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关键词： Antioxidants   cadmium stress   growth   nutrient profile   oxidative injury   pea   Acinetobacter schindleri SR-5-1  

摘要： Cadmium (Cd) contamination of agricultural soils disrupts plant signaling networks, impairing nutrient communication, photosynthetic efficiency, and stress responses. Microbial inoculants offer eco-biotechnological solutions by modulating signal perception and transduction under heavy metal stress. This field study investigated the role of Acinetobacter schindleri strain SR-5-1 in influencing pea (Pisum sativum L.) signaling pathways under Cd toxicity. Plants exposed to environmentally relevant Cd concentrations (250 and 500 & micro;M) exhibited disrupted chlorophyll biosynthesis, elevated oxidative stress markers, and impaired nutrient signaling. Inoculation with SR-5-1 restored chlorophyll levels, enhanced ROS-scavenging enzyme activities, and reduced lipid peroxidation, indicating microbial effects on oxidative signaling cascades. Importantly, the inoculated plants accumulated less Cd in the roots and leaves, reflecting microbial mediation of ion transporter activity and rhizosphere detoxification. SR-5-1 also improved nitrogen, iron, zinc, potassium, and magnesium acquisition, highlighting its role in nutrient uptake and homeostasis. These findings demonstrate that SR-5-1 functions as a bio-communicator, alleviating xenobiotic stress by modulating ROS and nutrient signaling pathways. The study underscores the ecological relevance of microbial inoculants in supporting integrative plant communication and resilience, positioning SR-5-1 as a promising bioresource for signaling-driven sustainable agriculture in Cd-affected soils.

关键词： Human mobility   mobile phone data   machine learning   floating population  

摘要： Population mobility is a fundamental driver of urban development and socioeconomic processes, providing a critical foundation for scientific analysis and evidence-based decision-making. Despite its importance, most existing studies and applications continue to rely on static resident (de jure) population data, which fail to represent the spatiotemporal dynamics of human activity. In this study, we develop a comprehensive framework to map nationwide hourly floating (de facto) population across South Korea at 1 km spatial resolution for the period 2022-2024 by integrating mobile phone-based records with a machine-learning approach. The proposed framework incorporates a diverse set of spatial and temporal predictors, including building characteristics, land cover, accessibility indicators, temporal variables, and meteorological conditions, enabling the model to capture spatial heterogeneity and short-term temporal variability that are often neglected in prior population mapping studies. Quantitative evaluation demonstrates strong model performance, with leave-one-year-out cross-validation yielding high temporal generalization (Pearson correlation coefficients r = 0.981-0.993) and spatial cross-validation across unseen metropolitan regions indicating robust transferability (r = 0.847-0.941). Qualitative analyses reveal interpretable and realistic mobility patterns, including elevated nighttime populations in residential areas and pronounced daytime peaks in commercial and industrial zones, particularly around midday (13:00). The model also successfully captures city-specific mobility responses, holiday-related population redistribution, and weather-dependent behavioral changes, such as increased residential presence on rainy days. These results represent a substantial improvement over conventional static population datasets and existing floating population products. By resolving hourly variations in human presence at high spatial resolution, the resulting dataset provid

关键词： Semaglutide   liraglutide   GLP-1 receptor agonists   CKD outcomes   meta-analysis  

摘要： Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in patients with chronic kidney disease (CKD but existing evidence regarding their efficacy and safety remains inconsistent. To evaluate the cardiorenal outcomes and adverse effects of GLP-1 RAs in this population, we conducted a systematic review and meta-analysis of randomized controlled trials from PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science up to December 2024. Nine trials involving 21,717 patients, the vast majority of whom had T2DM, were included. GLP-1RAs treatment for CKD was associated with decreasing the incidence of major adverse kidney events (MAKE;RR, 0.84;95% CI, 0.76-0.94) and major adverse cardiac and cerebrovascular events (MACE;RR, 0.84;95% CI, 0.72-0.97 reducing all-cause mortality (RR, 0.83;95% CI, 0.76-0.90) and albuminuria level (SMD, -1.22;95% CI, -1.53 - 0.90). Gastrointestinal events associated with GLP-1 RA treatments including nausea (RR, 4.14;95% CI, 2.70-6.33 vomiting (RR, 3.05;95% CI, 1.88-4.97 diarrhea (RR, 2.65;95% CI, 1.76-3.98 and dyspepsia (RR, 3.79;95% CI, 1.02-14.12) have garnered significant attention. In conclusion, administration of GLP-1RAs treatment demonstrates excellent cardiorenal protective effects in CKD, primarily in patients with co-existing T2DM, though with notable gastrointestinal concerns.

关键词： Renal ischemia-reperfusion injury   Ginsenoside Rg1   Nrf2/HO-1 pathway   fatty acid-binding proteins 1  

摘要： Ginsenoside Rg1 (G-Rg1) can effectively ameliorate lipopolysaccharide-induced renal injury. The impact and mechanism of G-Rg1 in renal ischemia-reperfusion (I/R) injury are not yet understood. This study aimed to examine the role and mechanism of G-Rg1 in kidney I/R injury. The renal I/R injury mice and mouse kidney cells were applied as renal I/R injury models. Researchers analyzed the functions and mechanisms of G-Rg1 using techniques like cell proliferation, apoptosis, clone formation assay, ELISA, HE staining, immunohistochemical staining, Immunofluorescence staining, qRT-PCR, and Western blot analysis. Our findings indicate that G-Rg1 pretreatment protects against renal I/R injury by lowering serum creatinine and urea nitrogen levels, mitigating histological damage and apoptosis, and reducing inflammation and oxidative stress. These beneficial effects were accompanied by the suppression of fatty acid binding protein 1 (FABP1) and heme oxygenase-1 (HO-1) expression and the promotion of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. However, the therapeutic effect of G-Rg1 was inhibited by FABP1 overexpression. The mechanism by which G-Rg1 ameliorates renal I/R injury may be related to the inhibition of FABP1 expression and thus regulation of the Nrf2/HO-1 pathway.

关键词： Multidrug resistance   ABCB1   ABCB1 inhibitors   aminocoumarin-derived coumarin   triazolo[1,5-a]pyrimidine  

摘要： ABCB1-mediated drug efflux is a key determinant of multidrug resistance (MDR) in cancer. To overcome this mechanism, a series of thiol-substituted aminocoumarin-derived, coumarin-containing triazolo[1,5-a]pyrimidine derivatives (5a-5s) was synthesised, and compound 5r (NYH-707) was identified as the most potent ABCB1 inhibitor. NYH-707 markedly restored paclitaxel sensitivity in SW620/Ad300 MDR cells, reducing the IC50 from 4.55 +/- 0.73 & micro;M to 0.011 +/- 0.002 & micro;M (reversal factor = 413.6). Molecular docking predicted strong binding (-9.7 kcal/mol) through hydrogen bonding with LYS-826 and SER-880 and pi-pi stacking with PHE-994. CETSA confirmed direct ABCB1 engagement, while drug-accumulation assays demonstrated inhibition of ABCB1-mediated efflux. In vivo, co-administration of NYH-707 and paclitaxel significantly suppressed SW620/Ad300 xenograft growth without detectable systemic toxicity. These findings indicate that NYH-707 acts as a potent and selective ABCB1 modulator capable of reversing MDR likely by modulating ABCB1 conformational dynamics, thereby enhancing chemotherapeutic efficacy in resistant tumours.

关键词： EGFR kinase inhibition   tubulin polymerisation   dual-target anticancer agents   ROS-mediated apoptosis   molecular docking and dynamics  

摘要： In this study, we report the Pictet-Spengler enabled synthesis of a series of eighteen carboxamide-substituted imidazo[1,2-a]quinoxaline derivatives (JRC-1-JRC-18) targeting epidermal growth factor receptor (EGFR) and tubulin. Compounds JRC-2 and JRC-6 exhibited potent antiproliferative effects against MCF-7 breast cancer cells, with IC50 values of 4.59 +/- 0.23 & micro;M and 4.01 +/- 0.14 & micro;M, respectively, outperforming erlotinib (IC50 = 9.39 +/- 0.16 & micro;M). In enzymatic assays, JRC-2 and JRC-6 inhibited wild-type EGFR with IC50 values of 294.45 nM and 383.90 nM, respectively. Notably, JRC-6 displayed microtubule-stabilising activity comparable to that of paclitaxel and induced ROS generation, mitochondrial membrane depolarisation, and G2/M phase cell cycle arrest. Molecular docking and molecular dynamics simulations confirmed stable binding of compounds at the EGFR ATP-binding site and the tubulin taxol-binding site. [GRAPHICS]

关键词： HIV-1   Vpr   m6A   ALKBH5   microglial activation  

摘要： HIV-1 infection activates microglia and triggers neuroinflammation, which is the primary cause of HIV-associated neurological complications. Our previous study demonstrated that HIV-1 infection upregulates m6A modification in microglia, and in this study, we investigated the underlying regulatory mechanisms. Through viral protein screening, we identified Vpr as the protein responsible for increasing m6A modification. Further analysis revealed that HIV-1 infection reduces the level of the m6A demethylase ALKBH5. Vpr deleted HIV-1 infection and Q65R mutant Vpr expression experiments demonstrated that Vpr is capable of degrading ALKBH5 protein via the ubiquitin-proteasome pathway by interacting with ALKBH5. Addition of m6A inhibitors or overexpression of ALKBH5 inhibited Vpr-induced microglial activation and the production of inflammatory cytokines, suggesting that the upregulation of m6A modification might play a crucial role in microglial activation induced by Vpr. As microglial activation is a major cause of neuroinflammation leading to neuronal damage, this study provides new insights for understanding the interactions between HIV-1 and microglia, and might provide new ideas for the prevention strategies study on the neuroinflammation caused by HIV-1 infection.

关键词： LncRNA H19   M1 polarization   macrophage   MiR-145-5p   systemic lupus erythematosus  

摘要： Systemic lupus erythematosus (SLE) represents a prototypical autoimmune disorder characterized by multi-organ involvement due to loss of immune tolerance. Emerging evidence implicates macrophage polarization dynamics as a pivotal contributor to SLE pathogenesis, with epigenetic regulation by long noncoding RNAs (lncRNAs) emerging as a critical regulatory mechanism. To elucidate the pathogenic role of exosome-derived lncRNAs in this process, we performed comprehensive RNA sequencing analysis on circulating exosomes from SLE patients, identifying lncRNA H19 as a significantly upregulated candidate. Subsequent functional analyses using primary murine macrophages demonstrated that exogenous H19 administration recapitulated the pro-inflammatory phenotype observed in SLE, as evidenced by enhanced M1 macrophage differentiation, transmigration capacity, and renal infiltration patterns in experimental models. Notably, we primarily identified lncRNA H19 as a potential indicator in SLE, the knockdown of which might significantly attenuate these pathological manifestations. Mechanistic investigations revealed that H19 promoted the proliferation and migration of macrophages in vitro and exerted its regulatory function through competitive binding to miR-145-5p, thereby derepressing PAI-1 expression and subsequently activating the JAK2-STAT3 signaling cascade to orchestrate pro-inflammatory cytokine production. Overall, this study reveals novel molecular mechanisms underlying immune dysregulation in SLE, establishing exosomal lncRNA H19 as a key epigenetic modulator of macrophage polarization via the miR-145-5p/PAI-1/STAT3 axis, and proposes a novel potential therapeutic target for restoring immune homeostasis in patients with SLE before clinical practice.

关键词： PD-1   autoimmunity   agonist antibody   SHP2 recruitment   peripheral Th cells   immune balance   immune tolerance  

摘要： Precise inhibition of autoreactivity without concomitant induction of general immunosuppression is an overarching goal that remains elusive for the treatment of autoimmune diseases. PD-1 is preferentially expressed on activated T cells that drive autoimmunity. These PD-1+ T cells could serve as a target for therapeutic intervention. Here, we report the discovery of a unique PD-1 agonist antibody, GenSci120, that exhibited potent and selective T-cell inhibition in vitro and T-cell depletion activity both in vitro and in vivo. Target engagement by GenSci120 directly promoted SHP2 recruitment into the PD-1 signaling pathway but also enhanced the binding of PD-1 to its natural ligands and augmented PD-L1-induced PD-1 signaling. Moreover, GenSci120 exhibited robust efficacy in several animal models of human autoimmune disease. Thus, GenSci120, by selectively depleting PD-1+ T cells and by directly (via PD-1 binding and SHP2 recruitment) or indirectly (via enhancing PD-1 and ligand interaction) stimulating PD-1 signaling, has the capability to restore immune balance in autoimmunity. In a first-in-human study in healthy adults (NCT06827457 GenSci120 demonstrated favorable safety/tolerability and pharmacokinetic profiles as well as robust pharmacodynamic effect. Together, these findings suggest the potential of GenSci120 as an innovative precision medicine for treating autoimmune diseases and support further evaluation of this investigational new drug in future clinical trials.

关键词： Macrophages   Insulin-like growth factor-1   acute lung injury   efferocytosis   acute respiratory distress syndrome  

摘要： BackgroundNo effective treatment strategy for acute respiratory distress syndrome (ARDS) has been established. Conflicting reports on the effects of insulin-like growth factor (IGF)-1 stimulation and the inhibition of IGF-1 receptor (IGF-1R) signalling in tissue injury across several organs have led to hesitation in advancing IGF-1-based treatment strategies for tissue damage.ObjectiveWe aim to examine whether IGF-1/IGF-1R signalling contributes to recovery from acute lung injury in mouse models and to further explore its potential mechanisms.MethodsLipopolysaccharide (LPS) was intratracheally injected into mice to create acute lung injury models. Experiments were conducted to acquire or inhibit IGF-1 signalling through the intratracheal injection of recombinant IGF-1 or JB1, an IGF-1 receptor antagonist during the recovery phase of the models, starting on day 4 after LPS administration. Bone marrow monocyte-derived macrophages (MDMs) cocultured with IGF-1 and/or JB1 were intratracheally injected during the recovery phase.ResultsInflammatory cell counts and lung injury scores were significantly decreased when recombinant IGF-1 was administered in the later phase, while they increased with the administration of JB1. On day 4 after LPS injection, IGF-1 receptor (IGF-1R, also known as CD221) was strongly expressed on macrophages, particularly in CD11c+SiglecF+ alveolar macrophages (AMs). Intratracheal injection of MDMs cocultured with IGF-1 decreased lung neutrophil counts, whereas the addition of JB1 to MDMs cocultured with IGF-1 counteracted the effect of IGF-1. JB1 also reduced efferocytosis capacity of AMs in the later phase. In the phagocytosis assay, LPS decreased the efflux capacity of macrophages, but recombinant IGF-1 improved this capacity regardless of the presence or absence of LPS.ConclusionIGF-1/IGF-1R signalling in macrophage facilitates the recovery from acute lung injury via enhancing efferocytosis. IGF-1 delivery potentially offers a new treatment str