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Epigenetic modifications play an important role in cellular senescence, and enhancer of zeste homolog 2 (EZH2) is a key methyltransferase involved in epigenetic remodeling in multiple myeloma (MM) cells. We have previously demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro; however, its specific mechanism remains unclear. This study shows that GSK126 induces cellular senescence in MM, which is characterized by the accumulation of senescence-associated heterochromatin foci (SAHF) and p21, and increased senescence-associated β galactosidase activity. Furthermore, EZH2 is inhibited in ribonucleotide reductase regulatory subunit M2 (RRM2)-overexpressing OCI-MY5 and RPMI-8226 cells. RRM2 overexpression inhibits the methyltransferase function of EZH2 and promotes its degradation through the ubiquitin-proteasome pathway, thereby inducing cellular senescence. In this senescence model, Lamin B1, a key component of the nuclear envelope and a marker of senescence, does not decrease but instead undergoes aberrant accumulation. Meanwhile, phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) is significantly increased. The inhibition of ERK1/2 phosphorylation in turn partially restores Lamin B1 level and alleviates senescence. These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation. These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence.

Background: Aging is associated with significant structural and functional changes in the spleen, leading to immunosenescence, yet the detailed effects on splenic vascular endothelial cells (ECs) and their immunomodulatory roles are not fully understood. In this study, a single-cell RNA (scRNA) atlas of EC transcriptomes from young and aged mouse spleens was constructed to reveal age-related molecular changes, including increased inflammation and reduced vascular development and also the potential interaction between splenic endothelial cells and immune cells. Results: Ten clusters of splenic endothelial cells were identified. DEGs analysis across different EC clusters revealed the molecular changes with aging, showing the increase in the overall inflammatory microenvironment and the loss in vascular development function of aged ECs. Notably, four EC clusters with immunological functions were identified, suggesting an Endothelial-to-Immune-like Cell Transition (EndICLT) potentially driven by aging. Pseudotime analysis of the Immunology4 cluster further indicated a possible aging-induced transitional state, potentially initiated by Ctss gene activation. Finally, the effects of aging on cell signaling communication between different EC clusters and immune cells were analyzed. Conclusions: This comprehensive atlas elucidates the complex interplay between ECs and immune cells in the aging spleen, offering new insights into endothelial heterogeneity, reprogramming, and the mechanisms of immunosenescence. [ABSTRACT FROM AUTHOR]

A novel 2D/2D g-C3N4/BiOCl (CN/BOC) heterojunction photocatalyst was synthesized by grinding appropriate amounts of CN, Bi(NO3)3·5H2O, glacial acetic acid and KCl at room temperature. The porous CN nanosheets not only facilitate the in situ nucleation and growth of BOC to form thin nanosheets and constitute an intimate contact interface, but also introduce more oxygen vacancies (OVs) in the grinding process. The 2D/2D CN/BOC heterojunction had a good interface and generates a built-in electric field, which can improve the separation of e− and h+. The synergistic effect of the heterostructure and OVs made the photocatalyst have significantly better performance than CN and BOC alone under visible light. The most efficient CN/BOC-5 could achieve a tetracycline (TC) degradation rate of 89.8% within 2 h, which was 1.9 and 1.2 times faster than CN and BOC, respectively. It catalyzed the reduction of CO2 to CO at a rate of 2.00 μ mol h−1 g−1, 1.1 and 3.2 times faster than CN and BOC, respectively. The mechanism for the photocatalysis of CN/BOC-5 was revealed. It was confirmed that the efficiency of photo-induced carrier separation and visible-light photo-absorption were both considerably increased by the synergistic interaction between OVs and 2D/2D heterojunction. This research may open up new possibilities for the logical design of efficient photocatalysts through combining 2D/2D heterojunctions with OVs for environmental remediation. Highlights: •Grinding synthesis of 2D/2D BiOCl/g-C3N4 heterostructure with oxygen vacancies (OVs). •The synergistic effect of heterostructure and OVs enabled excellent photoactivity. •Efficient photocatalytic degradation of organic pollutants and reduction of CO2. [ABSTRACT FROM AUTHOR]

Background: Large language models (LLMs) demonstrated advanced performance in processing clinical information. However, commercially available LLMs lack specialized medical knowledge and remain susceptible to generating inaccurate information. Given the need for self-management in diabetes, patients commonly seek information online. We introduce the Retrieval-augmented Information System for Enhancement (RISE) framework and evaluate its performance in enhancing LLMs to provide accurate responses to diabetes-related inquiries., Objective: This study aimed to evaluate the potential of the RISE framework, an information retrieval and augmentation tool, to improve the LLM's performance to accurately and safely respond to diabetes-related inquiries., Methods: The RISE, an innovative retrieval augmentation framework, comprises 4 steps: rewriting query, information retrieval, summarization, and execution. Using a set of 43 common diabetes-related questions, we evaluated 3 base LLMs (GPT-4, Anthropic Claude 2, Google Bard) and their RISE-enhanced versions respectively. Assessments were conducted by clinicians for accuracy and comprehensiveness and by patients for understandability., Results: The integration of RISE significantly improved the accuracy and comprehensiveness of responses from all 3 base LLMs. On average, the percentage of accurate responses increased by 12% (15/129) with RISE. Specifically, the rates of accurate responses increased by 7% (3/43) for GPT-4, 19% (8/43) for Claude 2, and 9% (4/43) for Google Bard. The framework also enhanced response comprehensiveness, with mean scores improving by 0.44 (SD 0.10). Understandability was also enhanced by 0.19 (SD 0.13) on average. Data collection was conducted from September 30, 2023 to February 5, 2024., Conclusions: The RISE significantly improves LLMs' performance in responding to diabetes-related inquiries, enhancing accuracy, comprehensiveness, and understandability. These improvements have crucial implications for RISE's future role in patient education and chronic illness self-management, which contributes to relieving medical resource pressures and raising public awareness of medical knowledge., (©Dingqiao Wang, Jiangbo Liang, Jinguo Ye, Jingni Li, Jingpeng Li, Qikai Zhang, Qiuling Hu, Caineng Pan, Dongliang Wang, Zhong Liu, Wen Shi, Danli Shi, Fei Li, Bo Qu, Yingfeng Zheng. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.11.2024.)