Objective: To investigate the efficacy of magnesium-strontium co-doped hydroxyapatite mineralized collagen (MSHA/Col) in improving the bone repair microenvironment and enhancing bone regeneration capacity, providing a strategy to address the insufficient biomimetic composition and limited bioactivity of traditional hydroxyapatite mineralized collagen (HA/Col) scaffolds. Methods: A high-molecular-weight polyacrylic acid-stabilized amorphous calcium magnesium strontium phosphate precursor (HPAA/ACMSP) was prepared. Its morphology and elemental distribution were characterized by high-resolution transmission electron microscopy (TEM) and energy-dispersive spectroscopy. Recombinant collagen sponge blocks were immersed in the HPAA/ACMSP mineralization solution. Magnesium-strontium co-doped hydroxyapatite was induced to deposit within collagen fibers (experimental group: MSHA/Col; control group: HA/Col). The morphological characteristics of MSHA/Col were observed using scanning electron microscopy (SEM). Its crystal structure and chemical composition were analyzed by X-ray diffraction and Fourier transform infrared spectroscopy, respectively. The mineral phase content was evaluated by thermogravimetric analysis. The scaffold's porosity, ion release, and in vitro degradation performance were also determined. For cytological experiments, CCK-8 assay, live/dead cell staining, alkaline phosphatase staining, alizarin red S staining, RT-qPCR, and western blotting were used to evaluate the effects of the MSHA/Col scaffold on the proliferation, viability, early osteogenic differentiation activity, late mineralization capacity, and gene and protein expression levels of key osteogenic markers [runt-related transcription factor 2 (Runx2), collagen type Ⅰ (Col-Ⅰ), osteopontin (Opn), and osteocalcin (Ocn)] in mouse embryonic osteoblast precursor cells (MC3T3-E1). Results: HPAA/ACMSP appeared as amorphous spherical nanoparticles under TEM, with energy spectrum analysis showing uniform distribution of carbon, oxygen, calcium, phosphorus, magnesium, and strontium elements. SEM results of MSHA/Col indicated successful complete intrafibrillar mineralization. Elemental analysis showed the mass fractions of magnesium and strontium were 0.72% (matching the magnesium content in natural bone) and 2.89%, respectively. X-ray diffraction revealed characteristic peaks of hydroxyapatite crystals (25.86°, 31°-34°). Infrared spectroscopy results showed characteristic absorption peaks for both collagen and hydroxyapatite. Thermogravimetric analysis indicated a mineral phase content of 78.29% in the material. The scaffold porosity was 91.6% ± 1.1%, close to the level of natural bone tissue. Ion release curves demonstrated sustained release behavior for both magnesium and strontium ions. The in vitro degradation rate matched the ingrowth rate of new bone tissue. Cytological experiments showed that MSHA/Col significantly promoted MC3T3-E1 cell proliferation (130% increase in activity at 72 h, P < 0.001). MSHA/Col exhibited excellent efficacy in promoting osteogenic differentiation, significantly upregulating the expression of osteogenesis-related genes and proteins (Runx2, Col-Ⅰ, Opn, Ocn) (P < 0.01). Conclusion The MSHA/Col scaffold achieves dual biomimicry of natural bone in both composition and structure, and effectively promotes osteogenic differentiation at the genetic and protein levels, breaking through the functional limitations of pure hydroxyapatite mineralized collagen. This provides a new strategy for the development of functional bone repair materials

ObjectiveThis study systematically analyzed the arginine metabolic dysregulation in the rat model of heart failure （HF）， providing a modern scientific basis for elucidating the pathogenesis of HF and offering new insights for the prevention and treatment of HF with traditional Chinese medicine （TCM）. MethodsA thoracotomy was performed to ligate the left anterior descending coronary artery of rats， which induced acute myocardial ischemia and thus led to the development of post-myocardial infarction heart failure. The rats were divided into a sham surgery group and a model group， with eight rats in each group. Serum targeted metabolomics analysis was performed using ultra-performance liquid chromatography-triple quadrupole mass spectrometry （UPLC-TQ-S）， and the spatial distribution of metabolites in cardiac tissue was observed using airflow-assisted desorption electrospray ionizationmass spectrometry imaging （AFADESI-MSI）. Targets associated with HF and arginine metabolism were screened from databases including GeneCards and the Gene Expression Omnibus （GEO）， a protein-protein interaction （PPI） network was constructed， and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway and Gene Ontology （GO） was performed. Finally， molecular docking was conducted to verify the binding between core metabolic components and key targets， and potential TCMs were predicted based on the core pathways and targets. ResultsCompared with the sham surgery group， the levels of arginine and citrulline in the serum of model rats were significantly decreased （P<0.01）， while those of proline， ornithine， creatine， creatinine and glutamate were significantly increased （P<0.05， P<0.01）. Cardiac mass spectrometry imaging showed a decreased abundance of arginine in the local myocardial tissue. Bioinformatics analysis identified 24 core functional targets， such as the angiotensin-converting enzyme （ACE）， neuronal nitric oxide synthase （NOS1）， 5-hydroxytryptamine receptor 2A （HTR2A）， and epidermal growth factor receptor （EGFR）， and enrichment analysis indicated that these targets were significantly involved in the calcium signaling pathway， neuroactive ligand-receptor interactions， and phosphatidylinositol signaling pathway. Molecular docking confirmed strong binding activities between arginine， citrulline and HTR2A， as well as between creatine， creatinine and EGFR. Based on pathway-target prediction， potential TCM interventions， such as ginseng and magnolia， were identified. ConclusionThis study revealed characteristic arginine metabolic disorder in HF， and the core targets of HF were closely associated with the phosphatidylinositol signaling pathway. It provides a modern biological interpretation of the pathogenesis of HF in TCM from the perspectives of metabolites and signaling pathways， and offers valuable insights for targeted therapy of HF and the development of TCM.

ObjectiveThis study systematically analyzed the arginine metabolic dysregulation in the rat model of heart failure （HF）， providing a modern scientific basis for elucidating the pathogenesis of HF and offering new insights for the prevention and treatment of HF with traditional Chinese medicine （TCM）. MethodsA thoracotomy was performed to ligate the left anterior descending coronary artery of rats， which induced acute myocardial ischemia and thus led to the development of post-myocardial infarction heart failure. The rats were divided into a sham surgery group and a model group， with eight rats in each group. Serum targeted metabolomics analysis was performed using ultra-performance liquid chromatography-triple quadrupole mass spectrometry （UPLC-TQ-S）， and the spatial distribution of metabolites in cardiac tissue was observed using airflow-assisted desorption electrospray ionizationmass spectrometry imaging （AFADESI-MSI）. Targets associated with HF and arginine metabolism were screened from databases including GeneCards and the Gene Expression Omnibus （GEO）， a protein-protein interaction （PPI） network was constructed， and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway and Gene Ontology （GO） was performed. Finally， molecular docking was conducted to verify the binding between core metabolic components and key targets， and potential TCMs were predicted based on the core pathways and targets. ResultsCompared with the sham surgery group， the levels of arginine and citrulline in the serum of model rats were significantly decreased （P<0.01）， while those of proline， ornithine， creatine， creatinine and glutamate were significantly increased （P<0.05， P<0.01）. Cardiac mass spectrometry imaging showed a decreased abundance of arginine in the local myocardial tissue. Bioinformatics analysis identified 24 core functional targets， such as the angiotensin-converting enzyme （ACE）， neuronal nitric oxide synthase （NOS1）， 5-hydroxytryptamine receptor 2A （HTR2A）， and epidermal growth factor receptor （EGFR）， and enrichment analysis indicated that these targets were significantly involved in the calcium signaling pathway， neuroactive ligand-receptor interactions， and phosphatidylinositol signaling pathway. Molecular docking confirmed strong binding activities between arginine， citrulline and HTR2A， as well as between creatine， creatinine and EGFR. Based on pathway-target prediction， potential TCM interventions， such as ginseng and magnolia， were identified. ConclusionThis study revealed characteristic arginine metabolic disorder in HF， and the core targets of HF were closely associated with the phosphatidylinositol signaling pathway. It provides a modern biological interpretation of the pathogenesis of HF in TCM from the perspectives of metabolites and signaling pathways， and offers valuable insights for targeted therapy of HF and the development of TCM.

Triptolide （TP）， the core active component of the traditional Chinese medicine Tripterygium wilfordii ， exhibits remarkable pharmacological activities including anti-inflammatory， immunosuppressive and anti-tumor effects， and holds broad application prospects in the treatment of major diseases such as autoimmune diseases and malignant tumors. However， TP has a narrow therapeutic window and causes multi-organ toxicities including liver， kidney and reproductive toxicities， which severely restrict its safe clinical application and new drug development. Therefore， toxicity reduction and efficacy enhancement has become a core scientific problem urgently to be solved in this field. This paper systematically reviews the four core strategies for TP toxicity reduction and efficacy enhancement， including structural modification， dosage form improvement， herbal compatibility， and external therapies of traditional Chinese medicine. Among them， structural modification optimizes the toxic and efficacy characteristics of TP from the molecular structure level， with typica l derivatives including （5 R ）-5-hydroxy triptolide， ZT01， PG490-88， etc. Dosage form modification achieves toxicity reduction and efficacy enhancement via targeted and sustained-controlled drug release of diverse delivery systems. It includes triptolide preparations such as nanoparticles， liposomes， microemulsion gels and liquid crystals， possessing favorable clinical transformation potential. The herbal compatibility and external therapies of traditional Chinese medicine conform to the holistic view of traditional Chinese medicine and have a profound clinical application foundation， but their mechanisms of action are insufficiently elucidated， and they lack unified standardized specifications and high-quality evidence-based proof. In the future， we should rely on multi-omics technology to elucidate the toxic and efficacy mechanisms， integrate technologies to optimize preparations， improve the evaluation system and promote clinical transformation.

Purpose: Dual anti–human epidermal growth factor receptor 2 (HER2) drugs have become the standard regimen for neoadjuvant systemic treatment (NST) to HER2-positive breast cancer patients. However, the efficacy varies greatly among patients with different HER2 protein expression levels. Materials and Methods: A total of 575 HER2-positive breast cancer patients from multiple centers throughout China from 2013 to 2022 were retrospectively analyzed. We compared clinicopathological features in different HER2 immunohistochemistry classes (HER2 2+/in situ hybridization [ISH] + or HER2 3+), and their difference in response to NST and survival with single or dual anti-HER2 drugs. Drug sensitivity assays were used to evaluate different efficacy of anti-HER2 drugs in vitro. Results: Compared to HER2 3+ subgroup, the HER2 2+/ISH+ group had a higher proportion of hormone receptor–positive status (48.7% vs. 76.1%, p < 0.001), more HER2 protein loss after NST, lower pathological complete response (pCR) rate (46.07% vs. 16.24%, p < 0.001), and tended to have worse disease-free survival (DFS). In HER2 2+/ISH+ patients, treated with pertuzumab and trastuzumab in combination had no significant improvement in pCR (19.12% vs. 12.24%, p=0.287) and DFS (p=0.908) than using alone. Drug sensitivity assay showed poor efficacy with dual anti-HER2 drugs in HER2 2+/ISH+ cell lines; however, fam-trastuzumab deruxtecan drugs had a satisfactory effect. Conclusion Owing to the differences in clinicopathological features and treatment efficacy, we considered the HER2 2+/ISH+ group to be a distinct subtype and defined it as the HER2-moderate–positive subgroup. In this subgroup, dual anti-HER2 drugs did not exert significant improvement in pCR and DFS. Therefore, treatment optimization is warranted, with antibody-drug conjugate drugs as potential options.

Amyotrophic lateral sclerosis (ALS) is a chronic, progressive degenerative disease affecting both upper and lower motor neurons, primarily characterized by skeletal muscle weakness and atrophy. Notably, the same muscle group may exhibit asynchronous involvement. This study aims to investigate the involvement patterns of the orbicularis oculi (OOc) and orbicularis oris (OOr) in ALS patients, compare the findings with healthy controls (HCs) and myasthenia gravis (MG) patients, and explore the characteristics and clinical significance of facial muscle involvement in ALS.

Objective To investigate the predictive value of fluid-attenuated inversion recovery(FLAIR)vascular hyperintensity(FVH)combined with clinical indicators for the prognosis of intravenous thrombolysis in patients with acute cerebral infarction caused by middle cerebral artery(MCA)stenosis or occlusion.Methods This study retrospectively and consecutively enrolled patients with acute cerebral infarction caused by MCA stenosis or occlusion who underwent intravenous thrombolysis within 4.5 h of symptom onset at the Department of Neurology,Tianjin Huanhu Hospital,between January 2022 and October 2024.Baseline clinical data were collected,including sex,age,stroke risk factors(hypertension,diabetes,coronary heart disease,atrial fibrillation,prior stroke history,smoking,alcohol use),pre-thrombolysis blood pressure,National Institutes of Health stroke scale(NIHSS)score,serological markers(white blood cells,neutrophils,lymphocytes,blood glucose,uric acid,creatinine),completeness of the Willis circle,and thrombolysis time window(onset-to-treatment time:＜3.0h vs.3.0-4.5 h).FVH was assessed before thrombolysis using the Lee scoring system(0,1,or 2 points)based on FLAIR imaging.Inter-rater reliability for FVH scores between two radiologists was evaluated using Cohen's Kappa coefficient,with agreement levels defined as follows:almost perfect(Kappa value 0.81-1.00),substantial(Kappa value 0.61-0.80),moderate(Kappa value 0.41-0.60),fair(Kappa value 0.21-0.40),or slight/none(Kappa≤0.20).At 90 d post-thrombolysis,telephone follow-up was conducted to assess functional outcomes using the modified Rankin scale(mRS).Patients were dichotomized into favorable outcome group(mRS score 0-2)and poor outcome group(mRS score 3-6).Variables with statistical significance in univariate analysis underwent collinearity testing via variance inflation factor(VIF).Predictors with high collinearity(VIF＞10)were excluded,and the remaining variables were incorporated into a multivariate Logistic regression model to identify independent risk factors for thrombolysis prognosis.Individual clinical indicators and a combined predictive model were constructed,and their performances were evaluated using receiver operating characteristic curve analysis.The optimal cutoff values for individual and combined predictors were determined by maximizing the Youden index.Comparative analysis of individual clinical indicator and combined models were performed to assess predictive efficacy.Results Among 404 acute cerebral infarction patients treated with intravenous thrombolysis,282 achieved favorable outcomes while 122 had poor outcomes.FVH positivity was observed in 202 cases.(1)Inter-rater reliability:radiologists demonstrated substantial agreement in FVH scoring(Kappa=0.757,95%CI 0.702-0.812,P＜0.01).(2)Univariate analysis showed that significant intergroup differences were found in pre-thrombolysis laboratory values:white blood cell(9.21[7.37,10.85]×109/L vs.7.30[5.83,8.62]×109/L,Z=-7.064,P＜0.01),neutrophils(7.25[5.27,9.02]×109/L vs.4.93[3.81,6.20]×109/L,Z=-8.173,P＜0.01),lymphocytes(1.40[0.92,1.74]×109/L vs.1.57[1.16,1.99]×109/L,Z=-3.380,P=0.001),glucose(7.00[6.30,8.70]mmol/L vs.6.60[5.80,7.80]mmol/L,Z=-2.913,P=0.004),uric acid(318.50[257.50,392.00]μmol/L vs.340.50[282.00,416.25]μmol/L,Z=-2.168,P=0.030),and NIHSS score(8[5,10]vs.3[1,5],Z=-9.286,P＜0.01),FVH score(1[0,2]vs.0[0,1],Z=-4.036,P＜0.01).(3)Collinearity testing excluded white blood cell(VIF=20.561,margin of tolerance=0.049)due to high correlation with neutrophils(VIF=20.303,margin of tolerance=0.049).The rest variables with significant statistic difference in the univariate Logistic analysis were incorporated into the multivariable Logistic regression analysis,high neutrophils(OR,1.489,95%CI 1.314-1.688,P＜0.01),NIHSS score(OR,1.306,95%CI 1.213-1.407,P＜0.01),FVH score(OR,1.976,95%CI 1.398-2.794,P＜0.01)pre-thrombolysis were the independent risk factors for the poor outcome of acute cerebral infarction patients with intravenous thrombolysis treatment.(4)Predictive performance:the optimal cutoff values of FVH score,NIHSS score and neutrophils pre-thrombolysis was 1.000,5.000 and 6.586×109/L respectively,and their area under the curve(AUC)were 0.616(95%CI 0.566-0.663;55.7%sensitivity,63.1%specificity),0.789(95%CI 0.746-0.828;77.7%sensitivity,71.3%specificity),0.756(95%CI 0.711-0.797;80.9%sensitivity,59.8%specificity),respectively;the cutoff value of combined model was 0.786(AUC=0.863;95%CI 0.825-0.895,71.6%sensitivity,88.5%specificity).Conclusion The high FVH score,NIHSS score and neutrophil count pre-thrombolysis were independent predictors of poor prognosis of intravenous thrombolysis in patients with acute cerebral infarction,and the model combining the aforementioned predictors has enhanced predictive value.

Sepsis is a common critical illness in the pediatric intensive care unit，with a high prevalence and mortality rate，and is characterized by acute onset，rapid progression，and poor prognosis，which poses a significant challenge for the pediatric intensive care unit.Bile acids play an important role in the occurrence and development of sepsis，and are involved in the regulation of inflammation，immune function and other pathophysiological processes.Alterations in bile acids in early sepsis are associated with disease progression and prognosis.Therefore，further research on the role of bile acids in sepsis can provide new ideas for the clinical diagnosis and treatment of sepsis，and help to improve the early identification and prognosis of sepsis.This article reviewed the role of bile acids in pediatric sepsis.

Objective:To investigate the impact of different etiologies on the spatial distribution pattern of infarcts and the mapping pattern of focal symptoms in acute ischemic stroke (AIS) using a population-based standardized spatial analysis of MRI.Methods:This was a cross-sectional study. Clinical [age, sex distribution, admission National Institutes of Health Stroke Scale (NIHSS) score and 90-day modified Rankin Scale (mRS) score at discharge, etc.] and imaging data of 2 610 patients with AIS attending 9 Medical Centers from January 2015 to December 2021 were retrospectively analyzed. All patients were categorized into 1 718 cases of large artery atherosclerosis (LAA) type, 335 cases of cardioembolism (CE) type, and 557 cases of small artery occlusion (SAO) type according to TOAST typing. All patients underwent diffusion-weighted imaging, and the detected infarct lesions were segmented and aligned to the standardized space using artificial intelligence-assisted methods, and the spatial distribution frequency heatmaps of lesion locations in patients with different TOAST subtypes were plotted and compared with each other by χ2 test. Lesion-symptom image brain maps with different clinical symptoms were further plotted, and differences of lesion-symptom image relationships among different TOAST subtypes were observed and compared with each other by interaction effect. Results:In all patients, the favored sites of infarct lesions were the bilateral middle cerebral artery region in the anterior circulation and the occipital and brainstem regions in the posterior circulation. Compared with the LAA type, the CE type lesions were more likely to occur in the anterior cerebral artery region, the occipital lobe, and the cerebellum posterior, while the SAO type lesions were more likely to occur in the perforator artery supply area. The lesion-symptom mapping results showed that AIS patients with infarct lesions in the frontoparieto-temporal region in the presence of a left middle cerebral artery supply had higher admission NIHSS scores and higher discharge 90-day mRS scores for the LAA type than for the CE type( P<0.05); AIS patients with infarcted lesions in the brainstem region and some cerebellar regions in the presence of vertebrobasilar artery supply had higher admission NIHSS scores and higher discharge 90-day mRS scores for the CE type than for the LAA type( P<0.05). Conclusion:At the population level, brain mapping reveals specific infarct distribution patterns and differences in lesion-symptom mapping patterns of different etiologies AIS patients, providing imaging evidence for the understanding of AIS pathogenetic mechanisms and clinical management.

BACKGROUND:Human endometrial mesenchymal stem cells can directly repair the damaged endometrium,promote angiogenesis,and restore the morphological structure of the uterus.However,after the direct injection of stem cells into the damaged endometrium,the cell survival rate is low,the retention time is short,and the repair effect is limited.OBJECTIVE:To observe the effect of polycaprolactone-hyaluronic acid electrospinning membrane combined with human endometrial mesenchymal stem cells on endometrial injury in rats.METHODS:(1)Cell experiment:Human endometrial mesenchymal stem cells were extracted by collagenase digestion method.Polycaprolactone-hyaluronic acid electrospinning membrane was prepared by electrospinning technology.The human endometrial mesenchymal stem cells were inoculated on polystyrene culture plate and polycaprolactone-hyaluronic acid electrospinning membrane.The proliferation and adhesion of the cells were observed by DNA quantitative analysis,WST-1 cell activity test,phalloidin staining,and scanning electron microscopy.The mRNA expressions of CD90 and Meflin in electrospun membrane were detected by qRT-PCR.(2)Animal experiments:27 female SD rats in estrus were selected to establish uterine adhesion model by mechanical scratching method and randomly divided into three groups with nine rats in each group:The blank control group did not receive any treatment;the control group was implanted with polycaprolacton-hyaluronic acid electrospinning membrane;the experimental group was implanted with polycaprolacton-hyaluronic acid electrospinning membrane/human endometrial mesenchymal stem cell mesh.Samples were collected at 3,7,and 14 days after surgery.Hematoxylin-eosin staining was used to observe the morphological structure of uterus and the number of glands.qRT-PCR and immunofluorescence staining were used to observe the expression of CD31 and vascular endothelial growth factor in uterine tissue.RESULTS AND CONCLUSION:(1)Cell experiment:Compared with polystyrene culture plate,polycaprolactone-hyaluronic acid electrospinning membrane could promote the proliferation and adhesion of human endometrial mesenchymal stem cells.Polycaprolactone-hyaluronic acid electrospinning membrane supported the expression of CD90 and Meflin genes of human endometrial mesenchymal stem cells.(2)Animal experiments:Hematoxylin-eosin staining showed that polycaprolactic-hyaluronic acid electrospinning membrane/human endometrial mesenchymal stem cell patch could promote the recovery of endometrial morphological structure after injury.The endometrial thickness and number of gland on day 14 after surgery were higher than those in blank control group and control group(P<0.05).qRT-PCR and immunofluorescence staining showed that the mRNA and protein expressions of CD31 and vascular endothelial growth factor in the experimental group were higher than those in the blank control group and the control group at 7 and 14 days after surgery(P<0.05).(3)The results showed that polycaprolacton-hyaluronic acid electrospinning membrane could improve the survival rate of stem cells and prolong the contact time between stem cells and the damaged tissue,and the composite transplantation of the two could better repair the damaged endometrial tissue.