Objective To explore the functional impact of A-to-I editing in the seed region of miR-411 during post-myocardial infarction (MI) fibrosis and elucidate its therapeutic potential. Methods Integrating GEO database with myocardial RNA-seq data from MI mouse models, we identified dynamic A-to-I RNA editing in small noncoding RNAs across MI progression (1 day to 8 weeks post-MI). Four miRNAs exhibited differential editing rates between MI and controls, with miR-411 showing progressive editing enhancement at seed region position 4 (P＜0.01). This editing event was validated in both murine MI models and human heart failure specimens. Results The A-to-I editing ratio change of the 4th nucleotide in the seed region of miR-411 mainly occurs in cardiac fibroblasts rather than cardiomyocytes, and the editing at this site depends on ADAR2 rather than ADAR1. Edited miR-411 (ED-miR-411) diverged from wild-type miR-411 (WT-miR-411) in suppressing collagen-related pathways (extracellular matrix [ECM]-receptor interaction, collagen-containing ECM, ECM organization; P＜0.01) in cardiac fibroblasts. Mechanistically, dual-luciferase assays confirmed ED-miR-411 directly targeted the 3′UTR and suppressed expression of type Ⅱ transforming growth factor (TGF)-beta receptor (TGFBR2) and CD44, which were key drivers of TGF-β-mediated fibroblast activation. ED-miR-411 overexpression blunted TGF-β-induced collagen synthesis and myofibroblast proliferation (P＜0.05). In vivo, intramyocardial delivery of ED-miR-411 mimics at 1 week post-MI reduced fibrosis by 40% and improved ejection fraction by 15% (P＜0.01 vs controls), whereas WT-miR-411 showed no therapeutic effect. Conclusions A-to-I editing of miR-411 emerges as an endogenous anti-fibrotic mechanism by repressing TGFBR2 and CD44, thereby disrupting TGF-β signaling and ECM dysregulation. Our findings highlight ED-miR-411 as a novel RNA-based therapeutic candidate to mitigate post-infarction cardiac remodeling.

Objective:Exploring the association between Life's Crucial 9 (LC9) and the risk of thyroid dysfunction (TD), as well as its potential predictive capacity.Methods:A total of 247 600 TD-free participants from the UK Biobank were enrolled in the study. The LC9 score was divided into three CVH groups: low (0-), medium (50-), and high (80-100). Cox proportional hazards regression models were used to calculate the HRs and 95% CIs of the risk of TD with LC9 CVH status. Calculate Harrell's concordance index ( C-index), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to evaluate the predictive ability of the LC9 score and Life's Essential 8 (LE8) score. Results:During a median follow-up of 12.3 years, 5 515, 911, and 4 869 new cases of TD, hyperthyroidism, and hypothyroidism were documented, respectively. Participants with a high LE8 CVH group had 57.00% ( HR=0.43, 95% CI: 0.38-0.49), 55.00% ( HR=0.45, 95% CI: 0.34-0.60), and 58.00% ( HR=0.42, 95% CI: 0.37-0.47) lower risk of TD, hyperthyroidism, and hypothyroidism, respectively, than those with low CVH group. Compared with the LE8 score, the improvement in C-index for the LC9 score predicted TD risk was 0.004 (95% CI: 0.001-0.007), the NRI was 0.101 (95% CI: 0.021-0.103), and the IDI was 0.001 (95% CI: 0.000-0.001). Conclusions:The better CVH status, defined by LC9, was associated with a lower risk of TD. Compared to the LE8 score, the LC9 score demonstrated a significant enhancement in both risk discrimination and reclassification capability for TD risk.

Objective To explore the objective characteristics of tongue in primary immune thrombocytopenia(ITP);To provide references for accurate syndrome differentiation.Methods Totally 112 patients with ITP were divided into groups according to their platelet count,TCM symptoms and drug treatment lines.Infrared thermal imager,hygrometer,colorimetry and image analysis software were used to detect the temperature,humidity,colorimetry and morphology of tongue body(TB),tongue coating(TC)and sublingual vessel(SV),and analyze their characteristics.The tongue was divided into five areas:tip of tongue(T),middle of tongue(M),behind of tongue(B),middle left of tongue(ML)and middle right of tongue(MR),and its temperature was measured.Humility(H)of tongue and tongue coating were measured by hygrometer.The images of tongue body,tongue coating and sublingual collaterals were taken,and the chromaticity indexes of R,G,B,L,a,b were analyzed by Adobe Photoshop 2023.The width,length and tortuosity of sublingual collaterals were under morphological analysis.Results ① Comparison of platelet count groups:compared with 30-50 platelet count group and more than 100 platelet count group,the TB-R of 51-100 platelet count group decreased(P<0.05,P<0.01),and compared with 30-50 platelet count group,the TB-a of 51-100 platelet count group decreased(P<0.01);compared with platelet<30 group and platelet 30-50 group,the TC-H of platelet>100 group increased(P<0.05,P<0.01);compared with platelet>100 group,the length of sublingual collaterals in platelet<30 group was longer(P<0.05).② Comparison of different TCM symptom groups:compared with the bleeding group and asymptomatic group,the M and SV-B in the fatigue group decreased(P<0.05,P<0.01);compared with the asymptomatic group,the TC-b in the anxious group was significantly higher(P<0.05).③ Comparison of administration groups:compared with the Danazol group and Chinese materia medica group,the TC-H in the glucocorticoid group was significantly higher(P<0.05,P<0.01).Conclusion There are differences in tongue characteristic indexes among ITP patients with different platelet counts,TCM symptoms and drug treatment lines,which can measure of tongue indexes to provide references for accurate syndrome differentiation of ITP.

Increasing evidence showed that histone deacetylase 6 (HDAC6) dysfunction is directly associated with the onset and progression of various diseases, especially cancers, making the development of HDAC6-targeted anti-tumor agents a research hotspot. In this study, artificial intelligence (AI) technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline, which combined Voting strategy based on compound-protein interaction (CPI) prediction models, cascade molecular docking, and molecular dynamic (MD) simulations. The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays. Among the identified compounds, Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity (IC₅₀ = 5.41 nM) than that of tubastatin A (TubA) (IC₅₀ = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 117.23 for HDAC1), which was further verified by the Western blot analysis. Additionally, Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells, exerting desirable antiproliferative activity (IC₅₀ = 2.59 μM). Furthermore, based on long-term MD simulation trajectory, the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis, thereby elucidating its binding mechanism. Moreover, the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation, thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

Objective:To establish HPLC fingerprint and methods for determining the contents of four iridoid glycosides of Gentiana rigescens; To evaluate the quality of Gentiana rigescens from different origins; To improve the quality control level of Gentiana rigescens medicinal materials.Methods:Using 15 batches of Gentiana rigescens from the main production areas and authentic production areas as raw materials, the common mode of HPLC fingerprints of Gentiana rigescens was established, and the chemical components of the common peaks were identified. Referring to the common mode of fingerprints, similarity analysis was conducted on the fingerprints of Gentiana rigescens from different origins. Using chemometric methods, cluster analysis (HCA), principal component analysis (HCA), and orthogonal partial least squares discriminant analysis (OPLS-DA) were performed on 15 batches of Gentiana rigescens, with the common peak area of fingerprint as the variable. The contents of four types of iridoid glycosides in Gentiana rigescens were determined. Combined with the fingerprints and the content results of four types of iridoid glycosides, the quality of Gentiana rigescens from different origins was evaluated.Results:The fingerprints of Gentiana rigescens contained 9 common peaks, with 4 identified iridoid glycosides. The similarity of the fingerprints of 15 batches of Gentiana rigescens ranged from 0.962 to 0.999. HCA and PCA divided the 15 batches of Gentiana rigescens into two categories. OPLS-DA analyzed 3 significantly different components, namely gentiopicroside, peak 7, and loganic acid. The content determination results showed that the average contents of loganic acid, swertiamarin, and gentiopicroside in Gentiana rigescens from Dali Bai Autonomous Prefecture and Yunnan Province were the highest, and the total amount of four iridoid glycosides was also significantly higher than that from other regions, indicating that the overall quality of Gentiana rigescens from Dali Bai Autonomous Prefecture and Yunnan Province was relatively good.Conclusion:This method is simple, fast, accurate, and can provide reference for improving the quality standards of Gentiana rigescens.

Objective To explore the relationship between plasma trimethylamine N-oxide(TMAO)level and atrial fibrillation(AF)by a clinical trial.Methods Totally 257 patients with AF were enrolled including 114 patients with paroxysmal AF and 143 with persistent AF.The control group had 122 non-AF patients;Plasma TMAO level,the demographic characteristics and clinical data of patients were collected.Regression analysis was performed to identify the association between TMAO and presence of AF.Results Plasma TMAO level of patients with AF was higher than that of patients without AF(3.9[2.4-5.9]vs.2.4[1.6-3.7]μmol/L,P＜0.001);Even after adjust-ment of confounding factors including age,hypertension,diabetes,heart failure and body mass index;Plasma TMAO level was still related to presence of AF(OR:1.290,95％CI:1.151-1.445;P＜0.001).The plasma TMAO level of patients with persistent AF was higher than that of patients with paroxysmal AF(4.4[2.8-6.8]vs.3.2[2.2-5.0]μmol/L,P＜0.01);Even after adjustment of confounding factors including age,hypertension,diabetes and heart failure and coronary heart disease;Plasma TMAO level was still related to persistent AF(OR:1.092,95％CI:1.009-1.182;P=0.029).Conclusions The level of plasma TMAO of patients with AF is higher than that of patients without AF.Elevated plasma TMAO level is related to an increased risk of AF.Elevated plasma TMAO level in patients with AF is related to an increased risk of persistent AF.

Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC50=5.41 nM)than that of tubastatin A(TubA)(IC50=15.11 nM),along with a favorable subtype selectivity profile(selectivity index ≈ 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC50=2.59 μM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

OBJECTIVE: To analyze the results of prenatal diagnosis for fetuses with a high risk for sex chromosome aneuploidies (SCAs) indicated by non-invasive prenatal testing (NIPT), and to assess the influence of maternal chromosomal factors on the results of NIPT. METHODS: A retrospective analysis was conducted on the clinical data of 454 pregnant women with a high risk for SCAs indicated by NIPT undergoing invasive prenatal diagnosis at the Medical Genetics Center of Northwest Women's and Children's Hospital from January 2022 to September 2024. The data has included prenatal diagnosis indications, results, pregnancy outcomes, and the chromosomal results of pregnant women. RESULTS: Among the 454 women (including 10 with twin pregnancy) with a high risk for SCAs indicated by NIPT, 149 (including 4 twin cases) were diagnosed with SCAs through invasive prenatal diagnosis. These had included 47,XXX (37 cases), 47,XXY (56 cases), 47,XYY (29 cases), 45,X (1 case), 48,XXYY (1 case), mosaicism (20 cases), sex chromosome structural abnormalities (6 cases), and small-scale pathogenic copy number variations (3 cases). 383 pregnant women (including 7 with twin pregnancy) had accepted chromosomal karyotyping analysis. In total 49 cases of SCAs abnormalities were detected. Among them, 41 cases were pregnant women with SCAs but normal fetal chromosomes, which yielded a false positive rate for NIPT caused by maternal factors by 10.7%. In addition, 8 cases (including 1 twin case) had SCAs abnormalities in both the pregnant woman and the fetus. Among the 383 pregnant women, 129 cases (including 3 twin cases) of fetal SCAs were diagnosed, which yielded an overall positive predictive value (PPV) of NIPT for SCAs by 33.7% (129/383). With the 41 false positive cases caused by maternal SCAs abnormalities excluded, the PPV of NIPT for SCAs will be increased to 37.7% (129/342). Among the 454 pregnant women, twin pregnancies have accounted for 2.2% (10/454). Among the confirmed cases of SCAs abnormalities, twin cases accounted for 2.7% (4/149). Among the 383 pregnant women undergoing chromosomal karyotyping, twin cases accounted for 1.8% (7/383). Among the detected cases of chromosomal abnormalities, twin cases accounted for 2.0% (1/49). By calculation, the proportion of singleton pregnant women with a high risk for SCAs indicated by NIPT was approximately 32.1%, and the proportion of twin pregnant women was approximately 38.6%, indicating that twin pregnancies could increase the positive rate of NIPT. CONCLUSION NIPT can improve the screening efficiency for SCAs, but its PPV is limited. Therefore, pregnant women with a high risk for SCAs indicated by NIPT need to undergo invasive prenatal diagnosis for a definite diagnosis, and twin pregnancies can increase the positive rate of NIPT. The study confirmed that chromosomal abnormalities in pregnant women can significantly affect the accuracy of NIPT in detecting fetal SCAs. Therefore, when NIPT indicates SCAs abnormalities, it is recommended to simultaneously conduct chromosomal testing on the pregnant women. The combined application of chromosomal karyotyping analysis, fluorescence in situ hybridization, and copy number variation detection techniques can significantly improve the diagnostic accuracy for SCAs, especially for the detection of mosaicisms.
Humans ; Female ; Pregnancy ; Sex Chromosome Aberrations ; Adult ; Retrospective Studies ; False Positive Reactions ; Prenatal Diagnosis/methods* ; Noninvasive Prenatal Testing/methods* ; Aneuploidy ; Male ; Sex Chromosome Disorders/genetics*

Gastric cancer with peritoneal metastasis (GCPM) is a common and lethal manifestation of advanced gastric cancer, with a median survival of only 5-11 months. This consensus was developed by 30 experts from Asia (China, Japan, Korea, and Singapore) using the Delphi method and the GRADE evidence grading system. A total of 29 statements were formulated, covering the diagnosis and assessment of GCPM, indications for laparoscopic exploration and NIPS (normothermic intraperitoneal and systemic treatment), treatment regimens, prevention and management of complications, criteria for conversion surgery, and postoperative intraperitoneal therapy. The consensus aims to standardize clinical practice and improve the prognosis of patients with GCPM.

Objective:To assess the feasibility and efficacy of transperineal laser ablation(TPLA)with single laser fiber in treating benign prostatic obstruction(BPO).Methods:From April 2021 to March 2024,a total of 13 BPO patients were selected from Beijing Friendship Hospital.TPLA was performed using a single laser fiber,which was guided by transrectal biplane ultrasound.The single laser fiber was used to undergo TPLA under the guidance of trans-rectal dual-plane ultrasound.The intraoperative time,ablation time,energy consumption,indwelling time of catheter,and complications were observed.The postoperative 6 months was chosen as the cut-off point of follow-up,and the pre and postoperative changes of international prostate symptom score(IPSS),quality of life index(QoL),prostate volume(PV),residual urine volume(RUV)and the maximum urine flow rate(Qmax)were compared.Results:All 13 patients successfully underwent TPLA with single laser fiber.The average operation time was(55.1±18.3)min,and the average ablation time was(16.3±1.7)min,and average energy consumption was(3951.6±459.7)J,and the median value of indwelling time of catheter was 7(7,10)days.The number of postoperative complication was 2 cases,and both them belonged to Clavien-Dindo grade II complication.At the postoperative 6th month,the IPSS,QoL,PV,Qmax and RUV of all patients were improved,all of which were better than preoperative these indicators,and the differences were significant(t=12.102,-3.228,-3.181,-2.581,-2.936,P<0.05).Conclusion:The application of single laser fiber in conducting TPLA operation is feasibility at technical aspect,and it can achieve the therapeutic goals of improving patients'symptoms and enhancing their quality of life.Although its operational time is slightly longer than that of using multiple fibers simultaneously,it can effectively reduce the cost of expenditure for consumables.