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关键词： 痴呆   石菖蒲   动物实验   大鼠   中药药理  

摘要： 目的研究石菖蒲对阿尔茨海默病(AD)模型大鼠海马神经细胞凋亡及PTEN诱导的激酶1(PINK1)/E3泛素蛋白连接酶(Parkin)信号通路的影响。方法取50只大鼠建立AD大鼠模型,随机分为模型组(AD组)、石菖蒲低剂量组(ATS-L组)、石菖蒲中剂量组(ATS-M组)、石菖蒲高剂量组(ATS-H组)、石菖蒲高剂量+自噬抑制剂3-MA组(ATS-H+3-MA组),每组10只,另取10只正常大鼠为对照组(Control组)。ATS-L组、ATS-M组、ATS-H组分别按0.5、1.0、2.0 g/(kg·d)予石菖蒲药液灌胃,ATS-H+3-MA组先按2.0 g/(kg·d)予石菖蒲药液灌胃,然后腹腔注射21 mg/(kg·d)的3-MA,Control组与AD组予等容积0.9%氯化钠注射液灌胃,均连续灌胃5周。比较各组大鼠逃避潜伏期、穿越平台次数、血清炎症因子[包括白细胞介素1β(IL-1β)、IL-6、肿瘤坏死因子α(TNF-α)]、乙酰胆碱(Ach)、乙酰胆碱酯酶(AchE)水平,观察大鼠海马组织病理损伤及神经元凋亡情况,免疫组化检测微管相关蛋白1轻链3B(LC3B)、Beclin1表达,免疫印迹检测B细胞淋巴瘤-2相关X蛋白(Bax)、半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)PINK1、Parkin蛋白表达。结果与Control组比较,AD组大鼠逃逸潜伏期增加(P<0.05),穿越平台次数减少(P<0.05),IL-1β、IL-6、TNF-α、AchE、神经元凋亡率、Bax、Caspase-3水平均升高(P<0.05),Ach、LC3B、LC3Ⅱ/LC3Ⅰ、Beclin1、PINK1、Parkin水平均下降(P<0.05)。与AD组比较,ATS-L、ATS-M、ATS-H组逃逸潜伏期缩短(P<0.05),穿越平台次数增加(P<0.05),IL-1β、IL-6、TNF-α、AchE、神经元凋亡率、Bax、Caspase-3水平均降低(P<0.05),Ach、LC3B、LC3Ⅱ/LC3Ⅰ、Beclin1、PINK1、Parkin水平均升高(P<0.05),且随着石菖蒲浓度的增加上述指标改善效果更好(P<0.05)。与ATS-H组相比,ATS-H+3-MA组能够逆转ATS-H组对各指标的改善作用(P<0.05)。结论石菖蒲能够减少AD大鼠海马组织损伤,降低炎症水平,提高ACh水平,减少神经元凋亡,其具体作用机制可能是通过激活PINK1/Parkin信号通路,促进线粒体自噬而发挥作用。

关键词： HIV-1   MSM   NFLG   CRF01_AE/B   URF  

摘要： Mutation and recombination are key mechanisms in the adaptation, spread, and genetic diversity of human immunodeficiency virus (HIV)-1. We identified two novel unique recombinant forms (URFs) from two persons living with HIV-1, both infected through homosexual contact in Hebei, China. Phylogenetic and recombinant analysis based on the near full-length genome (NFLG) sequences revealed that they originated from CRF01_AE and B. NFLG sequencing revealed complex recombinant patterns in both samples, indicating ongoing recombination and co-infection in men who have sex with men (MSM). The emergence of novel URFs underscores the complexity of the HIV-1 epidemic among MSM and highlights its evolving molecular diversity and epidemiological implications.

关键词： CAR-T cell therapy   Tumor microenvironment   Hypoxia   HIF-1α   T cell metabolic  

摘要： CAR-T cell therapy demonstrates high efficacy in hematological malignancies but remains limited in solid tumors, mainly due to the immunosuppressive hypoxic tumor microenvironment that impairs T cell infiltration and promotes exhaustion. Driven by clinical transcriptomic and protein evidence implicating hypoxia-inducible factor-1α (HIF-1α) in metabolic reprogramming, we developed a non-viral CAR-T cell preparation platform using a piggyBac transposon system to co-deliver a CAR construct and a small activating RNA (saRNA) to drive endogenous HIF-1α overexpression (HIF1A^OE). HIF1A^OE-CAR-T cells exhibited superior tumoricidal activity under hypoxic conditions (1% O₂) and enhanced infiltration in a 3D tumor spheroid model. Importantly, these beneficial effects were successfully validated across independent antigen-targeting CAR models. Metabolomic analyses and Seahorse metabolic flux profiling revealed that HIF-1α remodels cellular metabolism through a dual mechanism: augmenting aerobic glycolysis by upregulating GLUT1 and preserving mitochondrial integrity via the Nrf2/PGC-1α signaling axis. Furthermore, combining HIF1A^OE-CAR-T cells with an anti-CTLA4 nanobody resulted in synergistic tumour regression and improved infiltration in SCID-NOD mice, without significant toxicity. Collectively, activating endogenous HIF-1α in CAR-T cells is proposed as a promising strategy for the safe and effective treatment of solid tumors within hypoxic microenvironments.

关键词： Cefiderocol   High-level resistance   Pseudomonas aeruginosa   AFM-1   Gene amplification  

摘要： Cefiderocol (FDC) is a last-resort antibiotic against carbapenem-resistant Pseudomonas aeruginosa, yet mechanisms underlying high-level resistance remain unclear. Here, we report that meropenem exposure induces dynamic tandem amplification of bla_AFM-1, leading to markedly increased FDC resistance. This amplification occurs without changes in plasmid copy number and declines without antibiotic pressure, highlighting a clinically relevant pathway of indirect resistance selection.

关键词： 谷胱甘肽S-转移酶A1   急性肝损伤   氧化应激   内质网应激   炎症反应   程序性坏死  

摘要： 目的探讨淫羊藿苷（icariin，ICA）是否通过调控谷胱甘肽S-转移酶A1（GlutathioneS-transferaseA1，Gsta1）表达改善四氯化碳（CCl?）诱导的小鼠急性肝损伤，并阐明其可能作用机制。方法构建Gsta1敲减小鼠模型，随机分为对照组（Control）、空载组(shNC＋CCl4)、敲减组(shGsta1＋CCl4)及ICA组(shGsta1＋CCl4＋ICA)，ICA(200mg·kg-1)连续灌胃给药7d，末次给药2h后腹腔注射10%CCl4-橄榄油溶液1.0mL·kg-1致小鼠急性肝损伤，24h后收集血清和肝脏组织，全自动生化分析仪检测血清ALT、AST水平；采用试剂盒检测肝组织氧化应激指标（SOD、GSH-Px、CAT、MDA）及炎症因子（TNF-α、IL-1β、IL-6）表达水平；HE染色和TUNEL染色检测肝组织病理及凋亡水平；Real-timePCR和Westernblot检测Gsta1mRNA及HO-1、Nrf2、Gsta1、GRP78、CHOP、Caspase-3蛋白的表达。结果与敲减组相比，ICA组小鼠血清ALT、AST、炎症因子及MDA水平降低（P<0.05），SOD、GSH-Px、CAT活性明显升高（P<0.05），肝细胞病变与凋亡减轻，同时Gsta1mRNA及Gsta1、Nrf2、HO-1蛋白表达水平升高，GRP78、CHOP、Caspase-3蛋白表达水平下降（P<0.05）。结论ICA干预能显著改善CCl4诱导的Gsta1敲减型小鼠急性肝损伤，其作用机制可能与上调Gsta1表达，激活Nrf2/HO-1抗氧化通路，减轻内质网应激、炎症反应及细胞凋亡相关。

关键词： Automated insulin delivery   Diabetes   Exercise   Hybrid closed-loop   Observer   Sliding modes control window  

摘要： This study introduces a decision support tool designed to optimise glucose control during physical activity in individuals with type 1 diabetes mellitus (T1DM). The proposed methodology integrates the Hovorka-Hobbs mathematical model to simulate glucose-insulin dynamics at different intensity levels of exercise. A discrete-time observer is employed to estimate unmeasurable physiological states, while a sliding mode control strategy adjusts insulin delivery in response to physical activity. Validation is conducted through in silico experiments using a cohort of 256 virtual patients in three therapy scenarios: continuous subcutaneous insulin infusion (CSII), hybrid closed-loop (HCL), and full closed-loop (FCL). Each scenario includes structured meal and exercise routines over a 13-day period and defines analysis windows for evaluating glycaemic outcomes. The results demonstrate that HCL systems consistently outperform CSII and FCL, achieving an improvement in Time in Range (TIR) of up to 86% and reducing glucose variability by up to 82%. Furthermore, HCL significantly reduces the risk of hypoglycaemia and hyperglycaemia, confirming its effectiveness and adaptability in managing dynamic metabolic conditions. These findings support the potential of HCL systems for safe and personalised glucose management during physical activity.

关键词： Genetic polymorphism   Merozoite surface protein 1 C-terminal 42 kDa   Plasmodium vivax   Vietnam  

摘要： Plasmodium vivax merozoite surface protein-1 (PvMSP-1) is a major surface protein of merozoites and plays crucial roles in erythrocyte invasion by merozoites. PvMSP-1 undergoes sequential proteolytic cleavages during erythrocyte invasion, resulting in four fragments of 82, 30, 38, and 42 kDa. The carboxy-terminal 42 kDa fragment (PvMSP-1₄₂) is further cleaved into two smaller fragments of 33 kDa (PvMSP-1₃₃) and 19 kDa (PvMSP-1₁₉). PvMSP-1₄₂ is an attractive vaccine candidate since it induces antibody production in naturally exposed humans, and specific antibodies against this region inhibit merozoite invasion. However, the genetic polymorphisms of PvMSP-1₄₂ reported in global P. vivax isolates emphasize the importance of molecular surveillance for the vaccine candidate. In this study, we analyzed genetic polymorphism profiles and natural selection in PvMSP-1₄₂ from 88 Vietnamese P. vivax isolates collected in four malaria-endemic provinces in Vietnam. Vietnamese PvMSP-1₄₂ exhibited genetic polymorphisms resulting from nucleotide substitutions and meiotic recombination, and balancing selection might preserve the diversity of the gene. Most polymorphic sites were identified in PvMSP-1₃₃, while PvMSP-1₁₉ was relatively well-conserved. Global PvMSP-1₄₂ displayed similar, but not identical, polymorphic features and natural selection profiles. No geographical clustering was identified. Nevertheless, PvMSP-1₁₉ was well-conserved across global populations. These findings expand our understanding of the genetic structure and evolutionary dynamics of PvMSP-1₄₂, and provide valuable information for developing an effective malaria vaccine based on the protein.

关键词： Ammonia  

摘要： In this study, two different ferric hydroxyphosphate (FHP and FHP-B) catalysts, synthesized by the same procedure with or without the addition of aqueous ammonia have shown excellent performance in the hydrogenolysis of glycerol to 1,3-propanediol (1,3-PDO) (conversion of glycerol: 60.7%; selectivity of 1,3-PDO: 87.9%) and acetalization of glycerol to solketal (conversion of glycerol: 94.9%; solketal selectivity: 98.3%). Simultaneously converting glycerol to two high-value-added chemicals is of great significance. Meanwhile, the two catalysts are characterized by a series of instruments, and the results show that the addition of aqueous ammonia alters the concentration of Brønsted and Lewis acidic sites of the catalysts, thus allowing them to attack different hydroxyl groups on glycerol. The Brønsted acid sites (BAS) of the FHP catalyst without the addition of aqueous ammonia were more selective for the breaking of the 2°–OH bond, whereas the FHP-B catalyst, due to the presence of aqueous ammonia, converted some BAS to Lewis acid sites (LAS) during the synthesis process. A large amount of LAS was inclined to attack glycerol’s 1°–OH bond, which is more favorable for the condensation reaction of glycerol and acetone. This finding innovatively provides a new strategy for the catalyst synthesis and a new perspective on reaction mechanism research.

关键词： Neoadjuvant therapy   Non–small cell lung cancer   Early-stage NSCLC   Immune Checkpoint Inhibitors   Perioperative Systemic Therapy  

摘要： The benefit of neoadjuvant or perioperative chemoimmunotherapy in resectable non–small cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) expression < 1% remains uncertain, as evidence is largely derived from subgroup analyses. We conducted a systematic review and network meta-analysis to compare the efficacy of individual chemoimmunotherapy regimens in this population.