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关键词： Neutrophils   Interleukin-1 beta   reactive oxygen species   mucin   chronic obstructive pulmonary disease  

摘要： Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and excessive mucin production. Two major gel-forming mucins, MUC5AC and MUC5B, correlate with worsened disease progression and pulmonary function. In COPD, neutrophils are important players in chronic inflammation that contribute to tissue damage through releasing reactive oxygen species (ROS). IL-1 beta, a pro-inflammatory cytokine, plays various roles in COPD disease progression. It is known to recruit and activate neutrophils and is also known to induce mucin production in bronchial epithelium. This study aimed to investigate whether IL-1 beta induces ROS production in neutrophils and whether neutrophil-derived ROS drives mucin secretion in bronchial epithelial cells. HL-60-derived neutrophils were treated with IL-1 beta or vehicle and neutrophil ROS production was assessed through flow cytometry. Using a co-culture system, human bronchial epithelial cells were exposed to IL-1 beta-treated neutrophils, and MUC5AC and MUC5B levels on these cells were evaluated at RNA and protein levels through RT-qPCR, immunofluorescence, and ELISAs. IL-1 beta induced neutrophil ROS production. The elevated ROS production in neutrophils induced MUC5AC and MUC5B production at mRNA and protein levels in bronchial epithelial cells. Inhibition of ROS production in neutrophils using a NOX2 inhibitor reduced MUC5AC and MUC5B secretion in bronchial epithelial cells. IL-1 beta-induced neutrophil-derived ROS is a key driver of mucin hypersecretion in bronchial epithelial cells, potentially contributing to COPD disease *** registration: Not applicable.

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： 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： 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 *** 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 *** (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 *** 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 ***-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

关键词： Parkinson's disease   N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives   monoamine oxidase B   neuroprotective agents   selective inhibitors  

摘要： Monoamine oxidase B (MAO-B) inhibitors may be an effective therapeutic approach for Parkinson's disease. This study designed and synthesised a series of N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives and evaluated their inhibitory activity against human MAO-B (hMAO-B). Most compounds exhibited inhibitory activity and selectivity, with compounds 29 and 34 demonstrating the strongest inhibitory potency (IC50 = 0.066 +/- 0.03 mu M and 0.070 +/- 0.002 mu M, respectively) and selectivity indices (SI > 151 and 134), which were superior to the positive control rasagiline. Enzyme kinetic studies confirmed that these representative active compounds exhibited mixed reversible inhibition of hMAO-B. Molecular docking and kinetic analyses indicated that compound 29 binds stably to the hMAO-B active site. Concurrently, they exhibited low neurotoxicity and protective effects against 6-OHDA-induced damage in SH-SY5Y neuroblastoma cells. Therefore, we propose these active compounds as potential drug candidates for further investigation.

关键词： Child health   community health   physical activity   nutrition   storytelling  

摘要： PurposeStorytelling has long conveyed knowledge, wisdom, and values across generations, making it a powerful tool for shifting perspectives and encouraging behaviour change. By engaging audiences emotionally, it creates a shared space where diverse viewpoints coexist, fostering empathy and understanding. This is especially valuable in public health, where translating scientific evidence into relatable, actionable knowledge is essential. The First 1,000 Days storytelling initiative in Burnie, Northwest (NW) Tasmania, demonstrated the benefits of community-driven narratives in improving the health and well-being of children from conception to age two. This study explored how storytelling could function as a core strategy within the broader initiative, while examining parents' lived experiences in workshops designed to empower healthier *** years practitioners and parents collaborated around four pillars-connection, nutrition, caring, and moving. Participants shared and reshaped personal narratives linked to each area. Facilitators emphasized dignity, autonomy, and inclusivity, creating a safe environment, particularly for disadvantaged *** combined expert knowledge with lived experience, building capacity to promote early childhood development across their networks and *** initiative illustrates how co-created storytelling effectively bridges lived experience and professional expertise, fostering reflection, empowerment, and sustainable, community-driven change in early childhood and maternal health.