Objective To explore the predictive model and its value of irAEs based on peripheral blood markers.Methods The baseline clinical data,laboratory tests,and irAEs follow-up results of 825 malignant tumor patients treated with PD-1/PD-L1 antibodies in the First Affiliated Hospital of Kunming Medical University were retrospectively collected from December 2020 to December 2023.The patients were divided into irAEs group and non-irAEs group according to the presence or absence of irAEs.The differences between and within groups were analyzed by t-test,rank-sum test,chi-square test and Fisher exact probability method.LASSO,Ridge and Elastic-net logistic regressions were used to screen the predictors and establish the risk prediction models for irAEs.Results 136 patients experienced 178 irAEs,of which endocrine toxicity accounted for 42.64％,hepatitis 35.29％,pneumonia 20.58％,grade≥G3 accounted for 19.07％,involving more than two organs accounted for 24.26％of the total number of irAEs.Univariate analysis showed that baseline CD4+T cell count,IL-6,IL-17,TSH,GLB and ALB were associated with irAEs.GLB,ALB,IL-17 and TSH were selected as the important risk factors by Ridge,LASSO and Elastic-Net logistic regression.The results showed that the AUC of the three algorithms were over 0.800.The AUC of internal validation set by LASSO-Logistic was 0.800(95％CI 0.739～0.862).The AUC of external validation set was 0.800(95％CI 0.739～0.861)and the DCA curve results indicated the highest net return for this predictive model.Conclusion GLB,ALB,IL-17 and TSH are independent predictors of irAEs,and the predictive model of irAEs based on them is effective.

ObjectiveThe U6 promoter is an essential element for driving sgRNA expression in the clustered regularly interspaced short palindromic repeat sequences/CRISPR-associated protein 9（CRISPR/Cas9）gene editing system in dicotyledonous plants. Endogenous U6 promoters typically exhibit higher transcriptional activity， which can significantly improve gene editing efficiency. This study aims to identify endogenous U6 promoters in Artemisia annua to optimize its CRISPR/Cas9 gene editing system， which holds significant importance for its molecular breeding. MethodsOn the basis of the highly conserved U6 snRNA sequences in Arabidopsis thaliana， endogenous U6 promoters were screened in the A. annua genome. Expression vectors were constructed with candidate AaU6 promoter driving the firefly luciferase （LUC） reporter gene， and then transiently transformed into Nicotiana benthamiana. Transcriptional activities of the promoters were measured and compared by in vivo imaging and the Dual Luciferase Reporter assay. ResultsEight endogenous U6 promoters were successfully cloned from A. annua. Sequences alignment revealed that all these promoters contained the two conserved cis-acting elements， upstream sequence element （USE） and TATA-box， which affected their transcriptional activity. Dual-luciferase activity assays indicated that the transcriptional activities of AaU6-3， AaU6-1， and AaU6-5 were significantly higher than that of the Arabidopsis AtU6-26 promoter， with AaU6-3 exhibiting the highest activity. ConclusionThis study identified three endogenous AaU6 promoters with high transcriptional activity in A. annua， providing key functional elements for establishing an efficient gene editing system in A. annua. These findings will contribute to advancing precision molecular breeding and high-quality germplasm innovation in A. annua.

A mounting body of research suggests that circRNAs significantly contribute to the develop-ment of myocardial fibrosis.The microarray results of human circular RNA expression profile indicated that circHERC4_041 expression increased in the myocardium of patients with heart failure,RT-qPCR a-nalysis confirmed that the myocardial expression level of circHERC4_041 in individuals with heart failure were considerably elevated compared to that in healthy organ donors.Fluorescence in situ hybridization(FISH)confirmed that circHERC4_041 was abundant in the cytoplasm of human cardiomyocyte AC16.Overexpression of circHERC4_041 in mouse myocardial fibroblasts(mCFs)mediated by adenovirus in-hibited the expression of fibrosis-related proteins in mCFs.Experiments involving cell proliferation,wound healing,and Transwell assays demonstrated that overexpression of circHERC4_041 suppressed the growth and mobility of mCFs(P＜0.001).Sequence analysis results suggested that circHERC4_041 con-tains potential ribosome entry sequence(IRES)and open reading frame(ORF).Western blot confirmed that circHERC4_041 could translate the 516 amino acid HERC4-516aa protein,which was mainly located in the cytoplasm of the cell.Cell functional experiments confirmed that circHERC4_041 inhibited the fi-brotic phenotype of mCFs by specifically translating HERC4-516aa(P＜0.05).The specific interaction between HERC4-516aa and transglutaminase 2(TGM2)was confirmed by IP-MS screening and Co-IP i-dentification.Further results found that the degradation of TGM2 was promoted through proteasome path-way.The overexpression of TGM2 in mCFs facilitated by adenoviral vectors could counteract the suppres-sive effects of HERC4-516aa on the fibrotic phenotype of mCFs.Therefore,this study confirmed that the HERC4-516aa protein translated by circHERC4_041 can specifically bind to TGM2 to inhibit the fibrotic phenotype of myocardial fibroblasts.

Objective:To analyze the epidemiological characteristics, spatial clustering, and correlation between dental fluorosis detection rates and meteorological factors in children aged 8 - 12 years old in 37 counties (cities, districts, hereinafter referred to as counties) affected by coal-burning-borne endemic fluorosis in Guizhou Province, and to provide a scientific basis for prevention and control of the disease.Methods:Monitoring data on dental fluorosis in children aged 8 - 12 years old from 2019 to 2022 were collected from the National Health Security Information System for Endemic Diseases. Meteorological data, including annual average temperature, annual average precipitation, annual sunshine hours, and annual average relative humidity, were obtained from the Guizhou Provincial Bureau of Statistics. Descriptive epidemiology, analytical epidemiology, and spatial correlation analysis methods were used to analyze the data. Visual maps were created based on the clustering levels of annual dental fluorosis detection rates (high-high, low-low, high-low, low-high). Spatial autocorrelation and meteorological factors were used to analyze the epidemiological characteristics, spatial clustering, and the impact of meteorological factors on dental fluorosis.Results:From 2019 to 2022, a total of 3 649 161 children aged 8 - 12 in the counties affected by coal-burning-borne endemic fluorosis were monitored, and 115 793 children were diagnosed with dental fluorosis, with a detection rate of 3.17%. The detection rates were 4.73% (45 093/954 338) in 2019, 3.35% (31 424/938 445) in 2020, 2.86% (21 727/760 195) in 2021, and 1.76% (17 549/996 183) in 2022, respectively. The dental fluorosis indices were 0.09, 0.07, 0.06, and 0.03, respectively. The number of counties with detection rates > 6% was 7, 5, 5, and 0 in 2019 - 2022, respectively. Dafang County consistently had the highest detection rates, with rates of 10.06% (6 783/67 408), 10.07% (1 955/19 421), 13.54% (4 017/29 667), and 4.83% (3 284/76 206) in 2019 - 2022, respectively. The Moran's I indices for dental fluorosis detection rates were 0.45, 0.53, 0.53, and 0.53 in 2019 - 2022, with Z = 4.29, 5.07, 5.31, and 5.10, respectively ( P < 0.05), indicating global spatial autocorrelation (positive) and spatial clustering of dental fluorosis detection rates. The number of counties with "high-high" clustering of detection rates was 7, 7, 6, and 7 in 2019 - 2022, mainly concentrated in the northwestern region, including Qixingguan District, Nayong County, Dafang County, Zhijin County, and Jinsha County of Bijie City. "Low-high" clustering areas were distributed in Zhongshan District of Liupanshui City in 2019, 2020, and 2022. The detection rate of dental fluorosis was associated with local annual average temperature (°C) and annual precipitation (mm) ( r = - 0.393, - 0.337, P = 0.016, 0.041). Conclusions:From 2019 to 2022, the detection rate of dental fluorosis in children aged 8 - 12 in coal-burning-borne endemic fluorosis areas in Guizhou Province has been decreasing year by year, and it shows spatial clustering. The high clustering area is in the northwest of Guizhou Province, which should be regarded as a key prevention and control area for coal-burning-borne fluorosis in the future. At the same time, areas with lower temperatures and precipitation should also strengthen prevention and control efforts.

This research investigated the contamination level,distribution of drug-resistant strains,and molecular epidemiologi-cal characteristics of Campylobacter,and further explored transmission pathways and prevention strategies.Cecum,chicken carcass,chicken product,and environmental samples,as well as swabs from workers'hands,were collected from a slaughterhouse in a large broiler group in the Jiaodong area between August 2023 and July 2024.Quantitative contamination assessment of Campylobacter in chicken carcasses and chicken products was performed.After microbial mass spectrometry identification,the representative strains of different links were selected for drug resistance testing and whole genome sequencing(WGS).On the basis of the sequencing results,the resistance genes,virulence genes,multilocus sequence typing(MLST),and phylogenetic characteristics of representative strains were analyzed.Homology comparisons were performed between isolates and strains from patients with diarrhea in the NCBI database.A total of 297 Campylobacter strains were isolated from 806 samples,and the overall detection rate was 36.85%.The detection rate of Campylobacter was highest in the evisceration process(47.33%),followed by the cutting process(35.64%).Overall,the Campylo-bacter detection rate first increased,then decreased,and subsequently increased.Drug sensitivity testing revealed that 90 isolates were resistant to nalidixic acid and ciprofloxacin,and 94.97%of isolates were resistant to tetracycline.WGS showed that both Campylo-bacter jejuni(C.jejuni)and Campylobacter coli(C.coli)carried many drug resistance and virulence genes.ST-14176 of C.jejuni was isolated for the first time herein.The predominant ST-8261 strain of C.jejuni and ST-860,ST-829,and ST-1586 strains of C.coli are known to cause human diarrhea.LOS expression genes associated with Guillain-Barré syndrome(GBS)were detected in both C.jejuni isolates from the slaughter chain and patients with GBS.Some strains exhibited close genetic relatedness to human-derived Campylo-bacter strains from the NCBI database.The detection rate of Campylobacter in the slaughterhouse first increased,then decreased,and subsequently increased,and the quantitative contamination level of each link was similar to the detection rate.Quantitative analysis of chicken carcasses/products revealed that the average bacterial load was highest in eviscerated carcasses(102.80 cfu/g),and the high-est amount of Campylobacter in chicken products reached 451.80 cfu/g.Abundant drug resistance genes and virulence genes were iden-tified,and the drug resistance genes were highly correlated with the drug resistance rate.Therefore,surveillance intensity and control measures for Campylobacter in slaughter processes should be strengthened.

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.
Reperfusion Injury/drug therapy* ; Reactive Oxygen Species/metabolism* ; Reactive Nitrogen Species/metabolism* ; Humans ; Liver/drug effects* ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

Objective To study the effect of Compound Jinguanlan preparation on acne vulgaris through the p38MAPK signaling pathway.Methods New Zealand White Rabbits were randomly divided into high,medium,and low concentration groups of Jinguanlan,a positive control group,a model control group,and a blank control group.A rabbit ear acne model was constructed and each group was given the corresponding drug intervention.The gross changes in the skin tissue of the rabbit ears were observed.HE staining was used to observe pathological changes.ELISA was used to detect the levels of IL-6 and TNF-α in the serum.Western blot was used to detec the levels of p38MAPK protein expression.Results Jinguanlan significantly inhibited the inflammation of acne vulgaris,reducing swelling,erythema,hyperkeratosis,and inflammatory cell infiltration in the rabbit ears.ELISA results showed that compared with the model control group,the levels of IL-6 and TNF-α in the serum of each concentration of Jinguanlan group were significantly reduced,with the high concentration group showing a more pronounced decrease(P＜0.01).Western blot results indicated that compared with the model group,the relative expression of p38 MAPK protein in the Jinguanlan group was reduced.Conclusion Jinguanlan can inhibit the inflammatory response of acne vulgaris,and its effect may be achieved by regulating the p38MAPK signaling pathway and reducing the expression levels of IL-6 and TNF-α in the serum.

Objective To explore the disinfection effect of periodic hypochlorous acid infusion on water supply pipelines.Methods Water specimens from 6 water outlets of central sterile supply department were collected at baseline for microbial culture.After introducing a slightly acidic hypochlorous acid water generator,water speci-mens were collected every 10 days.Continuous disinfection with hypochlorous acid was carried out on the 1st-3rd day,and discontinued on the 4th-10th day.Water specimens of 6 water outlets were collected on the 1st,4th,7th,and 10th day of each cycle,in total 3 cycles.Microbial culture and metagenomic next-generation sequencing(mNGS)analysis were conducted simultaneously on all water specimens from the outlets of the endoscope cleaning tank.Results Before disinfection of the pipeline,a total of 18 bottles of water specimens were collected.Bacterial count of water specimens from 10 bottles(55.56％)was between 102 and 104 CFU/mL,mainly Sphingomonas ad-hesins and Bacillus cereus.After disinfection,only 2 out of 72 water specimens(2.78％)exceeded the bacterial lim-it.The mNGS results showed that three most dominant bacterial genera in the pre-disinfection water specimens were Sphingomonas,Methylobacterium,and Ralstonia,with stringent mapped reads number(SMRN)ranging from 10 000 to 100 000;while the most dominant bacterial genera in post-disinfection water specimens were Lacto-baci-llus,Ralstonia,Acinetobacter,and Bradyrhizobium.PCoA analysis showed that there was a statistically sig-nificant difference in β-diversity of water specimens before and after disinfection(P＜0.05).Conclusion Periodic hypochlorous acid infusion disinfection can effectively remove bacterial biofilms in water pipelines,but there is a risk of bacterial biofilm recovery during disinfection suspension.In the future,monitoring and management of medical water should be strengthened.