课程文献中心 更多>>

关键词： HIV-1 reservoir   IL-15   thymosin alpha 1   human virtual memory CD8+T cells   immunological nonresponders  

摘要： Viral reservoir presents a significant challenge in HIV-1 cure. We previously observed that Thymosin alpha 1 (T alpha 1) may restrict the reservoir through the IL-15 pathway. However, the precise mechanism remains to be fully elucidated. Peripheral blood mononuclear cells (PBMCs) were obtained from people living with HIV-1 (PLWH). In vitro, THP-1 cells were differentiated into mature monocyte-derived dendritic cells (MoDCs) and co-cultured with PBMCs under various conditions. Intracellular HIV-1 p24 levels, CD8+ T and NK cell functionality, and reservoir size were evaluated. In vitro, T alpha 1 stimulation of MoDCs resulted in significant immune response and secretion of IL-15/RA complex (p < 0.001). This interaction with IL-2 R beta/gamma receptors on T cells enhanced the intracellular secretion of CCL3/5, IFN-gamma, and TNF-alpha in CD8+ T cells (p < 0.05), which inhibited p24 levels in CD4+ T cells (p = 0.002), and reduced HIV-1 integrated DNA levels (p = 0.012). Furthermore, the secretion levels of IFN-gamma, TNF-alpha, and GZMB in NK cells and proportion of CD8+ T-VM cells significantly increased following co-culture. These alterations were found to be markedly inversely associated with reservoir size and reactivation. However, these effects were observed in PBMCs from immunological responders (CD4+ T cell count > 350 cells/& micro;L) rather than nonresponders. T alpha 1 enhances CD8+ T cell function, promotes T-VM proliferation, and suppresses reservoir size and reactivation via IL-15 pathway activation in dendritic cells, which warrants testing in functional cure trials in the future.

关键词： Tramadol   ER stress   HIF-1 alpha   reactive oxygen species   paraptosis   ATF4   CHOP   postoperative pain   cytoplasmic vacuolization  

摘要： ObjectivesTramadol, a clinically approved analgesic widely used for managing postoperative pain, has recently been shown to possess anticancer properties in several tumor models, especially in breast cancer. In this study, we explored the intricate molecular mechanisms by which tramadol induces cytotoxicity in breast cancer cell *** invasive ductal carcinoma lines MCF-7 and MDA-MB-231 were used to verify the molecular cytotoxicity of tramadol using cell viability analysis, flow cytometry analysis, real-time polymerase chain reaction, western blotting, Seahorse biogenetic, and transmission electron microscopy *** findings demonstrate that tramadol induces the normoxic stabilization and nuclear translocation of hypoxia-inducible factor- 1 alpha (HIF-1 alpha) to activate hypoxia responsive genes. Concurrently, tramadol triggers endoplasmic reticulum (ER) stress and activates the p-eIF2 alpha/ATF4/CHOP signaling axis, leading to the generation of reactive oxygen species, impaired autophagy, mitochondrial dysfunction, including mitochondrial membrane depolarization and the decline of ATP production, cytoplasmic vacuolization, and lipid droplet accumulation which is characteristics of paraptosis-like cell death. Notably, the knockout of HIF-1 alpha or ATF4 significantly reduced tramadol-induced cytotoxicity, highlighting their crucial roles in mediating these cellular *** induced breast cancer cell death via paraptosis which highlights its therapeutic potential in targeting resistant cancer subtypes such as triple-negative breast cancer.

关键词： Esophageal cancer   radiotherapy   anti-PD-1 antibody   chemotherapy   elderly patients  

摘要： Background and purposeThe benefit of adding anti-PD-1 antibodies to definitive chemoradiotherapy (dCRT) in elderly patients with esophageal squamous cell carcinoma (ESCC) remains uncertain. This study evaluated its efficacy and safety versus dCRT *** and methodsWe retrospectively analyzed the patients aged >= 70 years with ESCC treated at three academic centers from 2009 to 2023. All patients received first-line dCRT and the study group additionally received anti-PD-1 antibodies (IO group). Propensity score matching (PSM) was applied to balance baseline *** total of 241 patients were enrolled, including 130 in the IO group and 111 in the dCRT group. After 1:1 PSM (110 patients per group), no significant differences in overall survival (OS) or progression-free survival (PFS) were observed. The median OS was 34.5 vs 33.7 months (HR = 0.86, 95%CI: 0.58-1.28, p = 0.467) and median PFS was 29.8 vs 17.8 months (HR = 0.79, 95%CI: 0.55-1.13, p = 0.194). Multivariate Cox analysis identified high nutritional risk as an independent predictor of worse OS (p = 0.014), while both advanced TNM stage (p = 0.030) and high nutritional risk (p = 0.016) were independently associated with shorter PFS. Subgroup analyses suggested that patients with good performance, better nutritional status or lower comorbidity burden may benefit from combination therapy. Grade 3-4 adverse events were comparable between two *** anti-PD-1 antibodies to dCRT did not result in a significant improvement in OS or PFS in the ESCC patients aged >= 70 years;however exploratory findings indicate a potential PFS signal in selected patients with favorable baseline conditions, which requires confirmation in prospective studies.

关键词： HIF-1 alpha   VEGF   lung   liver   roiler ascites syndrome  

摘要： Broiler ascites syndrome (BAS), a hypoxia-driven metabolic disorder, causes significant economic losses in poultry production. This study aimed to evaluate the pathological changes in the lungs and liver of broiler chickens and the expression of HIF-1 alpha and VEGF. HE, Masson and Van Gieson staining were used to observe histopathological changes in the lungs and liver, and molecular biology methods such as qPCR, Western blotting and immunohistochemistry were used to detect the expression of HIF-1 alpha and VEGF in the lungs and liver. The histopathological results revealed significant thickening and remodelling of the pulmonary artery wall in BAS broiler chickens;the boundaries of the vascular intima, media and adventitia were unclear;and there was a significant increase in the collagen fibre content around the arteries. Additionally, the hepatic cords were loosely arranged liver cords. The molecular biology results revealed that both the mRNA and protein expression levels of HIF-1 alpha and VEGF were significantly increased (p < 0.05) in the lungs and liver of AS broiler chickens. These findings establish an association between HIF-1 alpha/VEGF dysregulation and BAS pathogenesis, providing a foundation for mechanistic investigation.

关键词： Multicomponent vaccine   influenza   SARS-CoV-2   messenger RNA   phase 1/2   randomized clinical trial  

摘要： A multicomponent vaccine against seasonal influenza and COVID-19 could reduce disease burden in adults by providing simultaneous protection in a single-dose regimen. The first-generation, mRNA-based, multicomponent mRNA-1073 vaccine, combining antigens encoded by mRNA-1010 (influenza) and mRNA-1273 (COVID-19) vaccines, was investigated in a phase 1/2 clinical trial. This stratified, observer-blinded study randomly assigned healthy adults (18-75 years) to receive mRNA-1073 (25-mu g, 50-mu g, or 100-mu g) + placebo, mRNA-1273 (50-mu g) + placebo, mRNA-1010 (50-mu g) + placebo, or co-administered mRNA-1010 (50-mu g) + mRNA-1273 (50-mu g) on day 1. Primary study objectives were safety and reactogenicity. Secondary study objectives assessed humoral immunogenicity against vaccine-matched influenza and SARS-CoV-2 strains at day 29 and all evaluable time points through day 181. An exploratory objective was to further characterize immune responses across the study vaccines. Overall, 550 participants were randomly assigned to receive study vaccination. mRNA-1073 exhibited dose-dependent reactogenicity. Most solicited adverse reactions were grade 1 or 2 in severity;no grade 4 events, serious adverse events related to study vaccination, or deaths were reported. A single dose of mRNA-1073 elicited durable immune responses through 6 months against all vaccine-matched influenza and SARS-CoV-2 strains. Systems serology analysis indicated that mRNA-1073 induced robust, balanced antibody responses with comparable immune profiles to mRNA-1010 + mRNA-1273. mRNA-1073 had an acceptable safety profile and elicited durable immune responses against all vaccine-matched influenza and SARS-CoV-2 strains, supporting ongoing evaluations of mRNA-based multicomponent vaccines that simultaneously protect against seasonal influenza and COVID-19 in a single ***: *** identifier: NCT05375838 (https://***/study/NCT05375838).

关键词： Random forest regression   soil moisture mapping   Sentinel-1 C-band SAR   SMOS-IC   NDVI   croplands and grasslands  

摘要： This study presents a methodology to retrieve surface soil moisture (SM) at 1-km scale over croplands and grasslands using Sentinel-1 radar backscatter, harmonized Landsat/Sentinel-2 NDVI, and ancillary environmental variables. A Random Forest (RF) model was trained on the coarse (25-km) SMOS-IC product (2017-2024) to learn relationships between predictors and SM and then applied to generate fine-scale estimates. Only SMOS-IC pixels dominated by cropland and grassland selected to improve the reliability of the estimation. The RF achieved good performance at the training scale (R = 0.79, RMSE = 5.68 vol.% and negligible bias). When transferred to 1-km grids, independent validation using International Soil Moisture Network observations (2015-2024) yielded an R value of 0.49, an RMSE of 11.2 vol.%, an unbiased RMSE of 9.55 vol.%, and a global bias of 5.8 vol.%. Spatial comparison with GLASS SM indicated generally strong correlations, especially in humid regions. However, limitations remain, including a systematic underestimation inherited from SMOS-IC and reduced performance over areas with fine-textured soils. Accuracy also decreases under very dense vegetation and following recent heavy rainfall events (>30 mm). Despite these challenges, the 1-km High-resolution SM dataset offers valuable spatial detail on soil moisture variability, supporting improved agricultural management and local-scale monitoring.

关键词： Acute kidney injury   cisplatin   ischemia reperfusion injury   salvianolic acid C   gluconeogenesis   fructose-1, 6-bisphosphatase 1  

摘要： This research was targeted to investigate the pharmacological effects and mechanisms of Salvianolic acid C (SAC), a natural compound extracted from the Chinese traditional herbal Danshen (Salviae Miltiorrhizae Radix et Rhizoma), in acute kidney injury (AKI). Male C57BL/6J mice were used to create animal models and SAC (10 mg/kg, i.p.) or saline was administered 24 h before modeling. In both ischemia reperfusion injury (IRI) induced AKI and cisplatin (Cis) induced AKI models, SAC significantly alleviated the decline of renal function and destruction of renal pathological structure, which were correlated with reduced expression of renal injury markers and inhibited renal cell apoptosis. Non-targeted metabolomics sequencing revealed that the gluconeogenesis pathway was downstream of the renal protective effect of SAC in AKI. Further experiments revealed that the expression of key gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) was significantly decreased in AKI kidneys. AKI induced the reduction in glucose levels from serum and increase in lactate levels from serum and renal tissue. All of these metabolic changes were improved after the SAC treatment. The protective effects of SAC were reversed by an FBP1 inhibitor. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha) and forkhead box O1 (FOXO1), identified as gluconeogenesis promoting factor, were decreased after injection of cisplatin, which were reversed by SAC. Finally, molecular docking and SPR experiments revealed the direction interaction between FBP1 and SAC. Collectively, SAC possibly exerts its effect through a dual regulatory mechanism: by modulating the FOXO1/PGC1 alpha/FBP1 signaling axis and via direct interaction with FBP1.

关键词： Land subsidence   machine learning   SHAP   features optimization  

摘要： Land subsidence constitutes a major geological hazard, especially in swiftly urbanizing areas. This study examines the principal cities of southwestern China (Chengdu and Chongqing), where comprehending the processes contributing to subsidence and forecasting future dangers is crucial. Nevertheless, contemporary research seldom highlights a systematic feature screening procedure. This study utilized SHAP values in place of the conventional random forest method to measure land subsidence characteristics and employed a neural network to forecast regions at risk of future susceptibility. The findings indicate that the BP neural network model (RMSE = 0.468, MAE = 0.219) surpassed the RF model (RMSE = 0.557, MAE = 0.310). Following feature improvement, the model's performance was enhanced, resulting in a more precise prediction, with the obtained factors aligning with prior research. This feature optimization technique can aid in the selection of input variables and offer a robust theoretical framework for addressing and alleviating urban land subsidence.

关键词： Yishen Qingzhuo oral liquid   chronic renal failure   ferroptosis   Nrf2/HO-1 signaling pathway   oxidative stress  

摘要： This study investigated the therapeutic effect and underlying mechanism of Yishen Qingzhuo oral liquid (YSQZ) in a rat model of chronic renal failure (CRF). The CRF model was established by 5/6 nephrectomy. Rats were randomly divided into the sham, CRF, and CRF + low/high-dose YSQZ groups (CRF+YSQZ-L/H). Based on the therapeutic effect, the optimal drug dosage was selected. Subsequently, a ferroptosis inducer (erastin) and Nrf2 inhibitor (ML385) were administered, and rats were further divided into the CRF, CRF+YSQZ, CRF+YSQZ+erastin, and CRF+YSQZ+ML385 groups. The CRF group exhibited impaired renal function, along with elevated urinary protein and ferrous ion levels, relative to those in the sham group. Oxidative stress markers were also dysregulated. Histopathological damage was severe in the CRF group, including increased iron deposition, reduced mitochondrial counts, decreased or even complete loss of mitochondrial cristae, and extensive rupture of the mitochondrial outer membrane, indicators of ferroptosis. The expression of Nrf2/HO-1 pathway-related proteins was decreased, whereas fibrosis-related proteins were upregulated. Whereas the CRF group exhibited marked renal impairment, the CRF+YSQZ-L and CRF+YSQZ-H groups displayed significant improvement in renal function. These treatment groups also exhibited reductions in renal pathological damage, iron deposition, and ferroptosis. The expression of proteins related to the Nrf2/HO-1 ferroptosis pathway was increased, whereas fibrosis-associated proteins were downregulated, with more pronounced effects observed in the high-dose group. However, these protective effects of YSQZ were reversed by co-treatment with erastin or ML385. YSQZ exerts therapeutic effects in rats with CRF, likely by inhibiting ferroptosis through activation of the Nrf2/HO-1 signaling pathway.

关键词： Sentinel-1 data   rapeseed mapping   phenological stages   radar scattering   polarization decomposition  

摘要： Accurate and timely rapeseed mapping is critical for assuring national food security and supporting agricultural regulation. Time series synthetic aperture radar (SAR) data is widely used to monitor the growth of rapeseeds and identify rapeseed distribution in cloudy and rainy regions. However, the spatial and temporal variations in plantation conditions keep presenting a challenge for SAR-based rapeseed mapping over large areas. Additionally, the temporal dynamic patterns and mechanism of SAR scattering could be investigated to enhance the mapping of rapeseed. Therefore, using time-series Sentinel-1 SAR data, this study proposed a general multi-phenology rapeseed index (MPRI) for automatic rapeseed mapping. Central to this method is establishing the linkage between time-series SAR backscattering (including intensity and polarimetric) patterns with rapeseed phenology. First, the rapid growth, flowering, and maturity stages of rapeseed were identified using a pseudo scattering-type parameter that was derived from polarimetric decomposition on Sentinel-1 SAR data. Second, the multi-phenology rapeseed index (MPRI) was developed by incorporating three stage-specific indices. Third, an optimal threshold was applied on the MPRI probability maps to generate binary masks of rapeseed distribution. The proposed MPRI approach is further evaluated by mapping rapeseed across three sites with varying planting conditions in China's Yangtze River Basin. Comparative experiments were conducted against with three available standard methods, including the RSG-OC, CARM, and SARM methods. Results show that the MPRI approach achieved the best performance for rapeseed mapping, with an overall accuracy and an F1 score above 0.90 at all three sites, which exceed these comparative methods by 0.02 similar to 0.10 in overall accuracy and 0.03 similar to 0.12 in the F1 score. Further discussion also reveals that by explicitly incorporating the temporal dynamics of microwave scattering throughout