Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in Ampelopsis grossedentata (A. grossedentata), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE^-/-) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM's anti-AAA action is linked to heme oxygenase (HO)-1 (Hmox-1 for the rodent gene) and hypoxia-inducible factor (HIF)-1α in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific Hmox1 knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of Hmox-1 by triggering the nuclear translocation and activation of HIF-1α, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.

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:Electromyographic biofeedback therapy has demonstrated unique advantages of non-invasive,real-time feedback,personalized treatment and promotion of neuroplasticity,and can promote the recovery of motor function in patients with spinal cord injury.OBJECTIVE:To review the current application status and therapeutic effects of electromyographic biofeedback combined with exercise therapy,robotic exoskeletons,and virtual reality technology in the recovery of motor function after spinal cord injury.METHODS:Relevant literature was retrieved from CNKI and PubMed databases up to May 2024.The search terms included"spinal cord injury,EMG biofeedback,physical therapy,robotic exoskeleton,VR,motor function,exercise"in both English and Chinese.Finally,71 articles were included for review.RESULTS AND CONCLUSION:Mechanisms by which electromyographic biofeedback therapy promotes spinal cord injury rehabilitation include promoting neural plasticity changes,strengthening neuromuscular connections and improving movement patterns.Electromyographic biofeedback,as an emerging tool for treating spinal cord injury,is often used in conjunction with other therapeutic methods,including exercise therapy,robotic exoskeletons,and VR,to promote the recovery of motor function after spinal cord injury.The effectiveness of combination therapy has been significantly improved.However,there are still some problems and challenges,such as the lack of detailed analysis of the mechanism,the lack of large-scale trials that provide strong evidence for combined efficacy,and the limited adaptability of the technology.Future research can focus on these aspects:to improve the personalization and accuracy of electromyographic biofeedback;to develop new rehabilitation equipment and expand the application areas of electromyographic biofeedback combined with more advanced technologies or engineering equipment;to apply electromyographic biofeedback to gait training systems,respiratory training systems,and limb-linkage rehabilitation systems,so as to improve the accuracy of the feedback and the effect of personalized treatment plans.At the same time,the ease of use and comfort of the equipment will be improved.

This study investigated the prevalence and potential mechanisms of gentamicin heterore-sistance in Streptococcus isolates from dairy cows.In this study,A total of 39 Streptococcus isola-ted from raw milk were collected,and the minimum inhibitory concentration(MIC)of gentamicin and other drugs on the isolates was determined by micro broth dilution method,and the K-B paper diffusion method,colony analysis profile(PAP),and resistance stability test were used to investigate the heteroresistance characteristics of Streptococcus,and the mechanism of heteroresis-tance was analyzed based on whole genome sequencing and resequencing.Seven suspected heterore-sistance strains were identified by K-B paper diffusion method,accounting for 17.95％(7/39)of the total number of suspected strains.PAP confirmed that the MIC to MNIC ratio of L147,L108 and L174 was greater than 8,and the frequency of resistant subgroups ranged from 1.38×10-5 to 8.18 × 10-5,which was greater than 1 × 10-7,confirming that they were heteroresistance strains.Resistance stability tests revealed that the resistant subpopulations of all three strains were not stably inherited.Whole-genome sequencing revealed mutations in the ribosomal target genes of aminoglycoside antibiotics,rsmA,rsmB and rsmE,compared with the reference genome,which may lead to heteroresistance to gentamicin in Streptococcus.The occurrence of heteroresistance of Streptococcus to gentamicin is high in dairy sources,so more attention should be paid to the occur-rence of heteroresistance when using gentamicin for clinical treatment.

This study investigated the prevalence and potential mechanisms of gentamicin heterore-sistance in Streptococcus isolates from dairy cows.In this study,A total of 39 Streptococcus isola-ted from raw milk were collected,and the minimum inhibitory concentration(MIC)of gentamicin and other drugs on the isolates was determined by micro broth dilution method,and the K-B paper diffusion method,colony analysis profile(PAP),and resistance stability test were used to investigate the heteroresistance characteristics of Streptococcus,and the mechanism of heteroresis-tance was analyzed based on whole genome sequencing and resequencing.Seven suspected heterore-sistance strains were identified by K-B paper diffusion method,accounting for 17.95％(7/39)of the total number of suspected strains.PAP confirmed that the MIC to MNIC ratio of L147,L108 and L174 was greater than 8,and the frequency of resistant subgroups ranged from 1.38×10-5 to 8.18 × 10-5,which was greater than 1 × 10-7,confirming that they were heteroresistance strains.Resistance stability tests revealed that the resistant subpopulations of all three strains were not stably inherited.Whole-genome sequencing revealed mutations in the ribosomal target genes of aminoglycoside antibiotics,rsmA,rsmB and rsmE,compared with the reference genome,which may lead to heteroresistance to gentamicin in Streptococcus.The occurrence of heteroresistance of Streptococcus to gentamicin is high in dairy sources,so more attention should be paid to the occur-rence of heteroresistance when using gentamicin for clinical treatment.

BACKGROUND:Electromyographic biofeedback therapy has demonstrated unique advantages of non-invasive,real-time feedback,personalized treatment and promotion of neuroplasticity,and can promote the recovery of motor function in patients with spinal cord injury.OBJECTIVE:To review the current application status and therapeutic effects of electromyographic biofeedback combined with exercise therapy,robotic exoskeletons,and virtual reality technology in the recovery of motor function after spinal cord injury.METHODS:Relevant literature was retrieved from CNKI and PubMed databases up to May 2024.The search terms included"spinal cord injury,EMG biofeedback,physical therapy,robotic exoskeleton,VR,motor function,exercise"in both English and Chinese.Finally,71 articles were included for review.RESULTS AND CONCLUSION:Mechanisms by which electromyographic biofeedback therapy promotes spinal cord injury rehabilitation include promoting neural plasticity changes,strengthening neuromuscular connections and improving movement patterns.Electromyographic biofeedback,as an emerging tool for treating spinal cord injury,is often used in conjunction with other therapeutic methods,including exercise therapy,robotic exoskeletons,and VR,to promote the recovery of motor function after spinal cord injury.The effectiveness of combination therapy has been significantly improved.However,there are still some problems and challenges,such as the lack of detailed analysis of the mechanism,the lack of large-scale trials that provide strong evidence for combined efficacy,and the limited adaptability of the technology.Future research can focus on these aspects:to improve the personalization and accuracy of electromyographic biofeedback;to develop new rehabilitation equipment and expand the application areas of electromyographic biofeedback combined with more advanced technologies or engineering equipment;to apply electromyographic biofeedback to gait training systems,respiratory training systems,and limb-linkage rehabilitation systems,so as to improve the accuracy of the feedback and the effect of personalized treatment plans.At the same time,the ease of use and comfort of the equipment will be improved.

Objective:To develop a risk prediction model of acute cerebral infarction (ACI) in patients with type 2 diabetes mellitus (T2DM).Methods:It was a cross-sectional study. The clinical data of 798 patients with T2DM hospitalized in the Department of Endocrinology and Neurology of Shanxi Bethune Hospital from August 2021 to October 2023 were collected. Based on whether they had concurrent ACI, the patients were divided into T2DM with ACI group (case group) and pure T2DM group (control group). The patients were then allocated to a training set ( n=558) and a validation set ( n=240) in a 7∶3 ratio by the sample functions in R software. LASSO regression was employed to screen and optimize variables, and a multivariate logistic regression analysis was used to establish the nomogram prediction model. The discriminative ability, calibration, and clinical usefulness of the risk prediction model were assessed with receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis, respectively. Results:LASSO regression identified gender, age, systolic blood pressure, fasting plasma glucose (FPG), albumin (ALB), and carotid vascular condition as the variables for prediction. The multivariable logistic regression analysis showed that female ( OR=0.489, 95% CI: 0.308-0.778) and ALB ( OR=0.846, 95% CI: 0.795-0.901) were protective factors for ACI occurrence in T2DM patients, while age ( OR=1.051, 95% CI:1.025-1.077), systolic blood pressure ( OR=1.047, 95% CI: 1.034-1.059), FPG ( OR=1.185, 95% CI: 1.089-1.288), and carotid plaque ( OR=7.359, 95% CI: 3.050-17.756) were risk factors. The area under the ROC curve (AUC) for risk of ACI in the training set was 0.863(95% CI: 0.833-0.893), and it was 0.846(95% CI: 0.797-0.896) for the validation set. Calibration curves and the Hosmer-Lemeshow goodness-of-fit test indicated good model fit (training set χ2=8.311, P=0.404; validation set χ2=3.957, P=0.861). Decision curve analysis showed that the clinical effectiveness of the model was higher when the threshold probabilities of the training set and the validation set was 0.02-0.93 and 0.12-0.99, respectively. Conclusion:In this study, a prediction model of ACI risk in T2DM patients was successfully established.

Objective To investigate the relationship between protein SUMOylation level and the prognosis of papillary thyroid carcinoma(PTC)in males.Methods Protein SUMOylation levels in PTC was analyzed by bioinformatics based on GTEx and TCGA databases and validated by immunohistochemical staining and Western blotting in our clinical pairs specimens.The mRNA expression of the protein SUMOylation associated genes were measured by fluorescent quantitative real-time polymerase chain reaction(qRT-PCR)in surgical pairs specimens.Results The expression level of SUMOylation in the tumor tissues of PTC showed an elevated trend(P＜0.05),and was associated with poor prognosis of the patients by TCGA and GTEx databases analysis(P=0.021).In the clinical samples of our hospital,it was verified that the level of SUMOylation in tumor tissues was higher than that of the paired non-tumor tissues(P＜0.05).However,qRT-PCR showed no significant changes in the transcriptional level of the protein SUMOylation associated genes in most cases.Conclusions Protein SUMOylation in thyroid tumor tissues were higher than that in paired non-tumor tissues,and the higher SUMOylation levels levels in tumor tissues were,the shorter overall survival time of the patients was.

Objective To investigate the differential expression of miR-124-3p in peripheral blood and clinical sig-nificance of patients with β-thalassemia.Methods Peripheral blood samples were collected from 33 patients with β-thalassemia and 30 healthy controls in Ningde Municipal Hospital Affiliated to Ningde Normal University from June 2021 to August 2022.The expression level of miR-124-3p was detected.Luciferase reporter gene was used to verify the interaction between miR-124-3p and ERF 3'UTR.The correlation between differential expression of miR-124-3p and β-thalassemia was analyzed and the clinical diagnostic value of miR-124-3p for β-thalassemia was eval-uated.Results Compared with healthy control individuals,the expression of miR-124-3p was significantly up-reg-ulated in patients with β-thalassemia(P＜0.001).The genotype of miR-124-3p high expression group was 84.2%β0(16/19),the genotype of low expression group was 55.6%β+(10/18).ROC curve analysis showed that miR-124-3p had predictive efficacy for β-thalassemia(AUC:0.842).Luciferase reporter gene analysis showed that ERF gene was the regulatory target of miR-124-3p.Conclusions The differential expression of miR-124-3p in patients with β-thalassemia is closely related to the genotype and clinical severity of thalassemia,and ERF is negatively reg-ulated by miR-124-3p.miR-124-3p may be an effective diagnostic biomarker for β-thalassemia.

Objective To explore the effects of deletion of protein 4.1R on hepatocyte proliferation,apoptosis,and glycolysis and the molecular mechanisms.Methods A 4.1R-/-HL-7702 cell line was constructed using CRISPR/Cas9 technique,and with 4.1R+/+HL-7702 cells as the control,its proliferative capacity and cell apoptosis were assessed using CCK-8 assay,EdU-488 staining,flow cytometry and Annexin V-FITC/PI staining at 24,48,72 h of cell culture.The changes in glucose uptake,lactate secretion,ATP production and pH value of the culture supernatant of 4.1R-/-HL-7702 cells were determined.The mRNA expressions of the key regulatory enzymes HK2,PFKL,PKM2 and LDHA in glycolysis were detected with qRT-PCR,and the protein expressions of AMPK,p-AMPK,Raptor and p-Raptor were determined using Western blotting.Results Western blotting and sequencing analysis both confirmed the successful construction of 4.1R-/-HL-7702 cell line.Compared with the wild-type cells,4.1R-/-HL-7702 cells exhibited a lowered proliferative activity with increased cell apoptosis.The deletion of protein 4.1R also resulted in significantly decreased glucose uptake,lactate secretion and ATP production of the cells and increased pH value of the cell culture supernatant.qRT-PCR showed significantly decreased mRNA expressions of the key regulatory enzymes in glycolysis in 4.1R-/-HL-7702 cells.Compared with those in HL-7702 cells,the expression levels of AMPK and Raptor proteins were decreased while the expression levels of p-AMPK and p-Raptor proteins increased significantly in 4.1R-/-HL-7702 cells.Conclusion Deletion of protein 4.1R in HL-7702 cells results in reduced proliferative capacity,increased apoptosis and suppression of glycolysis,and this regulatory mechanism is closely related with the activation of the downstream AMPK-mTORC1 signaling pathway.