is significantly correlated with long-time survival of patients with ESCC, and pCR after NCRT has an important value in predicting clinical prognosis for long-term survival of ESCC patients.

Surgical resection and radiotherapy have been commonly applied to the treatment of early- and intermediate-stage Merkel cell carcinoma. In recent years, immunotherapy based on immunogenic characteristics of Merkel cell carcinoma has been proved to be effective in the treatment of advanced Merkel cell carcinoma. This review focuses on advances in the treatment of Merkel cell carcinoma, and provides a reference for its clinical diagnosis and treatment.

Ghrelin is a hormone produced by the stomach that regulates energy metabolism after acting on the central nervous system.Cocaine amphetamine-regulated transcriptional peptide(CART)neurons participate in the regulation of feeding behavior and energy balance.It is known that CART neurons are influenced by hormones to regulate energy homeostasis,but whether ghre-lin exerts its pro-appetite function by influencing CART neurons is unknown.Therefore,this study focuses on the role of VMHCART neurons in the regulation of feeding and relative body weight by ghrelin.Firstly,the whole brain expression of CART was determined by immunofluorescence.Then the effect of intraperitoneal injection of ghrelin on the expression of DMHCART neurons was evalua-ted.Finally,the ghrelin was delivered to DMH and the changes of food intake and relative body weight of mice were measured.CART immunoreactive neurons were detected in medial preoptic nucleus(MPA),arcuate nucleus(ARC),dorsomedial hypothalamic nucleus(DMH),thalamic pa-raventricular nucleus(PVT)and raphe nucleus(ROb).Compared with the control group,periph-eral injection of ghrelin significantly increased the expression of DMHC ART immunoreactive neurons(P=0.037 3).DMH long-term injection of ghrelin resulted in an increase in body weight(P=0.004 0)and feed intake(P=0.023 1).The results provide anatomical evidence for the whole brain distribution of CART,which proves that ghrelin affects feed intake and body weight of mice through CART neurons in DMH,suggesting that specific neuron types and regional specificity are involved in ghrelin regulation of feed intake and energy homeostasis.

This study aims to construct C57/B6-L and A549 cell lines that stably overexpress circu-lar RNA LAMP3(circLAMP3),laying the foundation for further research on the biological func-tions of circLAMP3.Total RNA was extracted and reverse transcripted into cDNA from C57/B6-L and A549 cells to amplify the full-length sequence of circLAMP3.Then,the fragments of cir-cLAMP3 were ligated into pLC5-ciR vector to obtain pLC5-Mouse-circLAMP3 and pLC5-Human-circLAMP3 recombinant plasmids.The lentiviruses expressing circLAMP3 were packaged on tran-sient transfected HEK293T cells.C57/B6-L and A549 cells were infected with lentiviruses to gen-erate cell lines overexpressing circLAMP3 through puromycin screening.To verify the overexpres-sion efficiency of circLAMP3 of cell lines,we performed the fluorescence microscopy,PCR amplifi-cation,quantitative PCR(qPCR),and Sanger sequencing experiments.The results indicated that the overexpression plasmids of pLC5-Mouse-circLAMP3 and pLC5-Human-circLAMP3 were suc-cessfully constructed.Strong green fluorescence was observed under a fluorescence microscopy.C57/B6-L and A549 cell lines showed a significant increase in the expression of circLAMP3 by PCR and qPCR methods.Sanger sequencing results showed that the junction site of circLAMP3 was correct.This study successfully constructed C57/B6-L and A549 cell lines overexpressing circLAMP3,providing biomaterials for further exploration of the biological function of circLAMP3 in influenza virus replication.

Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD. Methods: Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. Results: In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-β/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression. Conclusions Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.

Objective:To evaluate our self-designed pubic symphysis orthotic compression anatomic plate (PSOCAP) in the treatment of fractures and dislocations around the pubic symphysis.Methods:A retrospective study was conducted to analyze the 16 patients with fracture or dislocation around the pubic symphysis who had been treated by our self-designed PSOCAP at Department of Traumatic Surgery, Center for Orthopaedic Surgery, The Third Hospital Affiliated to Southern Medical University from January 2021 to June 2022. There were 8 males and 8 females with an age of (41±19) years. According to the Tile classification for pelvic fractures, there were 3 cases of type B1, 2 cases of type B3, 1 case of type C1.2, 4 cases of type C1.3, 3 cases of type C2, and 3 cases of type C3. There were 8 cases of pubic symphysis separation and 8 fractures of the pubic ramus (2 ones at Nakatani zone Ⅰ and 6 ones at Nakatani zone Ⅱ). Time from injury to surgery was 16 (11, 53) days, ranging from 4 to 348 days. The fractures or dislocations around the pubic symphysis were exposed by the modified Stoppa approach, reduced with the assistance of PSOCAP and fixated with PSOCAP; the posterior pelvic ring was reduced and fixated by corresponding surgical methods. Recorded were the surgical time, intraoperative bleeding, postoperative quality of fracture reduction, surgical complications, and functional recovery at the last follow-up concerning the pelvic anterior ring.Results:Surgery went on successfully in the 16 patients. Their surgical time was (58±15) min, ranging from 40 to 90 min, and their intraoperative bleeding 85 (63, 150) mL, ranging from 50 to 250 mL. According to the Matta scoring, the fracture reduction was evaluated as excellent in 10 cases, as good in 3 cases and as fair in 3 cases. The (10±3)-month follow-up for the 16 patients revealed complete fracture union for all after (12±2) weeks. According to the Majeed scoring at the last follow-up, the pelvic function was evaluated as excellent in 5 cases, as good in 7 cases, and as fair in 4 cases. No such postoperative complications as fracture displacement or internal fixation failure occurred.Conclusion:Owing to the biplane and integrated structure, our self-designed PSOCAP can help reduce the fractures or dislocations around the pubic symphysis to achieve anatomical reduction and strong internal fixation, leading to good clinical efficacy.

Objective:To investigate the surgical method of LC-II screws for fragility fractures of the pelvis (FFP) in the elderly and evaluate its clinical efficacy.Methods:A retrospective analysis was performed on 45 patients with FFPs operated in our department from January 2011 to January 2022. The clinical information was as follows. The FFP classification of pelvic fracture was IIIA in 26 cases and IIIB in 19 cases. Among them, 22 cases were fixed with closed reduction and modified LC-II screws (experimental group), and 23 cases were fixed with open reduction and reconstruction plates (control group). In the experimental group, there were 6 males and 16 females. The age range was 62-90 years, with an average of 73.2±9.2 years. The FFP classification of pelvic fracture was IIIA in 12 cases and IIIB in 10 cases. In the control group, there were 8 males and 15 females. The age range was 60-87 years, with an average of 72.8±6.6 years. FFP classification of pelvic fracture was IIIA in 14 cases and IIIB in 9 cases. After admission, pelvic X-ray and CT scan were performed, and the surgery was prepared. In the experimental group, after closed reduction of the posterior ring, the modified LC-II screw was inserted below the anterior inferior iliac spine (AIIS) toward the sacroiliac joint and penetrated the sacroiliac joint. For combined anterior ring fractures, the INFIX was used for anterior ring fixation. In the control group, the posterior ring was fixed with a reconstruction plate and/or sacroiliac screw after open reduction through the lateral rectus approach (LRA). The clinical efficacy was evaluated between the experimental group and the control group.Results:All 45 patients were successfully operated and followed up for 6 months to 3 years. All the pelvic fractures healed. In the experimental group of 22 cases, the time from injury to operation was 3-9 days, with an average of 5.8±1.9 days; the operation time was 25-70 min, with an average of 42.0±12.9 min. The intraoperative bleeding was 20-40 ml, with an average of 29.1±6.7 ml. According to the X-ray reduction evaluation criteria of Matta, 7 cases were excellent, 11 cases were good and 4 cases were medium, with an excellent and good rate of 81.8%. According to rehabilitation criteria of Majeed, 10 cases were excellent, 6 cases were good and 6 cases were fair, with a total excellent and good rate of 72.7%. At the last follow-up, sacroiliac joint pain was evaluated by VAS score: 0 in 10 cases, <3 in 7 cases, and 4-6 in 5 cases. No internal fixation loosening occurred. In the control group, the time from injury to operation was 5-20 days, with an average of 9.9±3.8 days; the operation time was 50-150 min, with an average of 89.1±29.5 min; the intraoperative bleeding was 220-1 000 ml, with an average of 509.2±214.3 ml. According to the X-ray reduction evaluation criteria of Matta, 16 cases were excellent, 4 cases were good and 3 cases was medium, with an excellent and good rate of 87.0%. According to rehabilitation criteria of Majeed, 12 cases were excellent, 6 cases were good and 7 cases were fair, with a total excellent and good rate of 78.3%. At the last follow-up, sacroiliac joint pain was evaluated by VAS score: 0 in 14 cases, <3 in 6 cases, and 4-6 in 3 cases. In the control group, posterior ring plate loosening was found in 2 cases and anterior ring pubic ramus plate and screw loosening was found in 4 cases, but there was no reduction loss.Conclusion:The modified LC-II screw is theoretically feasible in the treatment of FFP. Preliminary clinical results show good safety and efficacy, providing a new idea for minimally invasive treatment of FFP.