ObjectiveTo investigate the effects of Liuwei Dihuangwan on mammalian target of rapamycin （mTOR）-mediated synaptic plasticity in the prefrontal cortex-hippocampus circuit in the rat model of valproic acid （VPA）-induced autism spectrum disorder （ASD） and to explore its potential mechanism for reducing behavioral abnormalities in ASD rats. MethodsThirteen SD pregnant rats were randomized into the VPA group （10 rats） and the control group （3 rats）. On gestational day 13， the VPA group was intraperitoneally injected with VPA solution （600 mg·kg^-1）， while the control group was injected with an equal volume of normal saline. Male pups of 21 days old from both groups underwent behavioral tests to screen the ASD model rats （32 rats）. These rats were then randomly assigned to the model （distilled water）， vitamin D （1 480 U·kg^-1）， low-dose （0.75 g·kg^-1） Liuwei Dihuangwan， and high-dose （1.5 g·kg^-1） Liuwei Dihuangwan groups， and normal male pups were selected as the blank group （distilled water）， with 8 rats in each group. Each group was treated with the corresponding drug or an equal volume of distilled water via gavage daily. After drug administration， behavioral tests were conducted again， followed by anesthesia and tissue collection. Nissl staining was carried out to observe the morphological changes of neurons in the prefrontal cortex and hippocampus. Transmission electron microscopy was used to observe changes in hippocampal synaptic structure. Immunohistochemistry and Western blot were employed to determine the expression of mTOR， phosphatidylinositol 3-kinase （PI3K）， and protein kinase B （Akt） in the prefrontal cortex， as well as synaptophysin-1 （SYP-1）， postsynaptic density 95 （PSD95）， and N-methyl-D-aspartate receptors （NMDARs） in the hippocampus. ResultsCompared with the control group， the model group exhibited severe growth retardation and developmental deformities， with abnormal behavioral performance and pathological damage to neurons and synapses in the prefrontal cortex and hippocampus. Compared with the model group， all treatment groups showed reduced behavioral abnormalities and pathological damage to neurons and synapses in the prefrontal cortex and hippocampus， with the most significant effects in the high-dose Liuwei Dihuangwan group. Immunohistochemistry and Western blotting results showed that compared with the control group， the model group exhibited significantly increased protein levels and phosphorylation ratios of p-mTOR， p-Akt， and p-PI3K in the prefrontal cortex （P<0.05， P<0.01）， and decreased protein levels of SYP-1 and PSD95 and increased protein level of NMDARs in the hippocampus （P<0.01）. Compared with those in the model group， the protein levels of p-mTOR， p-Akt， and p-PI3K in the prefrontal cortex decreased in the vitamin D and high-dose Liuwei Dihuangwan groups （P<0.05）， and the p-mTOR/mTOR， p-Akt/Akt， and p-PI3K/PI3K ratios in the prefrontal cortex declined in the vitamin D group （P<0.05）. The high-dose Liuwei Dihuangwan group showed a reduction in p-PI3K/PI3K ratio （P<0.05）. The protein level of SYP-1 and PSD95 in the hippocampus increased in the vitamin D， low-dose Liuwei Dihuangwan， and high-dose Liuwei Dihuangwan groups （P<0.05， P<0.01）， while the protein level of NMDARs decreased in the vitamin D and high-dose Liuwei Dihuangwan groups （P<0.01）. ConclusionLiuwei Dihuangwan significantly reduces VPA-induced ASD-like behaviors and enhances the regeneration and repair of neurons in the prefrontal cortex and synaptic structures in the hippocampus by downregulating of PI3K/Akt/mTOR expression in the prefrontal cortex， upregulating SYP-1 and PSD95 expression in the hippocampus， and inhibiting NMDARs expression.

Pasteurella multocida(Pm)type A is an important pathogen responsible for respiratory diseases,such as bovine pneumonia,which seriously restricts the development of cattle industry in China.Currently,the prevention of Pm infection-related diseases primarily relies on vaccination in production.However,the diverse Pm serotypes result in inadequate cross-immunological protection from vaccines.Therefore,it is of great significance to develop vaccines with cross-protection for the prevention and control of Pm infectious diseases.The previous studies conducted by our team have demonstrated that PmCQ2△cra exhibits a strong immune protective effect against Pm type A(PmA),Pm type B(PmB),and Pm type F(PmF).Transcriptomic sequencing results suggest that the cross-immunoprotective effect of PmCQ2△cra may be attributed to high expression levels of bacterial surface protective antigens.Consequently,four putative immune protective antigens,namely PmCQ2-5175,PmCQ2-6290,PmCQ2-0275 and PmCQ2-2640,were screened through bioin-formatics analysis in this study.Subunit vaccines formulated with these potential antigenic proteins exhibited protective efficacy of 62.5％,25％,12.5％and 10％against PmA-infected mice,respectively.Importantly,PmCQ2-5175,one of the most protective single-component antigen vac-cines,demonstrating a 75％cross-protection against PmB infection in mice.Furthermore,the pro-tective efficacy of the PmCQ2-5175 protein screened in this study was superior to that of the previ-ously reported Pm antigen protein plpE.Moreover,the fusion expression protein PmCQ2-5175-PLPE exhibited better protective effects against PmA compared to a single protein.The findings of this study will establish a theoretical foundation for the advancement of Pm subunit vaccines with broad-spectrum immune protection.

Objective To develop a core outcome set(COS)for clinical effectiveness trials of heart failure with preserved ejection fraction(HFpEF).Methods Outcome measures were collected through database literatures search,clinical experts questionnaire survey and semi-structured patients interview.Then,the outcome measures pool was constructed and domains were divided.Candidate outcome measures of COS were screened through two rounds of Delphi survey.Finally,a consensus meeting was held to determine COS and reach a consensus.Results A total of 317 outcome measures which could be divided into 6 domains were collected through literature research,questionnaire survey and semi-structured interview.15 candidate outcome measures of COS were screened through two rounds of Delphi survey.Finally,the consensus meeting reached consensus on a COS with 6 entries.Conclusion In this study,a COS for clinical effectiveness trials of HFpEF was developed,which is conducive to the standardization of efficacy evaluation.

As the global population ages and cancer diagnostic and treatment technologies improve, the number of elderly cancer survivors continues to increase, and their complex care needs challenge the traditional mono-disciplinary care model. This paper explores the dilemmas of implementing a long-term care system and suggestions for future research through a comprehensive overview of the care needs of elderly cancer survivors and the progress of interdisciplinary research, with the aim of providing a theoretical basis and practical reference for improving the long-term care system and enhancing patients' quality of life.

Objective To investigate the expression of ferritinophagy-related gene ELAV-like RNA binding protein 1(ELAVL1)in multiple myeloma(MM)and elucidate its diagnostic and prognostic value for MM.Methods First,we analyzed ELAVL1 expression level in healthy controls and MM patients using data from the GEO and TCGA databases.Subsequently,bone marrow specimens were collected from 28 newly diagnosed MM patients and 20 healthy controls,and qRT-PCR was employed to validate ELAVL1 expression.The diagnostic and prognostic potential of ELAVL1 was assessed using ROC curve analysis and Kaplan-Meier survival curves.Additionally,univariate and multivariate COX regression analyses were performed to identify independent risk factors for MM prognosis.Finally,KEGG and GO enrichment analyses were performed using the DAVID online platform.Results The level of ELAVL1 expression was significantly higher in newly diagnosed MM patients and refractory/relapsed MM patients than in the healthy controls(P＜0.001).Moreover,ELAVL1 expression was positively correlated with the International Staging System(ISS)stage of MM(P＜0.01).Furthermore,qRT-PCR validation confirmed that ELAVL1 expression was elevated in the 28 newly diagnosed MM patients compared to the 20 healthy controls(P＜0.001).ROC curve analysis demonstrated that ELAVL1 could effectively differentiate between newly diagnosed MM patients,healthy controls,and MGUS patients(P＜0.001 and P=0.000 2,respectively).Survival analysis revealed that high ELAVL1 expression was associated with shorter progression-free survival(P=0.0141)and overall survival(P=0.008 0).Univariate and multivariate COX regression analyses identified high ELAVL1 expression as an independent risk factor for poor MM prognosis(P=0.005 0).KEGG analysis suggested that ELAVL1 might be involved in the Hippo and MAPK signaling pathways.Conclusion High ELAVL1 expression in MM may serve as a biomarker for diagnosis and poor prognosis.ELAVL1 may promote MM initiation and progression via the Hippo and MAPK signaling pathways.

Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

Objective:To explore the protective effects and mechanisms of an indole-3-acetaldehyde (I3A)-loaded inulin-based hydrogel against radiation-induced intestinal injury.Methods:The gelation properties and injectability of the I3A-loaded inulin-based hydrogel were detected using a rheometer, and its biocompatibility was assessed via a CCK-8 assay. Eighteen C57BL/6 mice (aged: 6-8 weeks) were stratified by body weight and randomly assigned into three groups with 6 mice in each group: blank control, irradiation-only, and irradiation+ hydrogel protection. Abdominal irradiation was administered using 137Cs γ-rays at 17 Gy. The irradiation+ hydrogel protection group received 200 μl/day of I3A-loaded inulin-based hydrogel for two days before and 2-3 days after irradiation. Meanwhile, the irradiation-only group was treated with an equivalent volume of sterile water via gavage. The mice were euthanized four days post-irradiation, and their intestinal tissues were harvested. Hematoxylin-eosin (HE) staining, Ki67 immunohistochemistry, and TUNEL immunofluorescence were performed to assess histopathological damage, epithelial cell proliferation, and apoptosis, respectively. Quantitative real-time PCR (qRT-PCR) was employed to measure mRNA levels of inflammatory and antioxidant factors. Gut microbiota composition was analyzed via 16S rRNA sequencing. Results:The test results of the rheometer confirmed successful hydrogel formation. CCK-8 assays demonstrated excellent biocompatibility. Compared with the irradiation-only group, the irradiation+ hydrogel protection group exhibited preserved intestinal histoarchitecture, a 1.5-fold increase in intestinal cell proliferation ( t = 8.35, P < 0.05), and a 2-fold reduction in radiation-induced apoptosis ( t = 7.94, P < 0.05). Moreover, the hydrogel group showed significantly elevated expression of the anti-inflammatory cytokine IL-10 and antioxidant factors NRF-2 and HO-1 ( t = 3.16, 24.83, 5.92, P < 0.05), alongside reduced levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α ( t = 5.15, 3.82, 3.83, P < 0.05). Gut microbiota analysis revealed significant modulation in microbial composition and abundance in the hydrogel group. Conclusions:The I3A-loaded inulin-based hydrogel can significantly promote intestinal cell proliferation, reduce radiation-induced apoptosis, and enhance both anti-inflammatory and antioxidant responses. In addition, it regulates gut microbiota composition and abundance, protecting against radiation-induced intestinal injury.

Objective To propose a whole-life cycle management model for valvular heart disease (VHD), systematically elucidate its underlying logic and implementation pathways, and concurrently review and analyze its preliminary application outcomes. Methods Since 2020, West China Hospital of Sichuan University has established a management system encompassing "assessment-decision-intervention-follow-up", including: (1) a risk-stratified, tiered management pathway; (2) six core functions ("promotion, screening, prevention, diagnosis, treatment, and rehabilitation") coordinated by disease-specific managers; (3) an intelligent decision support information platform; and (4) a collaborative network of multidisciplinary teams and regional academic alliances. To evaluate the effectiveness of this management model, we retrospectively included three cohorts: (1) the population screened by echocardiography from 2020 to 2024, analyzing the detection rate of aortic valve disease and risk stratification; (2) patients enrolled in the whole-life cycle management from April 2021 to December 2024, assessing follow-up outcomes, hospital satisfaction, and changes in quality of life; (3) patients who underwent transcatheter aortic valve replacement (TAVR) from January 2022 to January 2024, evaluating the one-year all-cause mortality rate, perioperative complications, and improvements in New York Heart Association (NYHA) classification. Results Between 2020 and 2024, a total of 583 874 individuals underwent echocardiographic screening. A total of 48 089 patients with aortic valve disease were identified, including 3 401 (7.1%) high-risk patients, 18 657 (38.8%) moderate-risk patients, and 26 031 (54.1%) low-risk patients. Among them, 2 417 patients were enrolled in whole-life cycle management. Patient satisfaction scores showed a yearly increase, rising from 73.89 points before 2020 to 93.74 points in 2024. The 1-year mortality rate in the TAVR cohort decreased to 5.3%, significantly lower than the 8.2% observed under early standard management between 2014 and 2019 (P<0.01). Conclusion Through process optimization and resource integration, the VHD whole-life cycle management model has demonstrated significant effectiveness in standardizing diagnostic and follow-up procedures, enhancing patient satisfaction and quality of life, and reducing mortality. These outcomes highlight its practical value for broader implementation in China.