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 effects of quercetin on cuproptosis and L-type calcium currents in the myocardium of diabetic rats. METHODS: Forty SD rats were randomized into control group and diabetic model groups. The rat models of diabetes mellitus (DM) induced by high-fat and high-sugar diet combined with streptozotocin (STZ) injection were further divided into DM model group, quercetin treatment group, and empagliflozin treatment group (n=10). Blood glucose and body weight were measured every other week, and cardiac function of the rats was evaluated using echocardiography. HE staining, Sirius red staining, and wheat germ agglutinin (WGA) analysis were used to observe the changes in myocardial histomorphology, and serum copper levels and myocardial FDX1 expression were detected. In cultured rat cardiomyocyte H9c2 cells with high-glucose exposure, the effects of quercetin and elesclomol, alone or in combination, on intracellular CK-MB and LDH levels and FDX1 expression were assessed, and the changes in L-type calcium currents were analyzed using patch-clamp technique. RESULTS: The diabetic rats exhibited elevated blood glucose, reduced body weight, impaired left ventricular function, increased serum copper levels and myocardial FDX1 expression, decreased L-type calcium currents, and prolonged action potential duration. Quercetin and empagliflozin treatment significantly lowered blood glucose, improved body weight, and restored cardiac function of the diabetic rats, and compared with empagliflozin, quercetin more effectively reduced serum copper levels, downregulated FDX1 expression, and enhanced myocardial L-type calcium currents in diabetic rats. In H9c2 cells, high glucose exposure significantly increased myocardial expressions of FDX1, CK-MB and LDH, which were effectively lowered by quercetin treatment; Elesclomol further elevated FDX1, CK-MB and LDH levels in the exposed cells, and these changes were not significantly affected by the application of quercetin. CONCLUSIONS Quercetin ameliorates myocardial injury in diabetic rats possibly by suppressing myocardial cuproptosis signaling and restoring L-type calcium channel activity.
Animals ; Quercetin/pharmacology* ; Calcium Channels, L-Type/metabolism* ; Diabetes Mellitus, Experimental/metabolism* ; Rats, Sprague-Dawley ; Rats ; Myocytes, Cardiac/drug effects* ; Myocardium/pathology* ; Male

Objective To evaluate the promoting effect of continuous low-intensity pulsed ultrasound(LIPUS)combined with microbubble(MB)cavitation therapy(hereinafter referred to as ultrasound cavitation therapy)on microcirculatory perfusion in the ischemic hindlimbs of mice,and to explore the non-invasive therapeutic potential of this treatment for limb arterial ischemic injury.Methods A mouse model of left hindlimb ischemia was established,and the mice were randomly assigned to 4 groups(16 mice per group)according to different treatment methods:model group,ultrasound contrast microbubble group(MB group),LIPUS treatment group(LIPUS group),and ultrasound cavitation therapy group(LIPUS+MB group).Mice in the model group were injected with 0.1 mL of normal saline via the tail vein,those in the MB group were injected with 0.1 mL of MB via the tail vein,those in the LIPUS group were treated with LIPUS on the ischemic hindlimb after injection of 0.1 mL of normal saline via the tail vein,and those in the LIPUS+MB group were treated with LIPUS on the ischemic hindlimb after injection of 0.1 mL of MB via the tail vein;each group was injected once a day for a total of 7 d.On the 1st,4th and 7th days after treatment,the microcirculatory perfusion in the ischemic hindlimbs of mice was evaluated using contrast-enhanced ultrasound.The effects of different treatments on promoting microcirculatory perfusion in the ischemic hindlimbs of mice were assessed by combining hematoxylin-eosin(H-E)staining and CD31 immunohistochemical staining of the gastrocnemius muscle tissue in the hindlimbs.Results The left hindlimb ischemia model was successfully constructed,and all model mice showed obvious ischemic microcirculation perfusion disorders with good model stability.After the 7th day of treatment,the LIPUS+MB group showed a increase in microcirculation perfusion in the ischemic hindlimb,with the ratio of microvascular flow on the ischemic to non-ischemic sides higher than that of the LIPUS group([94.33±4.51]%vs[70.33±2.09]%,P＜0.05).H-E staining results showed that the LIPUS+MB group had more newly formed capillaries and myofibroblasts in the gastrocnemius muscle,with better muscle structure repair compared to the LIPUS group,while the model group and MB group showed muscle cell necrosis,disorganized arrangement of muscle bundles,and sparse capillaries.CD31 immunohistochemical analysis further confirmed that ultrasonic cavitation therapy significantly outperformed traditional LIPUS treatment in promoting microcirculation perfusion,microvascular neogenesis,and tissue repair in ischemic skeletal muscles(CD31 relative expression level 5.03±0.33 vs 3.57±0.21,P＜0.01).Conclusion Compared with single LIPUS treatment,continuous ultrasound cavitation therapy has a more significant effect on promoting microcirculation perfusion in the ischemic hindlimb of mice,which provides a new strategy for microcirculatory perfusion disorders in skeletal muscles of limbs caused by peripheral arterial ischemic diseases.

Objective: To predict and screen potential biomarkers of systemic lupus eythematosus(SLE) based on machine learning algorithms and structural biology, and to reveal their mechanisms of action and to provide new targets for disease diagnosis and treatment. Methods: Four machine learning algorithms, random forest(RF), eXtreme gradient boosting(XGBoost), support vector machine(SVM), least absolute shrinkage and selection operator(LASSO), were used to analyze the gene expression data of SLE patients in GEO(datasets: GSE121239 and GSE11907) to analyze the gene expression data of SLE patients and screen key markers. Peripheral blood single nucleated cells(PBMCs) from SLE patients were collected and RT-qPCR was used to detect differential gene expression levels. Subsequently, GSEA enrichment analysis was used to identify biomarker-related pathways. CIBERSORT immune infiltration analysis and protein interactions network were applied to calculate the sample immune cell infiltration abundance. Single-cell data were analyzed for gene expression specificity in immune cells. Interaction relationships in combination with AlphaFold3(AF3) were predicted. Results: Multiple algorithms were screened together to identify the unique marker gene HERC5 , and expression analysis of multiple datasets showed that HERC5 was highly expressed in SLE compared to the normal group (P < 0. 05) , and RT⁃qPCR verified the same trend (P = 0. 006 2) . Functional enrichment analysis identified the major pathway promoted by HERC5 in SLE as the interferon receptor signalling pathway (P < 0. 05) . Immune infiltration analysis showed that HERC5 was closely associated with immune cells (Neutrophils : r = 0. 39 , P < 0. 05 ; Memory B cells : r = 0. 33 , P < 0. 05 ; Activated dendritic cell : r = 0. 52 , P < 0. 05) . Most HERC5 ⁃related interacting proteins were associated with SLE ,and potential transcription factors of HERC5 and its related genes were also significantly associated with immune responses. Conclusion The HERC5 gene is an important biomarker for SLE , which upregulates the interferon pathway to promote SLE progression and provides a new target for SLE diagnosis and treatment.

Objective: To explore the association between greenness surrounding school and aggression among primary school students, and to explore the potential mediating roles of social support, loneliness, particulate matter (PM2.5) and Nitrogen Dioxide (NO2) in this association, in order to provide a scientific reference for preventing and ameliorating aggressive behaviors of primary school students. Methods: The data was used from a survey of children and adolescents conducted in 2015. The Chinese version of the Buss-Warren Aggression Questionnaire was used to assess total and subtypes of aggression, and the mean values of normalized difference vegetation index (NDVI) of 100 m, 500 m, 1 000 m circular buffers surrounding school were used to indicate the participants greenness exposure. PM2.5 and NO2 datas were obtained from the China High Air Pollutants Dataset.Generalized Linear Mixed Models were used to assess the associations of greenness surrounding school with total and subtypes of aggression. Results: Per IQR increment of NDVI-500 m [OR(95%CI)=1.09(1.03-1.15)] and NDVI-1 000 m[OR(95%CI)=1.07(1.02-1.13)] were positively correlated with physical aggression among primary school children, and per IQR increment of NDVI-100 m [OR(95%CI)=0.94(0.90-0.99)], NDVI-500 m [OR(95%CI)=0.93(0.89-0.98)] and NDVI-1 000 m [OR(95%CI)=0.95(0.91-1.00)] were negatively associated with verbal aggression (P<0.05). Mediation analyses revealed that social support partially mediated the association between the NDVI-500 m and physical aggression (mediation ratio:18.0%) and verbal aggression (mediation ratio:-8.3%) among primary school students, and loneliness partially mediated the association between the NDVI-500 m and physical aggression and verbal aggression among elementary school students effects, with proportion mediated ratios of -10.0% and 21.0%, respectively (P<0.05). Conclusions Exposure to school surrounding greenness is likely to associated with physical aggression and verbal aggression in primary school students, and social support and loneliness may partially mediate these associations.

Ultrasound-stimulated microbubble cavitation(USMC)is a cavitation phenomenon triggered by oscillating microbubbles in ultrasound field,and this effect has led to breakthroughs in improving the permeability of cell membranes,enhancing the sensitivity of tumor cells to chemotherapy or immunotherapy,and increasing the penetration of thrombolytic drugs into blood clots and vascular recanalization.In recent years,the cross-fertilization of ultrasound medicine and materials science have given rise to the study of ultrasound-responsive multifunctional nanobubble to enhance USMC treatment.This article reviews the application and research progress of USMC in improving tissue perfusion in ischemic diseases,tumor chemotherapy and immunotherapy,ultrasonic thrombolysis,and other treatments.

Preoperative patients′ preparedness for selective surgery is of great significance in improving surgical efficiency, improving treatment outcomes, and optimizing the quality of medical care. The lack of unified standards for existing evaluation tools hinders their clinical application. This article provides a review of the development, content, reliability, validity, and application of existing evaluation tools, and compares and analyzes them, in order to provide reference for medical workers to select suitable evaluation tools and construct a patient-centered preoperative preparation strategy.

Objective:To summary the clinical phenotype and genotype characteristics of 2 cases of autosomal dominant mental retardation (MRD) caused by TRIO gene variation. Methods:Retrospective study of the clinical data of 2 cases of autosomal dominant MRD caused by TRIO gene mutations diagnosed at the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University in April 2019 and January 2023 was conducted. The clinical features were summarized and gene analysis and follow-up were carried out. Results:The 2 patients were 6 years and 5 months old and 5 months old males, respectively. Clinical manifestations included seizures, cognitive and motor disorders, low intelligent development; case 1 had microcephaly, attention deficit disorder, ataxia, and aggressive behavior, and case 2 had macrocephaly. Brain magnetic resonance imaging revealed cerebellar atrophy in case 1, and non-specific dilation of the subarachnoid space and hypoplasia of the corpus callosum in case 2. Analysis of chromosome karyotype and chromosome copy number variation in 2 children showed no abnormalities. Whole exome sequencing revealed novel missense mutations in the TRIO gene in both patients [NM_007118:c.4289C>A(p.Thr1430Lys), c.4111C>A(p.His1371Asn), respectively]. The application of rehabilitation function training and a variety of anti-seizure medications can not fully and effectively control the seizure. Conclusion:TRIO gene c.4289C>A(p.Thr1430Lys), c.4111C>A(p.His1371Asn) de novo missense variants were the genetic etiology of the 2 probands,causing rare autosomal dominant MRD type 44 and 63.

Objective:To investigate the clinical characteristics of patients with combined oxidative phosphorylation deficiency type 4 (COXPD4) related to TUFM gene variation, in order to improve clinicians′ understanding of the disease. Methods:A case of COXPD4 with cystic leukodystrophy admitted to the Children′s Hospital of Zhengzhou University in June 2021 was taken as the study subject, and her clinical characteristics and genetic testing results were retrospectively analyzed. The "combined oxidative phosphorylation deficiency type 4" " TUFM gene" "cystic leukodystrophy" "combined oxidative phosphorylation deficiency 4" "COXPD 4" " TUFM" and "cystic leukodystrophy" were used as keywords, and the documents on COXPD4 related to TUFM gene mutations were reviewed from Wanfang Data Knowledge Service Platform, CNKI, PubMed Document Database, and National Center for Biotechnology Information (NCBI) until August 2021. The COXPD4 patients that have been reported internationally were analyzed for clinical features and variant types. Results:The patient was a 2-month-old girl with clinical manifestations of delayed development and progressive aggravation, elevated lactic acid in serum and cerebrospinal fluid, and diffuse white matter dysplasia with multiple cystic lesions in cerebral magnetic resonance imaging (MRI). Whole exome sequencing showed TUFM gene complex heterozygous variants c.684_684+4delGGTGA and c.1105C>T, which had not been reported in the past. A total of 5 cases of COXPD4 were reported in 4 English literatures. Together with 1 case in this study, there were 4 cases with detailed clinical history data, including 1 male and 3 females. The clinical manifestations were severe early-onset lactic acidosis and developmental lag, and 3 cases were accompanied by progressive infantile encephalopathy. Among them, 3 cases underwent head MRI examination, all of which showed diffuse white matter signal with multiple cystic lesions, 2 cases with basal ganglia involvement and multiple cerebellar gyri deformity. Genetic test indicated different types of TUFM gene variation. Conclusions:COXPD4 is a rare hereditary mitochondrial disease. For cases with COXPD4 clinical and imaging features, TUFM gene mutations can be screened first.

Objective To observe the value of conventional ultrasound combined with ultrasonic elastography for evaluating the severity of active lesions of juvenile localized scleroderma(JLS).Methods Totally 27 JLS children with 46 active lesions were prospectively enrolled.The thickness,echo and blood flow of skin and subcutaneous tissue of JLS lesions and the paired sites were evaluated using conventional ultrasound,while the skin stiffness of all lesions and paired sites were assessed using shear wave elastography(SWE),and the strain ratio of lesions and surrounding skin were evaluated using strain elastography(SE).The thickness,echo and blood flow of skin as well as subcutaneous tissue,and the Young's modulus of skin were compared between JLS active lesions and the paired sites.The correlations of the individual sum total of each Young's modulus and the limited scleroderma activity index(LoSAI)or the limited scleroderma injury index(LoSDI)were explored.Results Compared with the paired site,no significant difference of the skin thickness was found among 46 JLS lesions(P＞0.05),but JLS lesions had thinner subcutaneous tissue(P＜0.05)and greater Young's moduli(all P＜0.05).The strain ratio of the lesions and surrounding skin were all larger than 2.For JLS children with active lesions,the individual sum total of Young's moduli had moderate rank correlations with LoSAI(rs=0.63-0.69,all P＜0.05),but there was no significant rank correlation with LoSDI(rs=0.27-0.33,P＞0.05).Conclusion Compared with the paired site,JLS active lesions had thinner subcutaneous tissue and stiffer skin.The higher the lesion skin stiffness,the more severe the JLS lesion activity.