Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO ^+/- ) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1^mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.

The pharmaceutical industry faces challenges in quality digitization for complex multi-stage processes, especially in small-sample systems. Here, an intelligent quality prediction and diagnostic (IQPD) framework was developed and applied to Tong Ren Tang's Niuhuang Qingxin Pills, utilizing four years of data collected from four production units, covering the entire process from raw materials to finished products. In this framework, a novel path-enhanced double ensemble quality prediction model (PeDGAT) is proposed, which combines a graph attention network and path information to encode inter-unit long-range and sequential dependencies. Additionally, the double ensemble strategy enhances model stability in small samples. Compared to global traditional models, PeDGAT achieves state-of-the-art results, with an average improvement of 13.18% and 87.67% in prediction accuracy and stability on three indicators. Additionally, a more in-depth diagnostic model leveraging grey correlation analysis and expert knowledge reduces reliance on large samples, offering a panoramic view of attribute relationships across units and improving process transparency. Finally, the IQPD framework integrates into a Human-Cyber-Physical system, enabling faster decision-making and real-time quality adjustments for Tong Ren Tang's Niuhuang Qingxin Pills, a product with annual sales exceeding 100 million CNY. This facilitates the transition from experience-driven to data-driven manufacturing.

OBJECTIVES: To investigate the expression patterns and prognostic value of lipid metabolism-related genes in breast cancer. METHODS: RNA sequencing data and clinical information were obtained from The Cancer Genome Atlas breast cancer (TCGA-BRCA) dataset, including 1100 breast cancer tissue samples (18 paired with adjacent tissues) and 112 normal breast tissue samples. Differentially expressed lipid metabolism-related genes were screened from a predefined set of 2043 genes using Bioconductor in R, with a false discovery rate <0.05 and |log2(fold change)|>2. Eligible samples were randomly divided into a training cohort (n=651) and a validation cohort (n=431) at a 6∶4 ratio. Prognostic lipid metabolism-related genes were identified using univariate Cox regression (P<0.005) and further refined via LASSO regression. A risk score model was constructed using multivariate Cox regression, and patients were stratified into high- and low-risk groups based on the median risk score. The model's performance was evaluated using Kaplan-Meier survival analysis with the log-rank test and time-dependent receiver operating characteristic (ROC) curves. A nomogram integrating age, TNM stage, clinical grade, and risk score was developed and validated using calibration curves and the concordance index. Immune cell infiltration was quantified using an immune scoring algorithm, and weighted gene co-expression network analysis (WGCNA) was applied to identify key modules associated with immune cell infiltration. Finally, to validate the function of the key gene ALDH2, small interfering RNA targeting ALDH2 was transfected into breast cancer cells, and its effects on invasion and migration were assessed using Transwell invasion and wound healing assays. RESULTS: A total of 185 differentially expressed lipid metabolism-related genes were identified. Univariate Cox and LASSO regression analyses identified three genes-ALDH2, CYP21A2, and IL24-which were incorporated into the multivariate Cox model. The prognostic model based on these genes demonstrated good predictive performance in both cohorts: patients in the high-risk group had significantly shorter overall survival (P<0.01), and the area under the ROC curve for predicting 1-, 3-, and 5-year survival rates was above 0.64. Analysis of the tumor microenvironment revealed an immunosuppressive phenotype in the high-risk group, characterized by reduced infiltration of several anti-tumor immune cells and downregulation of key immune checkpoint molecules such as PDCD1 and CTLA4. WGCNA suggested an association between ALDH2 and immune cell infiltration. Functional experi-ments confirmed that ALDH2 knockdown significantly enhanced the migration and invasion abilities of breast cancer cells. CONCLUSIONS This study established and validated a pro-gnostic model for breast cancer based on lipid metabolism-related genes. It revealed that low ALDH2 expression is closely associated with poor prognosis and immunosuppression, suggesting its potential as a prognostic biomarker and therapeutic target in breast cancer.

Objective: To evaluate the clinical efficacy of a novel autologous blood recovery device during the weaning process from extracorporeal membrane oxygenation (ECMO). Methods: A total of 16 patients who received ECMO support and underwent blood recovery during the weaning process from January 2022 to September 2024 at our hospital were included in the experimental group. In contrast, 58 patients who did not receive blood recovery during the weaning process were assigned to the control group. Transfusion components, costs, and changes in routine blood tests and coagulation functions were compared between the two groups from the day of weaning until 48 hours post-weaning. Results: Significant differences were observed in the volumes of red blood cell transfusions, plasma transfusions, and transfusion costs between the two groups from the day of weaning to 48 hours post-weaning (P<0.05). Additionally, in the experimental group, significant differences were noted in hemoglobin (Hb), platelet (Plt), and activated partial thromboplastin time (APTT) results when comparing values before and after extubation (P<0.05). Conclusion: The application of a novel autologous blood recovery device during ECMO weaning reduces patient costs, minimizes wastage of autologous blood, decreases reliance on exogenous blood transfusions, and mitigates the risks associated with allogeneic blood transfusion. This approach merits further promotion for clinical use.

Objective:To compare the dose-response effects of single-fraction ultra-high dose rate (FLASH) and conventional dose rate (CONV) whole abdominal irradiation (WAI) with X-rays on acute radiation-induced intestinal injury in mice, in order to identify optimal dose parameters and potential mechanisms.Methods:A total of 186 male C57BL/6J mice were randomly assigned to a non-irradiation group ( n=6), FLASH irradiation groups ( n=90), and CONV irradiation groups ( n=90). Acute radiation-induced intestinal injury models were established using single-fraction WAI with 11, 12, 13, 14, and 15 Gy X-rays (200 Gy/s for FLASH and 4 Gy/min for CONV). Changes in body weight, stool characteristics, and disease activity index (DAI) scores were assessed at 9 d post-irradiation. At 7 d post-irradiation at 11, 12, and 13 Gy, the intestines were collected for macroscopic examination and length measurement. The small intestine was selected for HE staining and quantitative analysis of intestinal crypt number and mucosal epithelial thickness. The survival of mice was assessed at 15 d post-WAI across all dose groups. Results:After single-fraction WAI at 11, 12, and 13 Gy, the body weight was higher in the FLASH group than that in the CONV group ( t=10.17, 12.65, 10.16, P<0.05). The DAI scores for the FLASH group were 1.00±1.10, 3.17±0.75, and 2.83±1.17, respectively, which were lower than those of the CONV group (4.33±0.52, 7.00±0.00, 8.60±0.55; t=8.70, 11.71, 14.99, P<0.05). However, after WAI at 14 Gy and 15 Gy, there were no significant differences in body weight and DAI between the FLASH group and the CONV group ( P>0.05). At 7 d after single-fraction WAI at 11, 12, and 13 Gy, mice in the FLASH group exhibited less intestinal congestion, edema, and shortening compared with the CONV group. The difference between the FLASH and CONV groups were statistically significant in small intestine length at 11 and 13 Gy ( t=4.42, 3.78, P<0.05), and in colorectal length at 11 and 12 Gy ( t=3.97, 3.12, P<0.05). Small intestine HE staining revealed superior preservation of intestinal architecture in the FLASH group compared with the CONV group, characterized by longer villi, increased crypt numbers, thicker mucosal epithelium, and enhanced structural integrity. The differences in crypt number and mucosal epithelial thickness were statistically significant ( tcrypt=13.10, 23.80, 11.90; tmucosal=5.75, 2.64, 7.74; P<0.05). At 15 d post-irradiation, the survival rate in the 15 Gy FLASH group was higher than that in the CONV group (50% vs. 10%, χ2=5.39, P<0.05), with a median survival extension of 6 d ( HR=0.340, 95% CI: 0.115 4-0.999 9). No significant survival differences were observed between the FLASH group and the CONV group at 11, 12, 13, and 14 Gy ( P>0.05). Conclusions:FLASH irradiation significantly alleviated acute radiation-induced intestinal injury from medium single-fraction WAI with 11, 12, and 13 Gy X-rays compared with CONV irradiation, and showed potential to improve mouse survival after single-fraction WAI at 15 Gy. This effect is likely associated with the preservation of intestinal crypts and exhibits a dose-dependent relationship.

Objective To analyze the differences in cerebral blood flow(CBF)characteristics among children with different subtypes of attention deficit and hyperactivity disorder(ADHD)and their relationship with executive function using arterial spin labeling(ASL)technology.Methods A case-control study was conducted,including children diagnosed with ADHD at the outpatient clinic of Peking University Sixth Hospital from July 2015 to December 2019 as the ADHD group,and typically developing schoolchildren from January to December 2021 as the healthy control group.Both groups underwent pseudo-continuous ASL(pCASL)scanning to measure CBF,and executive function was assessed using the parent version of the Behavior Rating Inventory of Executive Function(BRIEF).Differences in CBF between ADHD children and healthy controls were com-pared.For brain regions showing significant group differences,CBF values were extracted and linear regression models were constructed with BRIEF scores to further explore the relationship between regional CBF and execu-tive function.Results A total of 134 boys with ADHD were included[83 with ADHD predominantly inat-tentive subtype(ADHD-Ⅰ)and 51 with ADHD combined subtype(ADHD-C)],along with 25 healthy control boys.Intergroup comparisons revealed that the CBF in the left middle temporal gyrus was significantly lower in ADHD-C children compared to both ADHD-Ⅰ children(P=0.010)and healthy controls(P＜0.001),while no significant difference was observed between ADHD-Ⅰ children and healthy controls(P=0.280).After adjusting for age and total IQ scores,the linear regression model showed that the CBF in the left middle temporal gyrus of ADHD-C children was negatively correlated with the planning/organization score on the BRIEF(β=-0.062,P=0.030).Conclusions The CBF in the left middle temporal gyrus of boys with ADHD-C is significantly lower than that of boys with ADHD-Ⅰ and healthy controls.This reduced regional CBF may be associated with executive function deficits in organization and planning abilities in ADHD-C,providing new insights into the neurobiological mechanisms underlying ADHD subtypes.

Objective:To investigate the clinical characteristics of non-typhoidal Salmonella（NTS）enteritis in children and the drug resistance of NTS strains.Methods:The clinical data of 138 children who were hospitalized in Children's Hospital Affiliated to Xi'an Jiaotong University from 2022 to 2023 with diarrhea as the main complaint and NTS detected in stool culture were analyzed retrospectively, and the clinical characteristics and drug resistance were summarized.Results:Among 138 children with NTS enteritis，89 were males and 49 were females，with a male-to-female sex ratio of 1.81∶1 and an average age of 1.9（1.0,3.6）years，with a high incidence rate in June,July and August.Seventeen（12.31%）cases had a history of suspected unclean diet before illness.All the children had diarrhea symptoms with changes in fecal frequency and character，including 74 cases of pus and bloody stool，119 cases of mucus stool，and 70 cases of watery stool.One hundred and twenty-five（90.57%）cases had fever.Among 138 cases of fecal culture,there were 47 (34.05%) strains of Salmonella typhimurium,36(26.09%) strains of Salmonella enteritidis,and 55(39.85%) strains of other serotypes of Salmonella .One hundred and twenty-two（88.40%）NTS strains were resistant to more than one antimicrobial agent，and 29（21.01 %）were multi-drug resistant.The resistance rates to ampicillin，ampicillin/sulbactam，ceftriaxone，trimethoprim/sulfamethazole，ceftazidime，cefepime and piperacillin/tazobactam were 73.91%，71.01%，29.71%，29.71%，23.19%，11.59%，and 3.62%，respectively.All strains were sensitive to carbapenem antibiotics（meropenem，imipenem，and ertapenem）.The drug resistance rates of Salmonella typhimurium to ceftazidime and trimethoprim/sulfamethoxazole were higher than those of Salmonella enteritidis（38.30% vs 8.33%），the difference was statistically significant ( P < 0.05). Conclusion:Infants and young children are the high-incidence group of NTS enteritis，with the peak incidence period being from June to August each year，manifested by mucus-pus-blood stools, abdominal pain, vomiting，fever and other symptoms.Reasonable selection of antibiotics in time according to the local epidemic strains,changes of antimicrobial resistance and the results of drug sensitivity test of strains can effectively resist infection and reduce the production of drug-resistant beads.

Objective:To explore the impulsivity characteristics of patients with attention deficit hyperactivity disorder(ADHD)comorbid with borderline personality disorder(BPD)and the mediating role of emotion regula-tion strategies.Methods:A total of 96 patients with ADHD meeting the diagnostic criteria of the American Diagnos-tic and Statistical Manual of Mental Disorders,Fourth Edition(DSM-Ⅳ)were enrolled,48 of whom had comorbid BPD.Impulsivity was assessed with the Barratt Impulse Scale(BIS)and the impulse control difficulty dimensions of Emotional Regulation Difficulty Scale(DERS).Emotion regulation strategies were evaluated with the Emotion Regulation Questionnaire(ERQ).Results:No significant differences were found between the ADHD with and with-out BPD group in cognitive impulsivity,motor impulsivity,or non-planning impulsivity as assessed with the BIS(Ps＞0.05).However,the ADHD with BPD group showed higher scores on the DERS impulse control difficulty subscale(P＜0.001)and less frequent use of cognitive reappraisal strategies(P＜0.001).Cognitive reappraisal partially mediated the relationship between ADHD with BPD and impulse control difficulties,with an effect size of 25.9％.Conclusion:ADHD patients comorbid with BPD exhibit heightened emotional impulsivity,which might be partially mediated by reduced use of cognitive reappraisal.

BACKGROUND:Total flavonoids from Sophora flavescens have a variety of pharmacological effects,including anti-inflammatory,immunomodulatory,antioxidant,and anti-hepatic injury,but the therapeutic effects and mechanisms in non-alcoholic fatty liver disease are not clear.OBJECTIVE:To reveal the mechanism of total flavonoids from Sophora flavescens in the treatment of non-alcoholic fatty liver disease using bioinformatics,network pharmacology and zebrafish experimental validation.METHODS:A zebrafish model of non-alcoholic fatty liver disease was constructed to observe lipid accumulation,pathomorphologic changes,and expression of inflammatory genes in the liver of zebrafish after treatment with total flavonoids from Sophora flavescens.The active ingredients of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease-related targets were obtained from TCMSP,Swiss Target Prediction,and Bat-man databases.STRING was used to perform protein-protein interaction network analysis,GO functional enrichment and KEGG pathway enrichment analysis.Based on the GSE33814 dataset,the differentially expressed genes of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease intersection targets were screened out.Correlation analysis and receiver operating characteristic curve were performed using R4.3.2 software.Core genes were verified by the validation set GSE89632.RT-qPCR and western blot assays were performed to verify the expression of core pathway-related genes and proteins.RESULTS AND CONCLUSION:(1)Total flavonoids from Sophora flavescens could improve lipid accumulation in the liver of zebrafish with non-alcoholic fatty liver disease,significantly inhibited the elevation of lipid and aminotransferase levels in zebrafish(P<0.05),and regulated the expression of genes related to inflammation and lipid metabolism.(2)A total of 168 common targets were obtained using the network pharmacology,and top 10 core genes,identified by Cytoscape topology analysis,were HSP90AA1,STAT3,PIK3R1,MAPK1,AKT1,RXRA,PIK3CA,EGFR,JAK2,and ESR1.GO and KEGG analysis pathways mainly included insulin resistance,lipids,and atherosclerosis.There were a total of 59 differentially expressed genes after intersection of total flavonoids from Sophora flavescens and non-alcoholic fatty liver disease targets.The receiver operating characteristic curve and validation set analyses yielded six core targets that were significantly different between healthy individuals and patients with non-alcoholic fatty liver disease(P<0.01).(3)RT-PCR and western blot results verified that total flavonoids from Sophora flavescens inhibited the activation of the JAK2/STAT3 signaling pathway in zebrafish.To conclude,total flavonoids from Sophora flavescens may alleviate the inflammatory response through the JAK2/STAT3 signaling pathway,thus inhibiting lipid accumulation and improving non-alcoholic fatty liver disease.