ObjectiveTo investigate the association between noninvasive liver fibrosis markers and carotid plaque （CP） in patients with lean metabolic dysfunction-associated fatty liver disease （MAFLD）， and to provide a basis for screening high-risk populations. MethodsA total of 957 patients with lean MAFLD who underwent physical examination in Subei People’s Hospital from January 2021 to June 2023 was enrolled as the observation cohort， with the presence or absence of CP as the outcome， and fibrosis-4 （FIB-4） index and nonalcoholic fatty liver disease fibrosis score （NFS） were used to assess liver fibrosis degree. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical data between two groups. The multivariate logistic regression analysis， the restricted cubic spline analysis， the receiver operating characteristic curve， and the mediation effect analysis were used to investigate the association between liver fibrosis degree and CP. ResultsThe prevalence rate of CP was 36.6% in the lean MAFLD population. Compared with the non-CP group（n=607）， the CP group （n=350） had a significantly higher proportion of male patients， a significantly higher proportion of patients with smoking/diabetes/hypertension， and significantly higher levels of age， creatinine， blood urea nitrogen， triglycerides， fasting blood glucose， aspartate aminotransferase， aspartate aminotransferase/alanine aminotransferase ratio， NFS， and FIB-4 index， as well as significantly lower levels of platelet count and albumin （all P<0.05）. The multivariate logistic regression analysis showed that after adjustment for confounding factors， FIB-4 index （odds ratio［OR］=2.979， 95% confidence interval［CI］：2.141 — 4.219， P<0.001） and NFS （OR=1.747， 95%CI： 1.499 — 2.046， P<0.001） were positively correlated with CP. Both FIB-4 index and NFS had a good value in predicting CP. Hypertension had a significant indirect effect on the prevalence rate of CP through its impact on liver fibrosis markers， and its mediating effect accounted for 39.5% — 40.8% of the total effect （P<0.001）. ConclusionIn patients with lean MAFLD， NFS and FIB-4 index are significantly positively correlated with the prevalence rate of CP， and they can be used as potential epidemiological predictive indicators. Liver fibrosis markers may play a mediating role in the association between hypertension and CP. Interventions targeting hypertension and liver fibrosis markers may help to prevent and delay the progression of CP.

Computational modeling is an invaluable tool for mechanism analysis, directed engineering, and rational design of biological parts, metabolic networks, and even cellular systems. It can provide new technological solutions to address biological challenges at different levels and has become a central focus of research in biomanufacturing. In the computational modeling of proteins, which are the key parts in biological systems, the traditional physics-based methods (computer software and mathematical model) have been widely used to study the physical and chemical processes in the functioning of proteins, and have thus been recognized as a powerful tool for understanding complex biological systems and guiding experimental designs. As the scale of computational modeling continues to expand, traditional modeling techniques face difficulties in balancing computational accuracy and speed. In recent years, the explosive growth of biological data has made it possible to construct high-performance artificial intelligence (AI) models, which brings new opportunities to the computational modeling of proteins, and the AI-enhanced physics-based computational modeling technologies have emerged. This combined strategy not only incorporates the chemical knowledge and established physical principles but also is powerful in data processing and pattern recognition, which greatly improves the computational efficiency and prediction accuracy, as well as possesses stronger interpretation ability, transferability, and robustness. The AI-enhanced physics-based computational modeling technologies have already shown great potential and value in biocatalysis, paving a new way for the future development of biomanufacturing.
Artificial Intelligence ; Proteins/chemistry* ; Computer Simulation ; Software ; Computational Biology/methods*

Under the background of forensic medicine becoming a first-level discipline,the opportuni-ties and challenges of discipline development coexist.Starting from the actual situation and characteris-tics of local medical colleges and universities,this paper discusses the problems and solutions for the development of forensic medicine discipline from the perspective of building a regional high-level medical university.Combined with the experiences of carrying out forensic medicine education in our college,this paper supplies our thoughts and practices on improving the discipline system,enhancing the ability to serve society,perfecting the talent cultivation model and promoting forensic culture,to provide reference and inspiration for the development of forensic medicine in other universities,jointly promote the advancement of forensic medicine in China to a new stage,and contribute the wisdom and strength of forensic medical experts to the construction of a law-based China,a safe China and a healthy China.

Objective To explore the role of miR-429 in synovial mesenchymal stem cell-derived exosomes(SMSC-Exos)in repairing cartilage damage in temporomandibular joint osteoarthritis(TMJ OA)by extracting SMSC-Exos from human synovial tissue and screening differentially expressed microRNA(miRNA)through transcriptome sequencing.Methods Human synovial tissues were obtained from 6 patients who underwent surgery at the First Medical Center of the Chinese PLA General Hospital from June to December 2023,including 3 patients with osteoarthritis(OA group)and 3 control patients(control group),all of whom were male.SMSC-Exos were extracted from the synovial tissues for miRNA sequencing and differential expression analysis.Further,Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were performed on the target genes of differentially expressed miRNA to identify key functional miRNA and construct miRNA-target gene regulatory networks and protein-protein interaction(PPI)networks of target genes.An in vitro model of rabbit condylar cartilage cell inflammatory microenvironment induced by interleukin-1β(IL-1β)was established,with the control group cultured in DMEM/F12 basic medium and the inflammation-induced group cultured in DMEM/F12 basic medium containing 10 ng/ml IL-1β.RT-qPCR was used to detect the effects of overexpressed target miRNA on the mRNA expression levels of cartilage phenotype factors such as type Ⅱ collagen α1 chain(Col2a1),aggrecan(Acan),as well as inflammatory factors including a disintegrin and metalloproteinase with thrombospondin motifs 5(Adamts5)and cyclooxygenase-2(Cox-2).Results(1)SMSC-Exos were successfully isolated,cultured,and identified.(2)miRNA sequencing of SMSC-Exos from OA and control groups revealed 16 differentially expressed miRNAs(|log2FC|>2,P<0.05).Compared with control group,7 miRNAs were up-regulated and 9 were down-regulated in OA group.GO and KEGG analysis indicated that the target genes of miR-429 were mainly involved in development process,anatomical structure development,system development,cell development and differentiation,and were enriched in inflammation-related pathways such as mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase-protein kinase B(PI3K-Akt).(3)Functional validation of miR-429 in the rabbit condylar cartilage cell inflammatory model showed that overexpression of miR-429 increased the mRNA expression levels of Col2a1 and Acan(P<0.05)and decreased the mRNA expression levels of Adamts5 and Cox-2(P<0.05)in the inflammation-induced group.Conclusions miRNA sequencing of SMSC-Exos isolated and identified from human synovial tissues reveals a specific miRNA expression profile in OA patients,with miR-429 significantly down-regulated.Functional validation demonstrates that overexpression of miR-429 has reparative and anti-inflammatory effects on condylar cartilage cells in an inflammatory microenvironment.

Objective To investigate the association between four single nucleotide polymorphisms(SNP)(rs9340 in MAPK1,rs14804 in NRAS,rs712 and rs7973450 in KRAS)in the 3'UTR of ERK1/2 signaling pathway-related genes and non-small cell lung cancer(NSCLC).Methods A total of 478 NSCLC patients and 480 healthy controls were enrolled in this study.Four SNPs were genotyped by using TaqMan assays.The association between the four SNPs and NSCLC was analyzed.Results The distribution frequency difference of the allele of rs9340 was statistically significant between the control group and the non-small cell squamous cell carcinoma(SCC)group(P = 0.009),suggesting that the G allele of rs9340 may be a protective factor for non-small cell lung squamous cell carcinoma(OR = 0.67,95%CI:0.50～0.91).In addition,in the<50 years age group,the distribution frequency difference of the allele of rs9340 was statistically significant between the control group and the NSCLC group(P = 5.07×10-4),indicating that the G allele of rs9340 may be a protective factor for NSCLC(OR = 0.46,95%CI:0.29～0.72).Conclusion The SNP rs9340 in MAPK1 may be associated with the risk of NSCLC.

Objective Explore the impact of long-term blood glucose fluctuations and blood glucose control on the stroke incidence in patients with type 2 diabetes mellitus(T2DM).Methods An observa-tional cohort of patients with T2DM was established based on"Shanghai Community Chronic Disease Health Management Service Objects"on October 1st,2018.Follow-ups were conducted every three months,and fasting blood glucose(FBG)were tested at each visit.Basic epidemiological data were collected via the Shanghai Community Health Management Information Platform or survey questionnaires,and stroke incidents were gathered via the"Shanghai Cardio-Cerebrovascular Event Monitoring System".The first reported stroke incident within the observation period was considered.The observational deadline was December 31st,2021.Standard deviation of FBG was used to evaluate blood glucose fluctuation and FBG control rate was used to reflect blood glucose control status.Cox Proportional Hazards Model was utilized to analyze the impacts.Results The cumulative observation time was 91,826.1 person-years for the study,in which there were 1785 cases of stroke events observed,implying a cumulative incidence of 5.73%and incidence rate of 1943.9/100000 person-years.The mean number of follow-ups(10.29±3.07)per patient was recorded.The details of the stroke cases were as follows:transient ischemic attacks(n=111,6.22%),non-lacunar brain infarctions(n=754,42.24%),lacunar brain infarctions(n=798,44.71%),intracerebral hemorrhages(n=80,4.48%),non-intracerebral hemorrhages(n=8,0.45%),subarachnoid hemorrhages(n=12,0.67%),and unclassified strokes(n=22,1.23%).After excluding subjects with less than five follow-ups,the Cox Proportional Hazards Model suggested that increased standard deviation of FBG was an independent risk factor for the first stroke incident,and an increased blood glucose control rate was an independent protective factor.Both the standard deviation of FBG and the blood glucose control rate were not correlated with stroke recurrence.Conclusion Long-term blood glucose fluctuations and blood glucose control can predict the risk of a first stroke in patients with T2DM.The relationship between blood glucose fluctuations,blood glucose management,and stroke recurrence requires further studies.

Objective To explore the influence of extracellular matrix protein ABI-interactor 3-binding protein(ABI3BP)on vesicular stomatitis virus(VSV)genome replication and innate immune signaling pathway. Methods The small interfering RNA(siRNA)was transfected to knock down ABI3BP gene in human skin fibroblast BJ-5ta cells.VSV-green fluorescent protein(VSV-GFP)-infected cell model was established.The morphological changes and F-actin stress fiber formation were detected on ABI3BP knockdown cells by phalloidin immunofluorescence staining.The mRNA level of virus replication was detected by RT-qPCR in BJ-5ta cells after VSV-GFP infection;western blotting was performed to detect the changes in interferon regulatory factor 3(IRF3)andTANK-binding kinase 1(TBK1)phosphorylation levels. Results The VSV-GFP-infected BJ-5ta cell model was successfully established.Efficient knockdown of ABI3BP in BJ-5ta cells was achieved.Phalloidin immunofluorescence staining revealed structural rearrangement of intracellular F-actin after ABI3BP gene knockdown.Compared with the control group,the gene copy number of VSV-GFP in ABI3BP knockdown cells increased by 2.2-3.5 times(P＜0.01)and 2.2-4.0 times(P＜0.01)respectively when infected with VSV of multiplicity of infection 0.1 and 1.The expression of viral protein significantly increased in ABI3BP knockdown cells after virus infection.The activation of type-Ⅰ interferon pathway,as determined by phosphorylated IRF3 and phosphorylated TBK1,was significantly decreased in ABI3BP knockdown cells after VSV-GFP infection. Conclusions Extracellular matrix protein ABI3BP plays an important role in maintaining the formation and rearrangement of actin structure.ABI3BP gene deletion promotes RNA virus replication,and ABI3BP is an important molecule that maintains the integrity of type Ⅰ interferon pathway.

Objective:To analyze the current prevalence of pre-diabetes (PDM) and its relationship with overweight and obesity in an adult health check-up population.Methods:This study was a cross-sectional and retrospective cohort study and was applied using whole-cluster random sampling method. A total of 491 379 adults who underwent health check-ups at the Health Management Centre of Sichuan Provincial People′s Hospital from January 2017 to July 2023 were selected to analyze the epidemiological characteristics of PDM and overweight-obesity, as well as the trend of change over time. A retrospective cohort study was conducted on 19 001 of the subjects who underwent≥3 health check-ups and did not have diabetes and PDM at baseline, and the relationships between body mass index, waist circumference and the risk for developing PDM were analyzed using Cox proportional risk regression models. And the dose-response relationship between body mass index, waist circumference and the risk for developing PDM was analyzed using restricted cubic spline regression (RCS).Results:Of the 491 379 cases included in the cross-sectional study, 275 084 were male and 216 295 were female, 163 158 cases were under 40 years old, and 328 221 cases were 40 years old and above; the total prevalence of PDM was 19.41% in 2017-2023, with an overall increasing trend. Of the 19 001 people included in the cohort study, a total of 2 487 (13.09%) new cases of PDM were identified at the end of follow-up. After adjusting for confounding factors, overweight ( HR=1.150, 95% CI: 1.047-1.263), obesity ( HR=1.335, 95% CI: 1.149-1.552) and abdominal obesity ( HR=1.218, 95% CI: 1.105-1.342) were risk factors for PDM. The risk of PDM rised with the increase of body mass index (>22.9 kg/m 2, Pnon-linear=0.973) and waist circumference (>80 cm, Pnon-linear=0.830), with a linear dose-response mode. In different gender and age groups, it was found the greater the body mass index (>24.1 kg/m 2 for men,>21.5 kg/m 2 for women;>23.3 kg/m 2 for age≥40 years,>24.1 kg/m 2 for age<40 years) and waist circumference (>85 cm for men, >73 cm for women; >82 cm for age ≥40 years, >85 cm for age <40 years), the higher the risk of PDM. Conclusions:The prevalence of PDM is on the rise in the adult health check-up population. To prevent PDM, it is necessary to control the body mass index and waist circumference to a lower level than the overweight and obesity standards.

The deubiquitinases (DUBs), as the crucial peptidohydrolases in the ubiquitin system, can reverse and strictly regulate ubiquitination and play key roles in various biological processes, including the regulation of protein stability, cell signal transduction. Ubiquitin-specific protease 28 (USP28) involves multiple cancer-related signaling pathways by enhancing the stability of various cancer-related proteins, and is closely associated with the progression of colorectal, breast cancer, lung carcinomas, and pancreatic cancer. USP28 has been considered as a promising drug target in anticancer therapy, and the development of USP28 inhibitors has made some progress. In this article, we review the structure of USP28 and its interaction with substrates, discuss the research progress of USP28 in cancers and summarize the development of USP28 inhibitors.

Objective To observe the correlation between growth impairment induced by long-term oral glucocorticoids(GC)therapy and the ratio of FGF23/Klotho in children with primary nephrotic syndrome(PNS).Methods A prospective study was conducted on 56 children with GC-sensitive PNS who had discontinued GC therapy for more than 3 months and revisited the Department of Pediatrics of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine between June 2022 and December 2022.After monitoring qualitative and quantitative urine protein levels upon admission,the children with proteinuria relapse were treated with GC(GC group;n=29),while those without relapse did not receive GC treatment(non-GC group;n=27).In addition,29 healthy children aged 3 to prepuberty were selected as the control group.Height,bone age,growth rate,and the FGF23/Klotho ratio were compared among the groups.The correlations of the FGF23/Klotho ratio with height,bone age,and growth rate were analyzed.Results The FGF23/Klotho ratio in the GC group was significantly higher than that in the non-GC group after 1 month of GC therapy(P＜0.05),and the height and bone age growth rates within 6 months were lower than those in the non-GC group(P＜0.05).Correlation analysis showed significant negative correlations between the FGF23/Klotho ratio after 1 month of treatment and the growth rates of height and bone age within 6 months in children with PNS(r=-0.356 and-0.436,respectively;P＜0.05).Conclusions The disturbance in FGF23/Klotho homeostasis is one of the mechanisms underlying the growth impairment caused by long-term oral GC therapy.[Chinese Journal of Contemporary Pediatrics,2024,26(3):269-2741