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Control of telomerase recruitment and end protection by independent shelterin components
No full textAbstract Telomeres are proposed to alternate between “closed” states, in which chromosome ends are protected from DNA damage signaling and inaccessible to telomerase, and “open” states, where they become accessible for telomerase mediated elongation but less protected. Whether these states reflect distinct molecular mechanisms or mutually exclusive structural conformations remains unclear. Here, we develop a single-cell assay to monitor telomerase activity in mouse embryonic stem cells. Using this approach, we demonstrate that the shelterin component TPP1 is essential for telomerase recruitment via its interaction with TIN2, independently of POT1. In contrast, POT1 is dispensable for telomerase function but required for telomere end protection, acting independently of TPP1. These findings challenge the classical open-closed telomere model and reveal that telomerase recruitment and end protection are mediated by genetically and molecularly separable mechanisms
cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis
No full textAbstract Self-DNA triggers cGAS-STING-mediated type I interferon (IFN-I) to induce both protective and pathogenic immune responses; however, how self-DNA activates the cytosolic cGAS-STING pathway remains unclear. Here we show that the cGAS/STING/IFN-I axis is activated by self-DNA via a process termed ‘nucleocytosis’, in which nuclear DNA is extracted from dying cells by macrophages. Mechanistically, lysosomal malfunction, via both proton loss and palmitoyl-protein thioesterase 1 (PPT1) inhibition, triggers cell death and calreticulin accumulation in the nuclei. Live-cell imaging of secretion activity reveals that macrophages access the calreticulin-enriched nuclei of dying cells and extract DNA for cGAS-STING activation. Consistent with these findings, PPT1-targeting cationic amphiphilic drugs induce a cGAS-STING-dependent IFN-I response in vitro and in vivo. Our findings thus identify nucleocytosis as a macrophage function for nuclear DNA extraction and induction of the cGAS/IFN-I axis, and suggest that nucleocytosis-inducing cell death could be a druggable target for treating self-DNA-related inflammatory diseases
Functional and structural insights into interactions between β-Arrestin 1 and Gαs or Gαi1
No full textAbstract G proteins and arrestins are key transducers for G protein-coupled receptor (GPCR) signaling, mediating distinct downstream pathways. Recent evidence suggests that G proteins and β-arrestins (βarrs) can directly or functionally interact. However, the molecular details and functional consequences of Gα–βarr interactions remain poorly understood. Here, we quantify the binding affinities between βarr1 and Gαs or Gαi1 in various activation states using microscale thermophoresis (MST). βarr1 in the active conformational ensemble state favors binding, whereas Gα activation status is less determinant. Hydrogen/deuterium exchange mass spectrometry reveals distinct conformational changes between Gαs versus Gαi1 upon βarr1 binding, suggesting differential binding mechanism between Gαs–βarr1 and Gαi1–βarr1 complexes. Both the Ras-like domain and the α-helical domain of Gα contribute to complex formation. Functionally, a BODIPY-FL–GTPγS assay shows that βarr1 does not alter GDP/GTP turnover of Gαs or Gαi1, whereas β-strand XX (βXX) release assays demonstrate that Gαs enhances βarr1 C-tail release. Together, these results propose molecular mechanism of the interaction and asymmetric functional coupling within Gα–βarr complexes and uncover a previously underappreciated layer of GPCR signal transduction
Solvent-mediated partial ionicity enhances mechanical nanosizing effect of Mg-based hydrogen storage alloys
No full textAbstract The high ductility of Mg has posed major challenges for nanofabrication utilizing mechanical ball-milling. While the addition of organic solvents is effective, it has been unclear how they improve the ball-milling effect by modifying the material’s surface properties. Herein, we report that the solvent-mediated partial ionicity plays an important role in enhancing the nanosizing effect of Mg87.5Ni5.5Y7 alloy. This approach enables the Mg87.5Ni5.5Y7 particles to be 88 times smaller than those of the solvent-free procedure. The Mg87.5Ni5.5Y7 nanoparticles underwent complete dehydrogenation in 3 min at 300 °C and in 17 min at 240 °C, which can be stably cycled at least for 500 times. Solvent (THF) adsorption on Mg induces Mgδ +‒Mgδ− dipole structure. This increases the surface hardness of Mg-based alloy and maximizes the ball milling-driven structural deformation, thereby facilitating ion migration. Mg‒Mg bond breaking is caused by the resulting Coulombic repulsion between Mg atoms. These findings provide an affordable approach for nanoparticle fabrication of highly ductile materials
Extreme optical nonlinearities unveiled by ultrafast laser filamentation in semiconductors
No full textAbstract Sky-high optical nonlinearities make semiconductors ideal platforms for multifunctional photonic devices. The fabrication of such complex devices could greatly benefit from in-volume ultrafast laser writing for monolithic and contactless integration. Ironically, as exemplified for Si, nonlinearities act as an efficient immune system that self-protects the material from internal permanent modifications. Predicting high-intensity ultrashort-pulse propagation beyond Si is further limited by incomplete descriptions of carrier dynamics in narrow-gap materials. Here, we demonstrate that filamentation universally dictates ultrashort laser pulse propagation in various semiconductors. The effective key nonlinear parameters extracted differ markedly from past measurements with low-intensity pulses, while temporal scaling laws for these parameters are also derived. Based on these findings, appropriate temporal-spectral shaping is proposed for tailored energy deposition inside semiconductors. The effective parameters also provide predictive inputs for semiconductor backside processing, microelectronics security, and high-harmonic, supercontinuum and terahertz wave generation
A bibliometric analysis of progress and trends in pediatric glioma research
No full textAbstract This bibliometric study analyzes 4,861 publications on pediatric gliomas (PGs) from the Web of Science Core Collection (WoSCC) to map the field’s 60-year research trajectory. Despite recent scientific advances, the analysis of long-term trends, interdisciplinary dynamics, and comprehensive collaboration networks is still insufficient. USA leads in output, with St. Jude Children’s Research Hospital as the top institution and Childs Nervous System as the dominant journal. Pioneering authors including Bouffet Eric, Gutmann David H., Packer Roger, and Grill Jacques established foundational work guiding subsequent research. Keyword analysis identifies “Glioma” and “Children” as central themes. This study integrates the constantly evolving research frontiers and provides important insights for scholars’ future research
Prognostic benefit of preoperative radiotherapy for patients with metastatic larynx and hypopharynx cancers and XGBoost-based prognostic models to predict their survival
No full textAbstract Background To date, no study has systematically compared the prognostic benefit of preoperative radiation therapy (RT) and postoperative RT, RT alone, and surgery alone in this patient population. There is a clear clinical need for accurate survival prediction tools to address the concerns of both patients and clinicians. Methods Patients diagnosed with metastatic larynx and hypopharynx cancer (T1−2N1−3/T3-4 any N) were retrospectively analyzed. Cox regression was used to examine independent prognostic factors associated with overall survival (OS), propensity score matching (PSM) and Kaplan-Meier analysis were employed to compare survival outcomes between treatment groups. Finally, an extreme gradient boost (XGBoost) model was constructed to predict patient survival. Results A total of 18,988 eligible patients were included. PSM analyses showed that, compared with surgery alone, preoperative RT followed by surgery was associated with improved OS of patients with hypopharynx cancer (except pyriform sinus), those aged 70 years or older, and those who did not receive chemotherapy. The validation results show that our XGBoost model achieved an AUC value ranging from 0.716 to 0.745 on the test set and 0.759–0.805 on the external validation set. Feature importance evaluation and SHAP values indicated that sequence of RT and surgery, age at diagnosis, and N stage were the three most influential predictors. Conclusion We conducted a comprehensive exploration of the clinicopathology characteristics of patients with metastatic larynx and hypopharynx cancer, and prognostic models were constructed to accurately predict their survival. These findings may help formulate individualized treatment strategies and potentially improve patient prognosis
Systemic analysis of 1,4-dichlorobenzenes effects on lung adenocarcinoma environmental exposure and core target regulation prediction
No full textAbstract Objective To investigate the effects of 1,4-dichlorobenzene (1,4-DCB) on lung adenocarcinoma (LUAD) and elucidate its potential molecular mechanisms, thereby providing a basis for related LUAD risk assessment and intervention. Methods An integrated pipeline combined network toxicology, molecular docking, and immune multi-omics. After retrieving 1,4-DCB–LUAD intersection targets from multiple public repositories, a protein–protein-interaction network was constructed and pruned with TCGA data to identify core targets. Binding affinities were validated by molecular docking. Expression, prognostic value, and immune infiltration patterns of the core targets were subsequently analyzed. Simultaneously, 1,4-DCB toxicity was characterised and a residential exposure inventory was developed. Results 1,4-DCB exhibits moderate acute toxicity (LD50 = 500 mg/kg) and clear carcinogenic potential. The study identified 40 cross-target interactions and 8 core targets. MMP13 (− 5.7 kcal/mol) and CYP1A1 (− 6.7 kcal/mol) demonstrated the strongest binding affinities. MMP13 is overexpressed in lung adenocarcinoma, promoting tumor progression. Associated genes are enriched in extracellular matrix remodeling, inflammatory signaling, and the PI3K-Akt pathway. Conversely, CYP1A1 is downregulated and exhibits tumor-suppressive effects, with its interaction network enriched in cytochrome P450-mediated drug metabolism pathways. Conclusion 1,4-DCB may participate in the pathogenesis of LUAD through multiple pathways by interacting with MMP13 and CYP1A1, providing scientific basis for risk assessment, diagnosis, and intervention in LUAD. Graphical Abstrac
FAM168B identified as a novel candidate target for chimeric antigen receptor T cell-based cancer therapy
No full textAbstract Aging-related diseases, particularly cancer, remain major health challenges that demand new therapeutic strategies. Chimeric antigen receptor (CAR) T cell therapy has emerged as a powerful modality in immuno-oncology, enabling patient-derived T cells to be engineered ex vivo to recognize and eliminate tumor antigens. Here, we identify FAM168B (family with sequence similarity 168 member B, also known as myelin-associated neurite-outgrowth inhibitor, MANI) and its homolog FAM168A (tongue cancer resistance-associated protein 1, TCRP1) as candidate membrane-associated proteins expressed on cancer cell surfaces. The unique characteristics of FAM168B suggest its potential as a tumor-specific target for CAR T cell development. This approach could expand the therapeutic repertoire of CAR T cell therapy and support the design of more precise and versatile treatment strategies for diverse cancer types
Pan-cancer multi-dimensional characterization and biological significance of cholesterol 25-hydroxylase (CH25H)
No full textAbstract Background CH25H encodes an interferon-inducible hydroxylase that converts cholesterol to 25-hydroxycholesterol (25-HC), linking lipid homeostasis to immune regulation. Its pan-cancer relevance remains incompletely defined. Methods We integrated TCGA/GTEx transcriptomes with TCGA copy-number, mutation and DNA-methylation data, and immune infiltration estimates (TIMER/MCP-COUNTER/ssGSEA). For each cancer type, overall survival was modeled by an identical multivariable Cox regression (high vs. low CH25H by within-cancer median) adjusting for age, sex and pathologic stage; proportional hazards were assessed. Results CH25H was dysregulated across multiple malignancies with tumor-type-specific directions. Copy-number losses and promoter hypermethylation jointly associated with reduced mRNA levels. Survival analyses revealed a context-dependent pattern: higher CH25H aligned with favorable outcomes in several immune-active tumors, but with poorer prognosis in selected gastrointestinal cancers. CH25H positively correlated with effector immune infiltration and IFN-γ-dominant/inflammatory immune subtypes. These directions were concordant with multivariable Cox estimates; full per-cancer results are provided in Supplementary Table S1. Conclusions CH25H exhibits a context-dependent, biphasic role in cancer: on one hand, it may exert tumor-suppressive effects by enhancing anti-tumor immunity; on the other, it can promote tumor progression in specific cancer types or stages. Its expression is co-regulated by CNV and promoter methylation. CH25H and its enzymatic product, 25-HC, hold promise as both prognostic biomarkers and therapeutic targets in cancer immunotherapy
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