Core Insights - The article discusses a groundbreaking study that utilizes AI to discover aging interventions from extensive molecular data, highlighting the potential of AI in revolutionizing aging research [4][26][28]. Group 1: Research Development - The study introduces the ClockBase Agent, an AI platform that integrates over 40 aging clock models to analyze millions of molecular profiles from humans and mice, identifying over 500 interventions that significantly reduce biological age [4][10][15]. - The research team analyzed 43,602 intervention-control comparisons, revealing that 5,756 (13.2%) interventions exhibited significant age-regulating effects [15][18]. Group 2: Methodology - The ClockBase Agent employs a multi-agent system that functions like professional bioinformaticians, automatically parsing experimental data, generating hypotheses, and producing scientific reports [12][13]. - The system consists of three core agents: Coding Agent for data processing, Reviewer Agent for evaluating interventions, and Report Agent for integrating findings into readable reports [13]. Group 3: Key Findings - The study confirmed the biological relevance of aging clocks, with interventions concentrated in aging-related pathways such as cellular senescence and longevity regulation [18]. - Experimental validation of the compound Ouabain demonstrated its ability to delay aging in elderly mice, improve heart function, and reduce neuroinflammation [19][22][24]. Group 4: Implications and Future Outlook - The ClockBase Agent signifies a paradigm shift in aging research from hypothesis-driven to data-driven approaches, showcasing how AI can extract new knowledge from existing data [26][28]. - The platform is publicly available, allowing researchers to query the effects of various interventions, thus democratizing longevity medicine [26][28].

Core Viewpoint - The research highlights the potential of Vitamin B6, specifically its active form pyridoxal phosphate (PLP), in enhancing the stem-like characteristics and antitumor abilities of CD8+ T cells, suggesting its clinical application in cancer immunotherapy [2][10]. Group 1: Mechanism and Findings - Tumor-infiltrating lymphocytes (TILs) often exhibit dysfunction but can display stem-like behavior through unclear mechanisms [6]. - The study found that Vitamin B6 or PLP treatment enhances the persistence and stem-like phenotype of CD8+ T cells, improving their ability to eliminate tumors [6][8]. - PLP maintains T cell functionality by directly binding to and inhibiting p70S6 kinase (p70S6K), which in turn affects the phosphorylation of BACH2, promoting stem cell gene expression while suppressing exhaustion gene expression [6][11]. Group 2: Clinical Implications - In preclinical tumor models, PLP treatment improved the efficacy of anti-PD-1 monoclonal antibody therapy [7]. - The research underscores the clinical potential of strategies that enhance T cell functionality through Vitamin B6/PLP in cancer immunotherapy [10].

Core Insights - The article discusses a study published in Nature Cell Biology that systematically analyzes the protein networks of 18 types of nuclear condensates in human HeLa cells, revealing their functional associations and interactions [3][4][12] Group 1: Research Findings - The study developed algorithms to uncover functional relationships among nuclear condensates, leading to the creation of a human nuclear condensate map called NOVA Map, which predicts disease-related protein mutations and reveals stress dynamics [4][10] - Utilizing the PhastID proximity labeling technology, the research identified 2,390 significantly enriched proteins and 10,126 pairs of neighboring interactions, categorizing condensates into two groups: one related to DNA damage repair and the other to RNA processing [7][8] - The study confirmed the cooperative roles of Gems bodies with Cajal bodies and histone locus bodies in regulating telomerase maturation and promoting histone mRNA precursor processing [8] Group 2: Implications and Applications - The NOVA Map serves as a tool for understanding the nuclear distribution and interaction characteristics of proteins with frequent mutations in pancreatic neuroendocrine tumors, highlighting its clinical application potential [10][12] - Heat shock experiments demonstrated that heat shock factor-1 (HSF1) migrates to PML bodies and heterochromatin regions, participating in heat stress responses, indicating the stability of most condensates under stress [10]

Core Insights - The research reveals the long-standing commensal relationship between leopards and humans in China, lasting over 3,500 years, before the introduction of domestic cats via the Silk Road around the Tang Dynasty [3][10] - The study utilizes ancient DNA analysis from 22 cat remains across 14 archaeological sites in China, providing insights into the timeline and pathways of cat domestication and migration [7][10] Group 1: Historical Context - The study indicates that leopard cats cohabited with humans from the late Neolithic period (around 5,400 years ago) until the end of the Eastern Han Dynasty, establishing a symbiotic relationship [3][7] - Domestic cats, traced back to African wildcats, were introduced to China around the 6th to 7th century during the Tang Dynasty, likely through trade routes [5][8] Group 2: Methodology and Findings - The research team analyzed 22 skeletal samples using ancient DNA techniques, successfully recovering mitochondrial genomes and whole genomes from seven samples, confirming the long-term presence of leopard cats [7][10] - The earliest identified domestic cat remains date back to the Tang Dynasty, with a carbon dating of approximately 706-883 AD, suggesting an earlier introduction than previously thought [8][10] Group 3: Genetic Insights - Genetic analysis indicates that all domestic cats in China can trace their lineage back to African wildcats, supporting the theory of a single domestication origin [6][10] - The study highlights the genetic flow between local wildcats and domestic cats in regions like the Tibetan Plateau, indicating interactions between species [6]

Core Insights - The study reveals that innate immune activation and metabolic disruption lead to a novel form of cell death called Mitoxyperilysis, which could have implications for cancer treatment [2][10]. Group 1: Mechanism of Cell Death - Innate immune activation and metabolic disruption cause long-term contact between mitochondria and cell membranes, resulting in localized membrane rupture due to reactive oxygen species (ROS) [2][7]. - This new cell death mechanism, Mitoxyperilysis, is distinct from previously known forms such as pyroptosis and necroptosis, indicating a unique pathway for cellular demise [7][10]. Group 2: Implications for Cancer Treatment - The combination of innate immune activation and fasting can promote tumor regression, suggesting a potential therapeutic strategy for cancer treatment [2][9]. - In experiments, tumors in fasting mice showed significant regression after the activation of innate immunity, highlighting the effectiveness of this combined approach [9][10]. Group 3: Molecular Regulation - The study identifies mTORC2 as a regulator of Mitoxyperilysis, where inhibiting mTOR can restore cytoskeletal activity and maintain cell membrane integrity, preventing cell rupture [8][10]. - Both innate immune and metabolic signals are crucial for this process, as knocking out innate immune receptors can halt this form of cell death [8][10].

Core Viewpoint - Drug resistance remains the most severe challenge in targeted therapy for lung cancer, with cuproptosis showing promise in overcoming this resistance, although its potential in targeted treatment has yet to be fully explored [1]. Group 1: Research Findings - A study published by researchers from the Chinese Academy of Medical Sciences indicates that inducing cuproptosis enhances the sensitivity of lung cancer to the targeted drug osimertinib and overcomes drug resistance [2][3]. - The research team observed a high degree of synergistic effect between CuET (copper death induction) and osimertinib, indicating that cuproptosis induction increases the anticancer efficacy of osimertinib [5]. - In a secondary screening, cuproptosis was identified as a major vulnerability in osimertinib-resistant cell lines, with the key driver factor FDX1 significantly upregulated in these resistant cells [6]. Group 2: Mechanism of Action - The study highlights that the activation of bypass pathways, particularly involving AKT phosphorylation, is the most common mechanism of drug resistance, accounting for approximately 46% of cases [7]. - Induction of cuproptosis in combination with osimertinib significantly reduced p-AKT levels while increasing the expression of cuproptosis markers and apoptosis markers, suggesting a mechanism for overcoming drug resistance [7]. - In patient-derived organoid models, the combination of CuET and osimertinib outperformed single-agent treatments, demonstrating the potential for enhanced therapeutic efficacy [8]. Group 3: Clinical Implications - The findings suggest that targeting cuproptosis could be a promising strategy to overcome osimertinib resistance, linking it to the commonly overlooked AKT activation mechanism [10]. - With the development of copper ion carriers and nanoparticle delivery systems being actively pursued, these discoveries provide a pathway for clinical translation, necessitating prospective trials to evaluate safety and efficacy [10].

Core Insights - The article discusses the development of organoid models for studying human vascular aging and neural tube development, highlighting the molecular mechanisms involved in these processes [2][4][8]. Vascular Organoid Model - The vascular organoid model simulates Hutchinson-Gilford Progeria Syndrome (HGPS), revealing that downregulation of the SRF pathway drives vascular aging [4][7]. - The model reproduces various pathological features of HGPS, including accelerated aging protein accumulation and impaired vascular barrier function [7]. - SRF is identified as a key regulatory factor in vascular aging, with its expression significantly downregulated in both HGPS models and naturally aging non-human primate tissues [7]. - Functional experiments show that knocking down SRF replicates vascular aging phenotypes, while overexpressing SRF improves cell morphology and restores angiogenic capacity [7]. Neural Organoid Model - The neural organoid model reveals the critical role of YAP as a mechanosensor in neural tube morphogenesis [8][12]. - YAP deficiency disrupts the apical-basal polarity of neural stem/progenitor cells, leading to structural abnormalities in neural rosettes [12]. - The study identifies a regulatory axis involving YAP, TEAD4, and LEF1, which is essential for neural tube development, demonstrating the interplay between mechanical and biochemical signals [12]. Future Implications - The findings from both vascular and neural organoid models provide new insights into the molecular mechanisms of organ homeostasis, aging, and development [14][15]. - These results may pave the way for early diagnosis and targeted therapeutic strategies for related diseases [15].

Core Insights - The article discusses a significant breakthrough in the field of quantum simulation, specifically the realization and detection of higher-order nonequilibrium topological phases (HOTPs) using a programmable superconducting quantum processor [1][5]. Group 1: Research Background - Topological phases have emerged as a crucial research direction in condensed matter physics and quantum simulation, with higher-order topological phases challenging traditional bulk-boundary correspondence [3]. - The realization of higher-order topological phases in quantum systems has been a scientific challenge, with potential implications for revealing the quantum nature of topological states and enabling topological quantum computing based on non-Abelian statistics [4]. Group 2: Experimental Achievements - The research team successfully implemented quantum simulation and detection of both balanced and nonequilibrium second-order topological phases using the "Zuchongzhi 2" superconducting quantum processor [5]. - They developed theoretical designs for static and Floquet quantum circuits to construct higher-order topological Hamiltonians in a two-dimensional superconducting qubit array, addressing key challenges in the field [5]. - The experimental setup involved a 6×6 qubit array, where the team executed up to 50 Floquet periods of evolution operations, successfully realizing four different types of nonequilibrium second-order topological phases and exploring their energy spectra, dynamical behaviors, and topological invariants [5][7].

Core Insights - AlphaFold2, developed by Google DeepMind, has revolutionized scientific research by enabling accurate predictions of protein structures based solely on amino acid sequences since its launch in November 2020 [1][4][7]. Group 1: Impact on Scientific Research - Over the past five years, AlphaFold2 has assisted researchers worldwide in predicting millions of protein structures, marking a second renaissance in structural biology [7]. - The tool has significantly accelerated discovery processes, with researchers like Andrea Pauli stating that every project now utilizes AlphaFold [12]. - The Nature paper describing AlphaFold2 has garnered nearly 40,000 citations, indicating sustained interest from the scientific community [12]. Group 2: Applications and Discoveries - AlphaFold-Multimer, an extension of AlphaFold2, has enabled the discovery of three critical proteins involved in fertilization, challenging previous assumptions about the simplicity of sperm-egg interactions [8][10]. - The TMEM81-IZUMO1-SPACA6 protein complex plays a vital role in mediating sperm-egg binding, highlighting the complexity of fertilization mechanisms [10]. Group 3: User Engagement and Accessibility - AlphaFold has been accessed by approximately 3.3 million users across over 190 countries, with more than 1 million users from low- and middle-income countries, showcasing its global reach and accessibility [15]. - The AlphaFold database (AFDB) contains over 240 million predicted protein structures, covering nearly all known proteins on Earth [15]. Group 4: Influence on Structural Biology and Computational Biology - Researchers using AlphaFold have submitted about 50% more protein structures to the Protein Data Bank (PDB) compared to those who did not use the tool [18]. - AlphaFold has opened new research directions in computational biology, including AI-assisted drug discovery and protein design, leading to increased funding and interest in these areas [21]. Group 5: Future Prospects - AlphaFold2 is expected to aid in understanding disease mechanisms and potentially lead to new therapies, with AlphaFold3 anticipated to enhance drug discovery capabilities [24].

撰文丨王聪 编辑丨王多鱼 封面解读 ：在手术缝合中打结需要精确的力度控制——力度过小会导致缝合伤口裂开渗液，力度过大则会引起伤口肿胀并 限制血流。机器人辅助虽能解决该问题，但其复杂的传感系统在微创手术等空间受限的操作中受到限制。该研究分析简易活 结的力学特性，发现可通过机械传力方式实现伤口的一致性闭合，且无需电子设备参与。基于此，他们开发出了一种名为 " 排版丨水成文 当你 系鞋带 时，轻轻一拉就能感受到那个恰到好处的紧度——这日常动作背后隐藏的力学智慧，如今被 浙江大学 的研究团队成功引入高端医疗领域。 2025 年 11 月 26 日， 浙江大学医学院附属邵逸夫医院 蔡秀军 院士团队与 浙江大学 交叉力学中心 杨卫 院士团队合作 （ 杨栩旭 、 陈鸣宇 、 李铁风 为论文共同通讯作者， 薛耀庭 、 曹佳胜 、 冯涛 、 张凯航 为论文共同第一作者） ，在国际顶尖学术期刊 Nature 上发表了题为： Slipknot-gauged mechanical transmission and robotic operation 的研究论文，该论文该被选为当期 封面论文 。 该研究首次提出了 基于活结的力学传导机 ...