The excessive accumulation of advanced glycosylation end products(AGEs), the end products of non-enzymatic glycosylation reactions, can be involved in the pathological processes of various ocular diseases through mechanisms such as oxidative stress, inflammatory responses and apoptosis. In this paper, we systematically reviewed the key role of AGEs in diabetic keratopathy, cataract, glaucoma, age-related macular degeneration(ARMD)and diabetic retinopathy(DR). It was found that AGEs activate signalling pathways such as NADPH oxidase, MAPK and NF-κB by binding to the receptor RAGE, leading to reactive oxygen species(ROS)generation, release of inflammatory factors, and vascular endothelial dysfunction, which in turn induces delayed corneal healing, cross-linking of lens proteins, optic nerve degeneration, formation of choroidal neovascularisation(CNV), and blood-retinal barrier(BRB)disruption. For example, in diabetic keratopathy, AGEs delay wound healing via the ROS/NLRP3 inflammatory vesicle axis; in cataract, ascorbic acid-mediated cross-linking of lens proteins due to AGEs directly impairs lens transparency; and in DR, AGEs exacerbate microvascular damage by regulating vasucular endothelial growth factor(VEGF)expression and pericyte apoptosis. In addition, this article discusses the advances and limitations of AGEs detection techniques, such as the potential application of lens AGEscan fluorescence assay in screening for diabetic complications, and the need to develop tissue-specific assays for aqueous humour and vitreous. For therapeutic strategies, the research directions of inhibiting AGEs production, blocking RAGE signalling pathway and developing anti-glycosylation drugs are proposed to emphasise their clinical value in delaying disease progression. This review not only integrates the molecular mechanisms and clinical associations of AGEs in ocular diseases, but also provides a theoretical basis for targeted interventions, which is of great significance in exploring novel diagnostic and therapeutic strategies.

Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes.Among these,the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells.Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs.Several preclinical and clinical studies have revealed that the development pathway of B cells,and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites.Therefore,summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.

【Objective】 To measure and analyze foot development indicators of children under 3 years old, in order to provide basis for the correct clinical assessment of children foot development. 【Methods】 A total of 5 894 children under 3 years old who took physical examination in the Child Health Care Department of Xi′an People′s Hospital from August 2022 to March 2023 were randomly selected. Foot length, foot width, the ratio of foot width to length and arch index were measured by image processing system, and were compared among different age groups and sex groups. 【Results】 1) Foot length, foot width and arch index of children under 3 years old increased significantly with age, while the ratio of foot width to length decreased significantly with age(F=1 345.23, 396.21,184.65, 287.03, P<0.05). 2) There was no statistical significance in foot length, foot width and arch index between left and right foot of children under 3 years old(P>0.05). 3) Foot length and foot width of boys were greater than those of girls in all age groups, and the difference was statistically significant(tfoot length:3.45 - 10.19, tfoot width: 3.77 - 9.21, P<0.05). There was no significant difference in arch index between boys and girls in all age groups(P>0.05). 【Conclusion】 Foot shape of children under 3 years old changes with age, there are differences in foot length and width between boys and girls.

Objective:To develop three tDCS protocols based on the gait-related brain networks:the frontoparietal net-work(FPN),the dorsal-attention network(DAN),and the default network(DN),with the aim of specifical-ly modulating gait speed and gait variability and improving walking function. Method:In this study,healthy adults were recruited and randomly divided into 3 groups receiving different stimulation protocols:simultaneously enhancing the excitability of FPN and suppressing the excitability of DN(i.e.,FPN+/DN-tDCS),enhancing the excitability of DAN and suppressing the excitability of DN(i.e.,DAN+/DN-tDCS),and sham stimulation(Sham group).Normal,fast and dual-task gait tests were performed immediately before/after electrical stimulation,and spatiotemporal parameters and variability indicators of gait were collected.Two-way repeated measures ANOVA was used to assess the effects of three stimulation on gait characteristics under different conditions. Result:A total of 72 subjects were included in this study,64 of whom completed all tests.There were no significant interaction effects observed on gait spatiotemporal parameters in three conditions(normal,fast,dual-task walking conditions)and gait variability in normal walking between pre-and post-intervention assessments.In the fast gait task,there were significant interaction effects observed for stride length variability(F=3.671,P=0.031)and double support time variability(F=3.879,P=0.026).In the dual-task gait task,there were signif-icant interaction effects observed for stride width variability(F=3.940,P=0.025),gait speed variability(F=3.936,P=0.025),and double support time variability(F=4.913,P=0.011). Conclusion:The DAN+/DN-tDCS protocol were effective in reducing gait variability and improving gait stabili-ty during complex tasks in healthy adults.However,the FPN+/DN-tDCS protocol did not specifically improve gait speed under different conditions.

Objective:To investigate alterations in the glymphatic system of spinocerebellar ataxia type 3 (SCA3) patients based on quantitative MRI, and its association with genetic information and motor dysfunction.Methods:The study was a cross-sectional study. This prospective study recruited 39 confirmed SCA3 patients (SCA3 group) and 40 matched healthy controls (HC group) who were seen at the Southwest Hospital of Army Medical University from May 2017 to June 2023. All subjects underwent cranial MRI scanning. Clinical assessments were conducted on all participants using the scale for the assessment and rating of ataxia (SARA) and the international cooperative ataxia rating scale (ICARS). The automatic segmentation and volume measurement of the choroid plexus based on Freesurfer 6.0; the perivascular interstitial space (PVS) was automatically segmented based on the deep-learning model VB-Net, and the volume of the PVS in each brain region was quantified after manual correction. Independent samples t-test and Mann-Whitney U-test were used to analyze the changes in the class lymphatic system in the SCA3 group and the HC group. Pearson partial correlation analysis was used to explore the relationship between CAG repeats, the glymphatic system, and motor dysfunction. Results:The standardized choroid plexus volume in the SCA3 group was (1.24±0.36)×10 3 mm 3, and that in the HC group was (0.96±0.34)×10 3 mm 3, with a statistically significant difference ( t=4.01, P<0.001). PVS volumes in the frontal lobe, temporal lobe, parietal lobe, basal ganglia, cerebellum, thalamus, and brainstem regions in the SCA3 group were significantly higher than those of HC group ( P<0.05). Partial correlation analysis revealed that CAG repeats in SCA3 group were positively correlated with SARA, ICARS, and basal ganglia PVS volumes ( r=0.65, 0.58, 0.29; P=0.001, 0.001, 0.042). Cerebellar and temporal lobe PVS volumes were positively correlated with SARA ( r=0.59, 0.47; P=0.001, 0.003), and positively correlated with ICARS scores ( r=0.61, 0.40; P=0.001, 0.011). Choroid plexus volume was positively correlated with cerebellar and basal ganglia PVS volumes ( r=0.41, 0.31; P=0.009, 0.043). Conclusions:The glymphatic system of SCA3 patients have significant alteration and have association with CAG repeats and motor dysfunction.

Objective To evaluate the degree of brain atrophy in spinocerebellar ataxia type 3(SCA3)patients based on artificial intelligence(AI)technology,and to explore the correlation between the degree of brain atrophy and the severity of the disease.Methods The clinical and imaging data of 23 SCA3 patients(SCA3 group)and 24 healthy controls(HC)(HC group)were collected.The International Cooperative Ataxia Rating Scale(ICARS)was used to evaluate the severity of ataxia in patients with SCA3.AI technology was used to process the 3D-T1 WI MR image data of the SCA3 and HC groups to segment and measure the volume and volume percentage of brain,followed by correlation analyses between brain structural alterations and the severity of ataxia in SCA3 patients.Results There were no significant differences in gender and age between the two groups(P＞0.05).The SCA3 group had a significant reduction in the volume and volume percentage of various brain regions,such as the frontal,temporal,parietal,occipital,limbic,right cerebral white mat-ter,subcortical gray matter,cerebellum and brainstem,compared to the HC group(multiple hypothesis testing adjusted P＜0.01).In the SCA3 group,the ICARS showed positive correlation with patient age(r=0.571,P=0.004)and negative correlation with the vol-ume of the left cerebellar white matter,vermis,medulla oblongata,and the volume percentages of bilateral cerebellar white matter,vermis,pons,medulla oblongata(P＜0.05).Conclusion The significant atrophy of the supratentorial and subtentorial regions of the brain in SCA3 patients.The globus pallidus exhibits the most substantial atrophy,suggesting its potential as an imaging diagnostic marker of SC A3.

BACKGROUND: Changes in white matter (WM) underlie the neurocognitive damages induced by a human immunodeficiency virus (HIV) infection. This study aimed to examine using a bundle-associated fixel-based analysis (FBA) pipeline for investigating the microstructural and macrostructural alterations in the WM of the brain of HIV patients. METHODS: This study collected 93 HIV infected patients and 45 age/education/handedness matched healthy controls (HCs) at the Beijing Youan Hospital between January 1, 2016 and December 30, 2016.All HIV patients underwent neurocognitive evaluation and laboratory testing followed by magnetic resonance imaging (MRI) scanning. In order to detect the bundle-wise WM abnormalities accurately, a specific WM bundle template with 56 tracts of interest was firstly generated by an automated fiber clustering method using a subset of subjects. Fixel-based analysis was used to investigate bundle-wise differences between HIV patients and HCs in three perspectives: fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC). The between-group differences were detected by a two-sample t -test with the false discovery rate (FDR) correction ( P <0.05). Furthermore, the covarying relationship in FD, FC and FDC between any pair of bundles was also accessed by the constructed covariance networks, which was subsequently compared between HIV and HCs via permutation t -tests. The correlations between abnormal WM metrics and the cognitive functions of HIV patients were explored via partial correlation analysis after controlling age and gender. RESULTS: Among FD, FC and FDC, FD was the only metric that showed significant bundle-wise alterations in HIV patients compared to HCs. Increased FD values were observed in the bilateral fronto pontine tract, corona radiata frontal, left arcuate fasciculus, left corona radiata parietal, left superior longitudinal fasciculus III, and right superficial frontal parietal (SFP) (all FDR P <0.05). In bundle-wise covariance network, HIV patients displayed decreased FD and increased FC covarying patterns in comparison to HC ( P <0.05) , especially between associated pathways. Finally, the FCs of several tracts exhibited a significant correlation with language and attention-related functions. CONCLUSIONS Our study demonstrated the utility of FBA on detecting the WM alterations related to HIV infection. The bundle-wise FBA method provides a new perspective for investigating HIV-induced microstructural and macrostructural WM-related changes, which may help to understand cognitive dysfunction in HIV patients thoroughly.
Humans ; HIV ; HIV Infections ; Cognition ; Brain ; White Matter

OBJECTIVES: Multiple myeloma (MM) is a plasma cell malignancy occurring in middle and old age. MM is still an incurable disease due to its frequent recurrence and drug resistance. However, its pathogenesis is still unclear. Abnormal amino acid metabolism is one of the important characteristics of MM, and the important metabolic pathway of amino acids participates in protein synthesis as basic raw materials. Aminoacyl transfer ribonucleic acid synthetase (ARS) gene is a key regulatory gene in protein synthesis. This study aims to explore the molecular mechanism for ARS, a key factor of amino acid metabolism, in regulating amino acid metabolism in MM and affecting MM growth. METHODS: The corresponding gene number was combined with the gene expression profile GSE5900 dataset and GSE2658 dataset in Gene Expression Omnibus (GEO) database to standardize the gene expression data of ARS. GSEA_4.2.0 software was used to analyze the difference of gene enrichment between healthy donors (HD) and MM patients in GEO database. GraphPad Prism 7 was used to draw heat maps and perform data analysis. Kaplan-Meier and Cox regression model were used to analyze the expression of ARS gene and the prognosis of MM patients, respectively. Bone marrow samples from 7 newly diagnosed MM patients were collected, CD138⁺ and CD138^- cells were obtained by using CD138 antibody magnetic beads, and the expression of ARS in MM clinical samples was analyzed by real-time RT-PCR. Human B lymphocyte GM12878 cells and human MM cell lines ARP1, NCI-H929, OCI-MY5, U266, RPMI 8266, OPM-2, JJN-3, KMS11, MM1.s cells were selected as the study objects. The expression of ARS in MM cell lines was analyzed by real-time RT-PCR and Western blotting. Short hairpin RNA (shRNA) lentiviruses were used to construct gene knock-out plasmids (VARS-sh group). No-load plasmids (scramble group) and gene knock-out plasmids (VARS-sh group) were transfected into HEK 293T cells with for virus packaging, respectively. Stable expression cell lines were established by infecting ARP1 and OCI-MY5 cells, and the effects of knockout valyl-tRNA synthetase (VARS) gene on proliferation and apoptosis of MM cells were detected by cell counting and flow cytometry, respectively. GEO data were divided into a high expression group and a low expression group according to the expression of VARS. Bioinformatics analysis was performed to explore the downstream pathways affected by VARS. Gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) and high performance liquid chromatography (HPLC) were used to detect the valine content in CD138⁺ cells and ARP1, OCI-MY5 cells and supernatant of knockdown VARS gene in bone marrow samples from patients, respectively. RESULTS: Gene enrichment analysis showed that tRNA processing related genes were significantly enriched in MM compared with HD (P<0.0001). Further screening of tRNA processing-pathway related subsets revealed that cytoplasmic aminoacyl tRNA synthetase family genes were significantly enriched in MM (P<0.0001). The results of gene expression heat map showed that the ARS family genes except alanyl-tRNA synthetase (AARS), arginyl-tRNA synthetase (RARS), seryl-tRNA synthetase (SARS) in GEO data were highly expressed in MM (all P<0.01). With the development of monoclonal gammopathy of undetermined significance (MGUS) to MM, the gene expression level was increased gradually. Kaplan-Meier univariate analysis of survival results showed that there were significant differences in the prognosis of MM patients in methionyl-tRNA synthetase (MARS), asparaginyl-tRNA synthetase (NARS) and VARS between the high expression group and the low expression group (all P<0.05). Cox regression model multivariate analysis showed that the high expression of VARS was associated with abnormal overall survival time of MM (HR=1.83, 95% CI 1.10 to 3.06, P=0.021). The high expression of NARS (HR=0.90, 95% CI 0.34 to 2.38) and MARS (HR=1.59, 95% CI 0.73 to 3.50) had no effect on the overall survival time of MM patients (both P>0.05). Real-time RT-PCR and Western blotting showed that VARS, MARS and NARS were highly expressed in CD138⁺ MM cells and MM cell lines of clinical patients (all P<0.05). Cell counting and flow cytometry results showed that the proliferation of MM cells by knockout VARS was significantly inhibited (P<0.01), the proportion of apoptosis was significantly increased (P<0.05). Bioinformatics analysis showed that in addition to several pathways including the cell cycle regulated by VARS, the valine, leucine and isoleucine catabolic pathways were upregulated. Non-targeted metabolomics data showed reduced valine content in CD138⁺ tumor cells in MM patients compared to HD (P<0.05). HPLC results showed that compared with the scramble group, the intracellular and medium supernatant content of ARP1 cells and the medium supernatant of OCI-MY5 in the VARS-shRNA group was increased (all P<0.05). CONCLUSIONS MM patients with abnormal high expression of VARS have a poor prognosis. VARS promotes the malignant growth of MM cells by affecting the regulation of valine metabolism.
Humans ; Valine-tRNA Ligase ; Multiple Myeloma/genetics* ; Metabolomics ; Amino Acids ; RNA, Transfer

OBJECTIVE To observe the efficacy and safety of ceftazidime and avibactam sodium （CAZ/AVI） in the treatment of carbapenem-resistant organism （CRO） infection. METHODS The information of patients with CRO infection admitted to the Second Affiliated Hospital of Soochow University from September 2019 to March 2022 was collected， and the patients were retrospectively divided into observation group （48 cases） and control group （48 cases） according to the treatment plan. The control group was given Polycolistin B sulfate for injection intravenously at a dose of 500 000 U every 12 hours； no dose adjustment was performed in patients with renal insufficiency or receiving continuous renal replacement therapy （CRRT）. The observation group was given continuous micropump of CAZ/AVI for injection intravenously at a dose of 2.5 g every 8 hours for 2 continous hours； among them， the patients with renal insufficiency received an adjusted dose based on creatinine clearance， and no dose adjustment was performed in patients receiving CRRT. The clinical efficacy and microbiological efficacy as well as body temperature， white blood cell （WBC）， C-reactive protein （CRP） and procalcitonin （PCT） before and after treatment were compared between 2 groups. The prognosis and the occurrence of adverse drug reactions were recorded. The factors influencing the clinical efficacy were screened by Logistic regression analysis. RESULTS The effective rate and microbial clearance rate of the observation group were significantly higher than the control group （P＜0.05）. After treatment， body temperature， PCT and CRP of 2 groups were significantly lower than before treatment， and CRP of the observation group was significantly lower than the control （No.SDFEYJLC2105） group （P＜0.05）. There was no statistically significant differencebetween the two groups in terms of rehabilitation discharge rate， the proportion of patients transferred to general wards，the proportion of dead patients， and the total incidence ofadverse drug reactions （P＞0.05）. CAZ/AVI and prolonging therapy duration were more likely to achieve clinical benefits （odds ratios of 1.146， 7.707，P＜0.05）， while lung infection and CRRT may be independent risk factors for treatment failure （odds ratios of 0.182， 0.236， P＜0.05）. CONCLUSIONS CAZ/AVI has good efficacy and safety in the treatment of CRO infection， the appropriate extension of antibacterial treatment time can achieve a higher clinical response rate， while lung infection or CRRT may lead to treatment failure.

To investigate the effect of Zhiwei Fuwei Pills (ZWFW) on the expression of mammalian target of rapamycin (mTOR)/autophagy key molecule yeast Atg6 homologue (Beclin1)/microtubuleassociated protein 1 light chain 3 (LC3) signaling axis key molecules in gastric antrum tissue of rats with precancerous gastric lesions (PLGC). METHODS: SPF SD rats were randomly divided into normal group, model group, folic acid group, ZWFW low-dose, medium-dose, high-dose group. In addition to the normal group, the model group, folic acid group, ZWFW low-dose, medium-dose and high-dose groups, were used to establish the PLGC rat model by five factors compound modeling methods: N-methyl-N ' - nitro-n-nitroguanidine (MNNG) combined with hunger and satiation, ethanol intragastric administration, free drinking of ammonia and ranitidine feed. The rats were treated with normal saline, folic acid tablet aqueous solution (0.002 g/kg), ZWFW low-dose, medium-dose, high-dose aqueous solution (0.42, 0.84, 1.67 g/kg) for 4 weeks, and the stomach was removed by laparotomy. Hematoxylineosin (HE) staining was used to observe the histopathological changes in the antrum of rats, and real-time polymerase chain reaction (real-time PCR), Western blot (WB) and immunohistochemistry (IHC) were used to detect the expression of mammalian target of rapamycin mTOR, yeast Atg6 homologue 1 (Beclin1), microtubule-associated protein 1 light chain 3β (LC3B) mRNA and protein in the antrum of rats. RESULTS: Compared with the normal group, the Gastric antrum tissue of the model group was distended, thinner gastric wall, palegastric mucosa, atrophic and flat folds, disordered course and nodules and vegetations were visible. HE staining showed that compared with the normal group, the gastric mucosal glands in the model group were crowded and disordered, and the cell morphology was different, including a large number of goblet cells, basophilic cytoplasm, large, hyper-chromatic and irregular nuclei, and mucosal muscle infiltration and destruction. Compared with the model group, treated by ZWFW can significantly improve the pathological manifestations of gastric mucosal gland structure disorder and cell atypia. Compared with the normal group, mTOR mRNA and protein expression were significantly increased (P< 0.05) and Beclin1 and LC3B mRNA and protein expression were significantly decreased (P<0.05) in the antral tissue of rats in the model group; compared with the model group, mTOR mRNA and protein expression were decreased (P<0.05) in the medium and high dose groups of ZWFW, Beclin1 and LC3B protein expression in the antral tissue of rats in the low dose group of ZWFW and Beclin1 and LC3B mRNA and protein expression were increased (P<0.05) in the medium and high dose groups. CONCLUSION: Zhiwei Fuwei Pills can significantly improve the abnormal histopathological findings of gastric mucosa in PLGC model rats, and the mechanism may be related to the down-regulation of mTOR expression, up-regulation of Beclin1 and LC3B expression and then promoting autophagy.